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1
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Gao Y, Song Z, Gan W, Zou X, Bai Y, Zhao X, Chen D, Qiao M. Selective and iron-independent ferroptosis in cancer cells induced by manipulation of mitochondrial fatty acid oxidation. Biomaterials 2025; 320:123259. [PMID: 40112511 DOI: 10.1016/j.biomaterials.2025.123259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 02/20/2025] [Accepted: 03/14/2025] [Indexed: 03/22/2025]
Abstract
Despite the promise of ferroptosis in cancer therapy, selectively inducing robust ferroptosis in cancer cells remains a significant challenge. In this study, manipulation of fatty acids β-oxidation (FAO) by combination of mild photodynamic therapy (PDT) and inhibition of triglycerides (TGs) synthesis was found to induce robust and iron-independent ferroptosis in cancer cells with dysregulated lipid metabolism for the first time. To achieve that, TGs synthesis inhibitor of xanthohumol (Xan) and FAO initiator of tetrakis (4-carboxyphenyl) porphyrin (TCPP) were co-delivered by a nanoplexes composed of pH-responsive amphiphilic lipopeptide C18-pHis10 and DSPE-PEG2000. TCPP was found to rapidly increase the intracellular ROS under laser irradiation without inducing antioxidant response and apoptosis, activating the AMPK in cancer cells and accelerating mitochondrial FAO. Xan fueled the mitochondrial FAO with substrates by suppressing the conversion of fatty acids (FAs) to TGs. This also led to augmented intracellular polyunsaturated fatty acids (PUFAs) and PUFAs-phospholipids levels, increasing the intrinsic susceptibility of cancer cells to lipid peroxidization. As a result, the excessive ROS generated from the sustained mitochondrial FAO caused remarkably lipid peroxidation and ultimately ferroptosis. Collectively, our study provides a new approach to selectively induce iron-independent ferroptosis in cancer cells by taking advantage of dysregulated lipid metabolism.
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Affiliation(s)
- Yan Gao
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Zilin Song
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Wenxin Gan
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Xue Zou
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yaning Bai
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Xiuli Zhao
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Dawei Chen
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Mingxi Qiao
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
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2
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Xue Z, Wang L, Pan S, Yan J, You M, Yao C. The nucleic acid reactions on the nanomaterials surface for biomedicine. J Nanobiotechnology 2025; 23:308. [PMID: 40269855 PMCID: PMC12016162 DOI: 10.1186/s12951-025-03374-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Accepted: 04/06/2025] [Indexed: 04/25/2025] Open
Abstract
Integrating nucleic acids (NAs) with nanomaterials has substantially advanced biomedical research, enabling critical applications in biosensing, drug delivery, therapeutics, and the synthesis of nanomaterials. At the core of these advances are the reactions of NAs on nanomaterial surfaces, encompassing conjugation (covalent and non-covalent), detachment (physical and chemical), and signal amplification (enzyme-mediated signal amplification, enzyme-free signal amplification, and DNA Walker). Here, we review the fundamental mechanisms and recent progress in nucleic acid reactions on nanomaterial surfaces, discuss emerging applications for diagnostics, nanomedicine, and gene therapy, and explore persistent challenges in the field. We offer a forward-looking perspective on how future developments could better control, optimize, and harness these reactions for transformative advances in nanomedicine and biomedical engineering.
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Affiliation(s)
- Zhenrui Xue
- Department of Transfusion Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, People's Republic of China
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, 710049, People's Republic of China
| | - Lu Wang
- Department of Transfusion Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, People's Republic of China
| | - Shengnan Pan
- Department of Transfusion Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, People's Republic of China
| | - Jie Yan
- Department of Transfusion Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, People's Republic of China
| | - Minli You
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, People's Republic of China.
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, 710049, People's Republic of China.
| | - Chunyan Yao
- Department of Transfusion Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, People's Republic of China.
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3
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Xin X, Wu D, Zhao P, Li Y, Qin H, Dai J, Zhou Y, Lyu Y, Yang Y, Zhu Y, Shi H, Yang L, Yin L. Catch-to-Amplify Nanoparticles with Bacteria Surface for Sequential Mucosal Immune Activation for Acute Myeloid Leukemia Therapy. ACS NANO 2025; 19:14661-14679. [PMID: 40202129 DOI: 10.1021/acsnano.4c08515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/10/2025]
Abstract
Mucosal-mediated immune deficiency is associated with immune evasion and poor clinical outcomes in acute myeloid leukemia (AML). Here, we describe the elicitation of mucosal and systemic immune response by oral delivery of MDP-modified PEG-lipid (MDP-PEG-DSPE) and polylactic acid-polyhistidine (PLA-PHis) copolymer constructed nanosystem (mPOD) into Peyer's patches. To protect against gastrointestinal degradation, enteric-soluble capsules are utilized for encapsulating mPOD to promote penetration across intestinal mucus and engender robust Peyer's patch targeting initiated by MDP-PEG-DSPE. Compared with intravenous and intramuscular administration, the oral delivery of MDP-PEG-DSPE and 5'-triphosphate-modified RNA (ppp-RNA) into gut-associated lymphoid tissues reinforces dendritic cell maturation and migration, amplifies mucosal immune response, and boosts the production of secretory immunoglobulin A via retinoic acid-inducible gene I/nucleotide-binding oligomerization domain 2 (RIG-I/NOD2) signaling activation. In the AML murine model, the provoked mucosal immunity positively regulates the systemic cytotoxic immune reactions, which, in turn, eradicate disseminated malignant leukemic cells and provide defense against leukemia attacks.
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MESH Headings
- Animals
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/therapy
- Leukemia, Myeloid, Acute/pathology
- Nanoparticles/chemistry
- Mice
- Immunity, Mucosal/drug effects
- Humans
- Mice, Inbred C57BL
- Polyethylene Glycols/chemistry
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Affiliation(s)
- Xiaofei Xin
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
- NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing 210009, China
| | - Di Wu
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Pengbo Zhao
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Yuanyuan Li
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Huanyu Qin
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Jinyu Dai
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Yong Zhou
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Yifu Lyu
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Yang Yang
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Ying Zhu
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Hang Shi
- Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Lei Yang
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
- NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing 210009, China
| | - Lifang Yin
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
- NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing 210009, China
- Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 210009, China
- State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China
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4
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Poudel K, Vithiananthan T, Kim JO, Tsao H. Recent progress in cancer vaccines and nanovaccines. Biomaterials 2025; 314:122856. [PMID: 39366184 DOI: 10.1016/j.biomaterials.2024.122856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 09/03/2024] [Accepted: 09/26/2024] [Indexed: 10/06/2024]
Abstract
Vaccine science, nanotechnology, and immunotherapy are at the forefront of cancer treatment strategies, each offering significant potential for enhancing tumor-specific immunity and establishing long-lasting immune memory to prevent tumor recurrence. Despite the promise of these personalized and precision-based anti-cancer approaches, challenges such as immunosuppression, suboptimal immune activation, and T-cell exhaustion continue to hinder their effectiveness. The limited clinical success of cancer vaccines often stems from difficulties in identifying effective antigens, efficiently targeting immune cells, lymphoid organs, and the tumor microenvironment, overcoming immune evasion, enhancing immunogenicity, and avoiding lysosomal degradation. However, numerous studies have demonstrated that integrating nanotechnology with immunotherapeutic strategies in vaccine development can overcome these challenges, leading to potent antitumor immune responses and significant progress in the field. This review highlights the critical components of cancer vaccine and nanovaccine strategies for immunomodulatory antitumor therapy. It covers general vaccine strategies, types of vaccines, antigen forms, nanovaccine platforms, challenges faced, potential solutions, and key findings from preclinical and clinical studies, along with future perspectives. To fully unlock the potential of cancer vaccines and nanovaccines, precise immunological monitoring during early-phase trials is essential. This approach will help identify and address obstacles, ultimately expanding the available options for patients who are resistant to conventional cancer immunotherapies.
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Affiliation(s)
- Kishwor Poudel
- Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Tulasi Vithiananthan
- Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jong Oh Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Hensin Tsao
- Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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5
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Sanati M, Figueroa-Espada CG, Han EL, Mitchell MJ, Yavari SA. Bioengineered Nanomaterials for siRNA Therapy of Chemoresistant Cancers. ACS NANO 2024; 18:34425-34463. [PMID: 39666006 DOI: 10.1021/acsnano.4c11259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2024]
Abstract
Chemoresistance remains a long-standing challenge after cancer treatment. Over the last two decades, RNA interference (RNAi) has emerged as a gene therapy modality to sensitize cancer cells to chemotherapy. However, the use of RNAi, specifically small-interfering RNA (siRNA), is hindered by biological barriers that limit its intracellular delivery. Nanoparticles can overcome these barriers by protecting siRNA in physiological environments and facilitating its delivery to cancer cells. In this review, we discuss the development of nanomaterials for siRNA delivery in cancer therapy, current challenges, and future perspectives for their implementation to overcome cancer chemoresistance.
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Affiliation(s)
- Mehdi Sanati
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand 97178, Iran
| | - Christian G Figueroa-Espada
- Department of Bioengineering, University of Pennsylvania, 210 South 33rd Street, Philadelphia, Pennsylvania 19104, United States
| | - Emily L Han
- Department of Bioengineering, University of Pennsylvania, 210 South 33rd Street, Philadelphia, Pennsylvania 19104, United States
| | - Michael J Mitchell
- Department of Bioengineering, University of Pennsylvania, 210 South 33rd Street, Philadelphia, Pennsylvania 19104, United States
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
- Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
- Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Saber Amin Yavari
- Department of Orthopedics, University Medical Center Utrecht, 3584 Utrecht, The Netherlands
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, 3584 Utrecht, The Netherlands
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6
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Ma X, Tian Y, Yang R, Wang H, Allahou LW, Chang J, Williams G, Knowles JC, Poma A. Nanotechnology in healthcare, and its safety and environmental risks. J Nanobiotechnology 2024; 22:715. [PMID: 39548502 PMCID: PMC11566612 DOI: 10.1186/s12951-024-02901-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 10/03/2024] [Indexed: 11/18/2024] Open
Abstract
Nanotechnology holds immense promise in revolutionising healthcare, offering unprecedented opportunities in diagnostics, drug delivery, cancer therapy, and combating infectious diseases. This review explores the multifaceted landscape of nanotechnology in healthcare while addressing the critical aspects of safety and environmental risks associated with its widespread application. Beginning with an introduction to the integration of nanotechnology in healthcare, we first delved into its categorisation and various materials employed, setting the stage for a comprehensive understanding of its potential. We then proceeded to elucidate the diverse healthcare applications of nanotechnology, spanning medical diagnostics, tissue engineering, targeted drug delivery, gene delivery, cancer therapy, and the development of antimicrobial agents. The discussion extended to the current situation surrounding the clinical translation and commercialisation of these cutting-edge technologies, focusing on the nanotechnology-based healthcare products that have been approved globally to date. We also discussed the safety considerations of nanomaterials, both in terms of human health and environmental impact. We presented the in vivo health risks associated with nanomaterial exposure, in relation with transport mechanisms, oxidative stress, and physical interactions. Moreover, we highlighted the environmental risks, acknowledging the potential implications on ecosystems and biodiversity. Lastly, we strived to offer insights into the current regulatory landscape governing nanotechnology in healthcare across different regions globally. By synthesising these diverse perspectives, we underscore the imperative of balancing innovation with safety and environmental stewardship, while charting a path forward for the responsible integration of nanotechnology in healthcare.
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Affiliation(s)
- Xiaohan Ma
- Division of Biomaterials and Tissue Engineering, Eastman Dental Institute, Royal Free Hospital, University College London, Rowland Hill Street, London, NW3 2PF, UK.
| | - Yaxin Tian
- United InnoMed (Shanghai) Limited, F/2, E-1, No.299, Kangwei Rd, Pudong District, Shanghai, China
| | - Ren Yang
- Division of Biomaterials and Tissue Engineering, Eastman Dental Institute, Royal Free Hospital, University College London, Rowland Hill Street, London, NW3 2PF, UK
| | - Haowei Wang
- Centre for Precision Healthcare, UCL Division of Medicine, University College London, London, WC1E 6JF, UK
| | - Latifa W Allahou
- Division of Biomaterials and Tissue Engineering, Eastman Dental Institute, Royal Free Hospital, University College London, Rowland Hill Street, London, NW3 2PF, UK
- UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Jinke Chang
- UCL Centre for Biomaterials in Surgical Reconstruction and Regeneration, Division of Surgery & Interventional Science, University College London, London, NW3 2PF, UK
| | - Gareth Williams
- UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Jonathan C Knowles
- Division of Biomaterials and Tissue Engineering, Eastman Dental Institute, Royal Free Hospital, University College London, Rowland Hill Street, London, NW3 2PF, UK
- Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Med-Icine, Dankook University, Cheonan, 31116, South Korea
- UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, Cheonan, 31116, South Korea
| | - Alessandro Poma
- Division of Biomaterials and Tissue Engineering, Eastman Dental Institute, Royal Free Hospital, University College London, Rowland Hill Street, London, NW3 2PF, UK.
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7
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Haghighi E, Abolmaali SS, Dehshahri A, Mousavi Shaegh SA, Azarpira N, Tamaddon AM. Navigating the intricate in-vivo journey of lipid nanoparticles tailored for the targeted delivery of RNA therapeutics: a quality-by-design approach. J Nanobiotechnology 2024; 22:710. [PMID: 39543630 PMCID: PMC11566655 DOI: 10.1186/s12951-024-02972-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 11/03/2024] [Indexed: 11/17/2024] Open
Abstract
RNA therapeutics, such as mRNA, siRNA, and CRISPR-Cas9, present exciting avenues for treating diverse diseases. However, their potential is commonly hindered by vulnerability to degradation and poor cellular uptake, requiring effective delivery systems. Lipid nanoparticles (LNPs) have emerged as a leading choice for in vivo RNA delivery, offering protection against degradation, enhanced cellular uptake, and facilitation of endosomal escape. However, LNPs encounter numerous challenges for targeted RNA delivery in vivo, demanding advanced particle engineering, surface functionalization with targeting ligands, and a profound comprehension of the biological milieu in which they function. This review explores the structural and physicochemical characteristics of LNPs, in-vivo fate, and customization for RNA therapeutics. We highlight the quality-by-design (QbD) approach for targeted delivery beyond the liver, focusing on biodistribution, immunogenicity, and toxicity. In addition, we explored the current challenges and strategies associated with LNPs for in-vivo RNA delivery, such as ensuring repeated-dose efficacy, safety, and tissue-specific gene delivery. Furthermore, we provide insights into the current clinical applications in various classes of diseases and finally prospects of LNPs in RNA therapeutics.
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Affiliation(s)
- Elahe Haghighi
- Department of Pharmaceutical Nanotechnology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Samira Sadat Abolmaali
- Department of Pharmaceutical Nanotechnology, Shiraz University of Medical Sciences, Shiraz, Iran.
- Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Ali Dehshahri
- Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Ali Mousavi Shaegh
- Laboratory of Microfluidics and Medical Microsystems, Research Institute for Medical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
- Orthopedic Research Center, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
- Clinical Research Development Unit, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negar Azarpira
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Mohammad Tamaddon
- Department of Pharmaceutical Nanotechnology, Shiraz University of Medical Sciences, Shiraz, Iran.
- Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran.
- Department of Pharmaceutics, Shiraz University of Medical Sciences, Shiraz, Iran.
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8
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Wang G, Zhang M, Lai W, Gao Y, Liao S, Ning Q, Tang S. Tumor Microenvironment Responsive RNA Drug Delivery Systems: Intelligent Platforms for Sophisticated Release. Mol Pharm 2024; 21:4217-4237. [PMID: 39056442 DOI: 10.1021/acs.molpharmaceut.4c00334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
Cancer is a significant health concern, increasingly showing insensitivity to traditional treatments, highlighting the urgent need for safer and more practical treatment options. Ribonucleic acid (RNA) gene therapy drugs have demonstrated promising potential in preclinical and clinical trials for antitumor therapy by regulating tumor-related gene expression. However, RNA's poor membrane permeability and stability restrict its effectiveness in entering and being utilized in cells. An appropriate delivery system is crucial for achieving targeted tumor effects. The tumor microenvironment (TME), characterized by acidity, hypoxia, enzyme overexpression, elevated glutathione (GSH) concentration, and excessive reactive oxygen species (ROS), is essential for tumor survival. Furthermore, these distinctive features can also be harnessed to develop intelligent drug delivery systems. Various nanocarriers that respond to the TME have been designed for RNA drug delivery, showing the advantages of tumor targeting and low toxicity. This Review discusses the abnormal changes of components in TME, therapeutic RNAs' roles, underlying mechanisms, and the latest developments in utilizing vectors that respond to microenvironments for treating tumors. We hope it provides insight into creating and optimizing RNA delivery vectors to improve their effectiveness.
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Affiliation(s)
- Guihua Wang
- Institute of Pharmacy & Pharmacology, University of South China, Hengyang 421001, China
- Hunan Province Key Laboratory for Antibody-Based Drug and Intelligent Delivery System, School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua 418000, China
| | - Mengxia Zhang
- Hunan Province Key Laboratory for Antibody-Based Drug and Intelligent Delivery System, School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua 418000, China
- Department of Histology and Embryology, Hunan University of Chinese Medicine, Changsha 410128, China
| | - Weiwei Lai
- Institute of Pharmacy & Pharmacology, University of South China, Hengyang 421001, China
- Hunan Province Key Laboratory for Antibody-Based Drug and Intelligent Delivery System, School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua 418000, China
| | - Yuan Gao
- Hunan Province Key Laboratory for Antibody-Based Drug and Intelligent Delivery System, School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua 418000, China
| | - Shuxian Liao
- Institute of Pharmacy & Pharmacology, University of South China, Hengyang 421001, China
- Hunan Province Key Laboratory for Antibody-Based Drug and Intelligent Delivery System, School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua 418000, China
| | - Qian Ning
- Hunan Province Key Laboratory for Antibody-Based Drug and Intelligent Delivery System, School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua 418000, China
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, China
| | - Shengsong Tang
- Institute of Pharmacy & Pharmacology, University of South China, Hengyang 421001, China
- Hunan Province Key Laboratory for Antibody-Based Drug and Intelligent Delivery System, School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua 418000, China
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, China
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Deshmukh R, Sethi P, Singh B, Shiekmydeen J, Salave S, Patel RJ, Ali N, Rashid S, Elossaily GM, Kumar A. Recent Review on Biological Barriers and Host-Material Interfaces in Precision Drug Delivery: Advancement in Biomaterial Engineering for Better Treatment Therapies. Pharmaceutics 2024; 16:1076. [PMID: 39204421 PMCID: PMC11360117 DOI: 10.3390/pharmaceutics16081076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 08/06/2024] [Accepted: 08/07/2024] [Indexed: 09/04/2024] Open
Abstract
Preclinical and clinical studies have demonstrated that precision therapy has a broad variety of treatment applications, making it an interesting research topic with exciting potential in numerous sectors. However, major obstacles, such as inefficient and unsafe delivery systems and severe side effects, have impeded the widespread use of precision medicine. The purpose of drug delivery systems (DDSs) is to regulate the time and place of drug release and action. They aid in enhancing the equilibrium between medicinal efficacy on target and hazardous side effects off target. One promising approach is biomaterial-assisted biotherapy, which takes advantage of biomaterials' special capabilities, such as high biocompatibility and bioactive characteristics. When administered via different routes, drug molecules deal with biological barriers; DDSs help them overcome these hurdles. With their adaptable features and ample packing capacity, biomaterial-based delivery systems allow for the targeted, localised, and prolonged release of medications. Additionally, they are being investigated more and more for the purpose of controlling the interface between the host tissue and implanted biomedical materials. This review discusses innovative nanoparticle designs for precision and non-personalised applications to improve precision therapies. We prioritised nanoparticle design trends that address heterogeneous delivery barriers, because we believe intelligent nanoparticle design can improve patient outcomes by enabling precision designs and improving general delivery efficacy. We additionally reviewed the most recent literature on biomaterials used in biotherapy and vaccine development, covering drug delivery, stem cell therapy, gene therapy, and other similar fields; we have also addressed the difficulties and future potential of biomaterial-assisted biotherapies.
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Affiliation(s)
- Rohitas Deshmukh
- Institute of Pharmaceutical Research, GLA University, Mathura 281406, India;
| | - Pranshul Sethi
- Department of Pharmacology, College of Pharmacy, Shri Venkateshwara University, Gajraula 244236, India;
| | - Bhupendra Singh
- School of Pharmacy, Graphic Era Hill University, Dehradun 248002, India;
- Department of Pharmacy, S.N. Medical College, Agra 282002, India
| | | | - Sagar Salave
- National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad 382355, India;
| | - Ravish J. Patel
- Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, Changa, Anand 388421, India;
| | - Nemat Ali
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;
| | - Summya Rashid
- Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi Arabia;
| | - Gehan M. Elossaily
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, P.O. Box 71666, Riyadh 11597, Saudi Arabia;
| | - Arun Kumar
- School of Pharmacy, Sharda University, Greater Noida 201310, India
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10
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Sun L, Li Z, Lan J, Wu Y, Zhang T, Ding Y. Better together: nanoscale co-delivery systems of therapeutic agents for high-performance cancer therapy. Front Pharmacol 2024; 15:1389922. [PMID: 38831883 PMCID: PMC11144913 DOI: 10.3389/fphar.2024.1389922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 04/22/2024] [Indexed: 06/05/2024] Open
Abstract
Combination therapies can enhance the sensitivity of cancer to drugs, lower drug doses, and reduce side effects in cancer treatment. However, differences in the physicochemical properties and pharmacokinetics of different therapeutic agents limit their application. To avoid the above dilemma and achieve accurate control of the synergetic ratio, a nanoscale co-delivery system (NCDS) has emerged as a prospective tool for combined therapy in cancer treatment, which is increasingly being used to co-load different therapeutic agents. In this study, we have summarized the mechanisms of therapeutic agents in combination for cancer therapy, nanoscale carriers for co-delivery, drug-loading strategies, and controlled/targeted co-delivery systems, aiming to give a general picture of these powerful approaches for future NCDS research studies.
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Affiliation(s)
- Liyan Sun
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhe Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- The MOE Innovation Centre for Basic Medicine Research on Qi-Blood TCM Theories, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jinshuai Lan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- The MOE Innovation Centre for Basic Medicine Research on Qi-Blood TCM Theories, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ya Wu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tong Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- The MOE Innovation Centre for Basic Medicine Research on Qi-Blood TCM Theories, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yue Ding
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- The MOE Innovation Centre for Basic Medicine Research on Qi-Blood TCM Theories, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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11
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Abstract
The recent emergence of nanomedicine has revolutionized the therapeutic landscape and necessitated the creation of more sophisticated drug delivery systems. Polymeric nanoparticles sit at the forefront of numerous promising drug delivery designs, due to their unmatched control over physiochemical properties such as size, shape, architecture, charge, and surface functionality. Furthermore, polymeric nanoparticles have the ability to navigate various biological barriers to precisely target specific sites within the body, encapsulate a diverse range of therapeutic cargo and efficiently release this cargo in response to internal and external stimuli. However, despite these remarkable advantages, the presence of polymeric nanoparticles in wider clinical application is minimal. This review will provide a comprehensive understanding of polymeric nanoparticles as drug delivery vehicles. The biological barriers affecting drug delivery will be outlined first, followed by a comprehensive description of the various nanoparticle designs and preparation methods, beginning with the polymers on which they are based. The review will meticulously explore the current performance of polymeric nanoparticles against a myriad of diseases including cancer, viral and bacterial infections, before finally evaluating the advantages and crucial challenges that will determine their wider clinical potential in the decades to come.
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Affiliation(s)
- Maximilian
A. Beach
- School
of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Umeka Nayanathara
- School
of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Yanting Gao
- School
of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Changhe Zhang
- School
of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Yijun Xiong
- School
of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Yufu Wang
- School
of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Georgina K. Such
- School
of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia
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12
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Yang C, Lin ZI, Zhang X, Xu Z, Xu G, Wang YM, Tsai TH, Cheng PW, Law WC, Yong KT, Chen CK. Recent Advances in Engineering Carriers for siRNA Delivery. Macromol Biosci 2024; 24:e2300362. [PMID: 38150293 DOI: 10.1002/mabi.202300362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 11/29/2023] [Indexed: 12/28/2023]
Abstract
RNA interference (RNAi) technology has been a promising treatment strategy for combating intractable diseases. However, the applications of RNAi in clinical are hampered by extracellular and intracellular barriers. To overcome these barriers, various siRNA delivery systems have been developed in the past two decades. The first approved RNAi therapeutic, Patisiran (ONPATTRO) using lipids as the carrier, for the treatment of amyloidosis is one of the most important milestones. This has greatly encouraged researchers to work on creating new functional siRNA carriers. In this review, the recent advances in siRNA carriers consisting of lipids, polymers, and polymer-modified inorganic particles for cancer therapy are summarized. Representative examples are presented to show the structural design of the carriers in order to overcome the delivery hurdles associated with RNAi therapies. Finally, the existing challenges and future perspective for developing RNAi as a clinical modality will be discussed and proposed. It is believed that the addressed contributions in this review will promote the development of siRNA delivery systems for future clinical applications.
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Affiliation(s)
- Chengbin Yang
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518060, P. R. China
| | - Zheng-Ian Lin
- Polymeric Biomaterials Laboratory, Department of Materials and Optoelectronic Science, National Sun Yat-Sen University, Kaohsiung, 80424, Taiwan
| | - Xinmeng Zhang
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518060, P. R. China
| | - Zhourui Xu
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518060, P. R. China
| | - Gaixia Xu
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518060, P. R. China
| | - Yu-Min Wang
- Polymeric Biomaterials Laboratory, Department of Materials and Optoelectronic Science, National Sun Yat-Sen University, Kaohsiung, 80424, Taiwan
| | - Tzu-Hsien Tsai
- Division of Cardiology and Department of Internal Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, 60002, Taiwan
| | - Pei-Wen Cheng
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, 81362, Taiwan
- Department of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 80424, Taiwan
| | - Wing-Cheung Law
- Department of Industrial and Systems Engineering, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, 999077, P. R. China
| | - Ken-Tye Yong
- School of Biomedical Engineering, The University of Sydney, Sydney, New South Wales, 2006, Australia
| | - Chih-Kuang Chen
- Polymeric Biomaterials Laboratory, Department of Materials and Optoelectronic Science, National Sun Yat-Sen University, Kaohsiung, 80424, Taiwan
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13
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Xu L, Cao Y, Xu Y, Li R, Xu X. Redox-Responsive Polymeric Nanoparticle for Nucleic Acid Delivery and Cancer Therapy: Progress, Opportunities, and Challenges. Macromol Biosci 2024; 24:e2300238. [PMID: 37573033 DOI: 10.1002/mabi.202300238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/25/2023] [Indexed: 08/14/2023]
Abstract
Cancer development and progression of cancer are closely associated with the activation of oncogenes and loss of tumor suppressor genes. Nucleic acid drugs (e.g., siRNA, mRNA, and DNA) are widely used for cancer therapy due to their specific ability to regulate the expression of any cancer-associated genes. However, nucleic acid drugs are negatively charged biomacromolecules that are susceptible to serum nucleases and cannot cross cell membrane. Therefore, specific delivery tools are required to facilitate the intracellular delivery of nucleic acid drugs. In the past few decades, a variety of nanoparticles (NPs) are designed and developed for nucleic acid delivery and cancer therapy. In particular, the polymeric NPs in response to the abnormal redox status in cancer cells have garnered much more attention as their potential in redox-triggered nanostructure dissociation and rapid intracellular release of nucleic acid drugs. In this review, the important genes or signaling pathways regulating the abnormal redox status in cancer cells are briefly introduced and the recent development of redox-responsive NPs for nucleic acid delivery and cancer therapy is systemically summarized. The future development of NPs-mediated nucleic acid delivery and their challenges in clinical translation are also discussed.
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Affiliation(s)
- Lei Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China
- Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, P. R. China
| | - Yuan Cao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China
- Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, P. R. China
| | - Ya Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China
- Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, P. R. China
| | - Rong Li
- The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, P. R. China
| | - Xiaoding Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China
- Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, P. R. China
- The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, P. R. China
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14
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Jin Z, Al Amili M, Guo S. Tumor Microenvironment-Responsive Drug Delivery Based on Polymeric Micelles for Precision Cancer Therapy: Strategies and Prospects. Biomedicines 2024; 12:417. [PMID: 38398021 PMCID: PMC10886702 DOI: 10.3390/biomedicines12020417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/07/2024] [Accepted: 02/08/2024] [Indexed: 02/25/2024] Open
Abstract
In clinical practice, drug therapy for cancer is still limited by its inefficiency and high toxicity. For precision therapy, various drug delivery systems, including polymeric micelles self-assembled from amphiphilic polymeric materials, have been developed to achieve tumor-targeting drug delivery. Considering the characteristics of the pathophysiological environment at the drug target site, the design, synthesis, or modification of environmentally responsive polymeric materials has become a crucial strategy for drug-targeted delivery. In comparison to the normal physiological environment, tumors possess a unique microenvironment, characterized by a low pH, high reactive oxygen species concentration, hypoxia, and distinct enzyme systems, providing various stimuli for the environmentally responsive design of polymeric micelles. Polymeric micelles with tumor microenvironment (TME)-responsive characteristics have shown significant improvement in precision therapy for cancer treatment. This review mainly outlines the most promising strategies available for exploiting the tumor microenvironment to construct internal stimulus-responsive drug delivery micelles that target tumors and achieve enhanced antitumor efficacy. In addition, the prospects of TME-responsive polymeric micelles for gene therapy and immunotherapy, the most popular current cancer treatments, are also discussed. TME-responsive drug delivery via polymeric micelles will be an efficient and robust approach for developing clinical cancer therapies in the future.
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Affiliation(s)
- Zhu Jin
- Correspondence: (Z.J.); (S.G.)
| | | | - Shengrong Guo
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China;
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15
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Ahmadi M, Ritter CA, von Woedtke T, Bekeschus S, Wende K. Package delivered: folate receptor-mediated transporters in cancer therapy and diagnosis. Chem Sci 2024; 15:1966-2006. [PMID: 38332833 PMCID: PMC10848714 DOI: 10.1039/d3sc05539f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 12/31/2023] [Indexed: 02/10/2024] Open
Abstract
Neoplasias pose a significant threat to aging society, underscoring the urgent need to overcome the limitations of traditional chemotherapy through pioneering strategies. Targeted drug delivery is an evolving frontier in cancer therapy, aiming to enhance treatment efficacy while mitigating undesirable side effects. One promising avenue utilizes cell membrane receptors like the folate receptor to guide drug transporters precisely to malignant cells. Based on the cellular folate receptor as a cancer cell hallmark, targeted nanocarriers and small molecule-drug conjugates have been developed that comprise different (bio) chemistries and/or mechanical properties with individual advantages and challenges. Such modern folic acid-conjugated stimuli-responsive drug transporters provide systemic drug delivery and controlled release, enabling reduced dosages, circumvention of drug resistance, and diminished adverse effects. Since the drug transporters' structure-based de novo design is increasingly relevant for precision cancer remediation and diagnosis, this review seeks to collect and debate the recent approaches to deliver therapeutics or diagnostics based on folic acid conjugated Trojan Horses and to facilitate the understanding of the relevant chemistry and biochemical pathways. Focusing exemplarily on brain and breast cancer, recent advances spanning 2017 to 2023 in conjugated nanocarriers and small molecule drug conjugates were considered, evaluating the chemical and biological aspects in order to improve accessibility to the field and to bridge chemical and biomedical points of view ultimately guiding future research in FR-targeted cancer therapy and diagnosis.
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Affiliation(s)
- Mohsen Ahmadi
- Leibniz Institute for Plasma Science and Technology (INP), Center for Innovation Competence (ZIK) Plasmatis Felix Hausdorff-Str. 2 17489 Greifswald Germany
| | - Christoph A Ritter
- Institute of Pharmacy, Section Clinical Pharmacy, University of Greifswald Greifswald Germany
| | - Thomas von Woedtke
- Leibniz Institute for Plasma Science and Technology (INP), Center for Innovation Competence (ZIK) Plasmatis Felix Hausdorff-Str. 2 17489 Greifswald Germany
- Institute for Hygiene and Environmental Medicine, Greifswald University Medical Center Ferdinand-Sauerbruch-Straße 17475 Greifswald Germany
| | - Sander Bekeschus
- Leibniz Institute for Plasma Science and Technology (INP), Center for Innovation Competence (ZIK) Plasmatis Felix Hausdorff-Str. 2 17489 Greifswald Germany
- Clinic and Policlinic for Dermatology and Venereology, Rostock University Medical Center Strempelstr. 13 18057 Rostock Germany
| | - Kristian Wende
- Leibniz Institute for Plasma Science and Technology (INP), Center for Innovation Competence (ZIK) Plasmatis Felix Hausdorff-Str. 2 17489 Greifswald Germany
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16
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Hembram KC. Poly(lactic acid) (PLA) as drug and gene delivery system for tumor. CANCER THERAPY 2024:143-177. [DOI: 10.1016/b978-0-443-15401-0.00007-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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17
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Gurunathan S, Thangaraj P, Wang L, Cao Q, Kim JH. Nanovaccines: An effective therapeutic approach for cancer therapy. Biomed Pharmacother 2024; 170:115992. [PMID: 38070247 DOI: 10.1016/j.biopha.2023.115992] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 11/23/2023] [Accepted: 12/06/2023] [Indexed: 01/10/2024] Open
Abstract
Cancer vaccines hold considerable promise for the immunotherapy of solid tumors. Nanomedicine offers several strategies for enhancing vaccine effectiveness. In particular, molecular or (sub) cellular vaccines can be delivered to the target lymphoid tissues and cells by nanocarriers and nanoplatforms to increase the potency and durability of antitumor immunity and minimize negative side effects. Nanovaccines use nanoparticles (NPs) as carriers and/or adjuvants, offering the advantages of optimal nanoscale size, high stability, ample antigen loading, high immunogenicity, tunable antigen presentation, increased retention in lymph nodes, and immunity promotion. To induce antitumor immunity, cancer vaccines rely on tumor antigens, which are administered in the form of entire cells, peptides, nucleic acids, extracellular vesicles (EVs), or cell membrane-encapsulated NPs. Ideal cancer vaccines stimulate both humoral and cellular immunity while overcoming tumor-induced immune suppression. Herein, we review the key properties of nanovaccines for cancer immunotherapy and highlight the recent advances in their development based on the structure and composition of various (including synthetic and semi (biogenic) nanocarriers. Moreover, we discuss tumor cell-derived vaccines (including those based on whole-tumor-cell components, EVs, cell membrane-encapsulated NPs, and hybrid membrane-coated NPs), nanovaccine action mechanisms, and the challenges of immunocancer therapy and their translation to clinical applications.
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Affiliation(s)
- Sangiliyandi Gurunathan
- Department of Biotechnology, Rathinam College of Arts and Science, Eachanari, Coimbatore 641 021, Tamil Nadu, India.
| | - Pratheep Thangaraj
- Department of Biotechnology, Rathinam College of Arts and Science, Eachanari, Coimbatore 641 021, Tamil Nadu, India
| | - Lin Wang
- Research and Development Department, Qingdao Haier Biotech Co., Ltd., Qingdao, China
| | - Qilong Cao
- Research and Development Department, Qingdao Haier Biotech Co., Ltd., Qingdao, China
| | - Jin-Hoi Kim
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Republic of Korea.
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18
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Singh N, Marwaha D, Gautam S, Rai N, Tiwari P, Sharma M, Shukla RP, Mugale MN, Kumar A, Mishra PR. Surface-Modified Lyotropic Crystalline Nanoconstructs Bearing Doxorubicin and Buparvaquone Target Sigma Receptors through pH-Sensitive Charge Conversion to Improve Breast Cancer Therapy. Biomacromolecules 2023; 24:5780-5796. [PMID: 38006339 DOI: 10.1021/acs.biomac.3c00795] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2023]
Abstract
In the current study, we aimed to develop lyotropic crystalline nanoconstructs (LCNs) based on poly(l-glutamic acid) (PLG) with a two-tier strategy. The first objective was to confer pH-responsive charge conversion properties to facilitate the delivery of both doxorubicin (DOX) and buparvaquone (BPQ) in combination (B + D@LCNs) to harness their synergistic effects. The second goal was to achieve targeted delivery to sigma receptors within the tumor tissues. To achieve this, we designed a pH-responsive charge conversion system using a polymer consisting of poly(ethylenimine), poly(l-lysine), and poly(l-glutamic acid) (PLG), which was then covalently coupled with methoxybenzamide (MBA) for potential sigma receptor targeting. The resulting B + D@LCNs were further modified by surface functionalization with PLG-MBA to confer both sigma receptor targeting and pH-responsive charge conversion properties. Our observations indicated that at physiological pH 7.4, P/B + D-MBA@LCNs exhibited a negative charge, while under acidic conditions (pH 5.5, characteristic of the tumor microenvironment), they acquired a positive charge. The particle size of P/B + D-MBA@LCNs was determined to be 168.23 ± 2.66 nm at pH 7.4 and 201.23 ± 1.46 nm at pH 5.5. The crystalline structure of the LCNs was confirmed through small-angle X-ray scattering (SAXS) diffraction patterns. Receptor-mediated endocytosis, facilitated by P/B + D-MBA@LCNs, was confirmed using confocal laser scanning microscopy and flow cytometry. The P/B + D-MBA@LCNs formulation demonstrated a higher rate of G2/M phase arrest (55.20%) compared to free B + D (37.50%) and induced mitochondrial depolarization (59.39%) to a greater extent than P/B + D@LCNs (45.66%). Pharmacokinetic analysis revealed significantly improved area under the curve (AUC) values for both DOX and BPQ when administered as P/B + D-MBA@LCNs, along with enhanced tumor localization. Tumor regression studies exhibited a substantial reduction in tumor size, with P/B + D-MBA@LCNs leading to 3.2- and 1.27-fold reductions compared to B + D and nontargeted P/B + D@LCNs groups, respectively. In summary, this two-tier strategy demonstrates substantial promise for the delivery of a drug combination through the prototype formulation. It offers a potential chemotherapeutic option by minimizing toxic effects on healthy cells while maximizing therapeutic efficacy.
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Affiliation(s)
- Neha Singh
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India
- Academy of Scientific and Innovation Research (AcSIR), Ghaziabad 201002, U.P., India
| | - Disha Marwaha
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Shalini Gautam
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Nikhil Rai
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Pratiksha Tiwari
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Madhu Sharma
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Ravi Prakash Shukla
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | | | - Akhilesh Kumar
- Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India
| | - Prabhat Ranjan Mishra
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India
- Academy of Scientific and Innovation Research (AcSIR), Ghaziabad 201002, U.P., India
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19
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Liu L, Liu M, Xiu J, Zhang B, Hu H, Qiao M, Chen D, Zhang J, Zhao X. Stimuli-responsive nanoparticles delivered by a nasal-brain pathway alleviate depression-like behavior through extensively scavenging ROS. Acta Biomater 2023; 171:451-465. [PMID: 37778483 DOI: 10.1016/j.actbio.2023.09.038] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 09/18/2023] [Accepted: 09/25/2023] [Indexed: 10/03/2023]
Abstract
Depression is one of the most common mental diseases, which seriously affects patients' physical and mental health. Emerging evidence has indicated that oxidative stress (OS) is a major cause of neurodegeneration involved in the pathogenesis of depression. Consequently, targeted reactive oxygen species (ROS) elimination is regarded as a promising strategy for efficient depression therapy. In addition, insufficient brain drug delivery is the main obstacle to depression therapy owing to the presence of the blood-brain barrier (BBB). To achieve the goals of bypassing the BBB and promoting antioxidant therapy for depression, a broad-spectrum ROS scavenging NPs was rationally designed through a nasal-brain pathway developed for combined ROS scavenging and brain drug delivery. A hexa-arginine (R6) modified ROS-responsive dextran (DEX) derivate was synthesized for antidepressant olanzapine (Olz) and H2 donor amino borane (AB) loading to prepare Olz/RDPA nanoparticles (NPs). Subsequently, the NPs were dispersed into a thermoresponsive hydrogel system based on poloxamer. In vitro and in vivo results demonstrated that Olz/RDPA in situ thermoresponsive hydrogel system could effectively deliver NPs to the brain via the nasal-brain pathway and alleviate depression-like behaviors through combined ROS depletion and inhibition of 5-HT dysfunction of the oxidative stress-induced. The proposed ROS-scavenging nanotherapeutic would open a new window for depression treatment. STATEMENT OF SIGNIFICANCE: ROS is an innovative therapeutic target involving the pathology of depression whereas targeted delivery of ROS scavenging has not been achieved yet. In the current study, ROS-responsive nanoparticles (Olz/RDPA NPs) were prepared and dispersed in a thermosensitive hydrogel for delivery through the nasal-brain pathway for the treatment of depression. Sufficient ROS depletion and improvement of delivery capacity by the nasal-brain pathway effectively could reverse oxidative stress and alleviate depressive-like behavior. Collectively, these nanoparticles may represent a promising strategy for the treatment of depression.
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Affiliation(s)
- Lin Liu
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China
| | - Min Liu
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China
| | - Jingya Xiu
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China
| | - Bowen Zhang
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China
| | - Haiyang Hu
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China
| | - Mingxi Qiao
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China
| | - Dawei Chen
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China
| | - Jiulong Zhang
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
| | - Xiuli Zhao
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
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20
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Han H, Xing L, Chen BT, Liu Y, Zhou TJ, Wang Y, Zhang LF, Li L, Cho CS, Jiang HL. Progress on the pathological tissue microenvironment barrier-modulated nanomedicine. Adv Drug Deliv Rev 2023; 200:115051. [PMID: 37549848 DOI: 10.1016/j.addr.2023.115051] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 07/21/2023] [Accepted: 08/04/2023] [Indexed: 08/09/2023]
Abstract
Imbalance in the tissue microenvironment is the main obstacle to drug delivery and distribution in the human body. Before penetrating the pathological tissue microenvironment to the target site, therapeutic agents are usually accompanied by three consumption steps: the first step is tissue physical barriers for prevention of their penetration, the second step is inactivation of them by biological molecules, and the third step is a cytoprotective mechanism for preventing them from functioning on specific subcellular organelles. However, recent studies in drug-hindering mainly focus on normal physiological rather than pathological microenvironment, and the repair of damaged physiological barriers is also rarely discussed. Actually, both the modulation of pathological barriers and the repair of damaged physiological barriers are essential in the disease treatment and the homeostasis maintenance. In this review, we present an overview describing the latest advances in the generality of these pathological barriers and barrier-modulated nanomedicine. Overall, this review holds considerable significance for guiding the design of nanomedicine to increase drug efficacy in the future.
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Affiliation(s)
- Han Han
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Lei Xing
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China; College of Pharmacy, Yanbian University, Yanji 133002, China
| | - Bi-Te Chen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Yang Liu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Tian-Jiao Zhou
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Yi Wang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Ling-Feng Zhang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
| | - Chong-Su Cho
- Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea.
| | - Hu-Lin Jiang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China; College of Pharmacy, Yanbian University, Yanji 133002, China.
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21
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Luo H, Wang Z, Mo Q, Yang J, Yang F, Tang Y, Liu J, Li X. Framework Nucleic Acid-Based Multifunctional Tumor Theranostic Nanosystem for miRNA Fluorescence Imaging and Chemo/Gene Therapy. ACS APPLIED MATERIALS & INTERFACES 2023. [PMID: 37421332 DOI: 10.1021/acsami.3c01611] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2023]
Abstract
Intelligent stimulus-responsive theranostic systems capable of specifically sensing low-abundance tumor-related biomarkers and efficiently killing tumors remain a pressing endeavor. Here, we report a multifunctional framework nucleic acid (FNA) nanosystem for simultaneous imaging of microRNA-21 (miR-21) and combined chemo/gene therapy. To achieve this, two FNA nanoarchitectures labeled with Cy5/BHQ2 signal tags were designed, each of which contained an AS1411 aptamer, two pairs of DNA/RNA hybrids, a pH-sensitive DNA catcher, and doxorubicin (DOX) intercalating between cytosine and guanine in the tetrahedral DNA nanostructure (TDN). In the acidic tumor microenvironment, the DNA catchers spontaneously triggered to form an i-motif and create an FNA dimer (dFNA) while releasing DOX molecules to exert a cytotoxic effect. In addition, the overexpressed miR-21 in tumor cells dismantled the DNA/RNA hybrids to produce vascular endothelial growth factor-associated siRNA via a toehold-mediated strand displacement reaction, thus enabling a potent RNA interfering. Also importantly, the liberated miR-21 could initiate cascade-reaction amplification to efficiently activate the Cy5 signal reporters, thereby realizing on-site fluorescence imaging of miR-21 in living cells. The exquisitely designed FNA-based nanosystem showed favorable biocompatibility and stability as well as acid-driven DOX release characteristics. Owing to the aptamer-guided targeting delivery, specific uptake of the FNA-based theranostic nanosystem by HepG2 cells was verified with confocal laser scanning microscopy and flow cytometry analyses, which therefore resulted in apoptosis of HepG2 cells while doing minimal damage to normal H9c2 and HL-7702 cells. Strikingly, both in vitro and in vivo experiments demonstrated the achievements of the FNA-enabled miR-21 imaging and synergistically enhanced chemo/gene therapy. This work thus represents a noteworthy advance on the FNA-based theranostic strategy that can effectively avoid the undesirable premature leakage of anticarcinogen and off-target of siRNA, and achieve on-demand reagents release for tumor diagnostics and treatment.
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Affiliation(s)
- Haikun Luo
- Key Laboratory of Micro-Nanoscale Bioanalysis and Drug Screening of Guangxi Education Department, Pharmaceutical College, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi 530021, China
| | - Zhao Wang
- Key Laboratory of Micro-Nanoscale Bioanalysis and Drug Screening of Guangxi Education Department, Pharmaceutical College, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi 530021, China
- School of Medicine, Xiamen University, Xiang-an South Road, Xiamen 361102, China
| | - Qian Mo
- Key Laboratory of Micro-Nanoscale Bioanalysis and Drug Screening of Guangxi Education Department, Pharmaceutical College, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi 530021, China
| | - Jianying Yang
- Key Laboratory of Micro-Nanoscale Bioanalysis and Drug Screening of Guangxi Education Department, Pharmaceutical College, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi 530021, China
| | - Fan Yang
- Key Laboratory of Micro-Nanoscale Bioanalysis and Drug Screening of Guangxi Education Department, Pharmaceutical College, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi 530021, China
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi 530021, China
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Theranostics, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi 530021, China
| | - Yujin Tang
- Department of Orthopedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, China
| | - Jia Liu
- Department of Orthopedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, China
| | - Xinchun Li
- Key Laboratory of Micro-Nanoscale Bioanalysis and Drug Screening of Guangxi Education Department, Pharmaceutical College, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi 530021, China
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi 530021, China
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Theranostics, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi 530021, China
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Wang J, Zhang Y, Dong S, Zha W, Liu C, Wang Y, Jiang Y, Xing H, Li X. Bivalent mRNA vaccines against three SARS-CoV-2 variants mediated by new ionizable lipid nanoparticles. Int J Pharm 2023:123155. [PMID: 37402442 DOI: 10.1016/j.ijpharm.2023.123155] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 05/04/2023] [Accepted: 06/15/2023] [Indexed: 07/06/2023]
Abstract
Lipid nanoparticles (LNPs)-based mRNA vaccines have shown great potential in the fight against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. However, it remains still a challenge to improve the delivery efficiency of LNPs and the long-term stability of their mediated mRNA vaccines. Herein, a novel ionizable lipid 2-hexyldecyl 6-(ethyl(3-((2-hexyldecyl)oxy)-2-hydroxypropyl)amino)hexanoate (HEAH) derived LNPs were developed for delivering the receptor binding domain (RBD) mRNAs. In vitro cell assays confirmed that the ionizable lipid HEAH with one ether bond and one ester bond derived LNPs possessed higher mRNA delivery efficiency compared with the approved ALC-0315 with two ester bonds used in the BNT162b2 vaccine. Notably, the HEAH-derived LNPs powder lyophilized did not significantly change for 30 days after storage at 37 °C indicating good thermostability. After two RBD mRNAs of Delta and Omicron variants were encapsulated into the HEAH-derived LNPs, a bivalent mRNA vaccine was obtained as a nanoparticle formulation. Importantly, the bivalent mRNA vaccine not only resisted Delta and Omicron and also generated protective antibodies against ancestral SARS-CoV-2. The HEAH-mediated bivalent vaccine induced stronger humoral and cellular immunity than those of the ALC-0315 group. Taken together, the ionizable lipid HEAH-derived LNPs show outstanding potential in improving the delivery efficiency of mRNA and the stability of mRNA vaccine.
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Affiliation(s)
- Ji Wang
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 214122, PR China
| | - Yanhao Zhang
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 214122, PR China
| | - Shuo Dong
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 214122, PR China
| | - Wenhui Zha
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 214122, PR China
| | - Chao Liu
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 214122, PR China
| | - Yang Wang
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 214122, PR China
| | - Yuhao Jiang
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 214122, PR China
| | - Hanlei Xing
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 214122, PR China
| | - Xinsong Li
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 214122, PR China.
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Leng Q, Imtiyaz Z, Woodle MC, Mixson AJ. Delivery of Chemotherapy Agents and Nucleic Acids with pH-Dependent Nanoparticles. Pharmaceutics 2023; 15:1482. [PMID: 37242725 PMCID: PMC10222096 DOI: 10.3390/pharmaceutics15051482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/18/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
With less than one percent of systemically injected nanoparticles accumulating in tumors, several novel approaches have been spurred to direct and release the therapy in or near tumors. One such approach depends on the acidic pH of the extracellular matrix and endosomes of the tumor. With an average pH of 6.8, the extracellular tumor matrix provides a gradient for pH-responsive particles to accumulate, enabling greater specificity. Upon uptake by tumor cells, nanoparticles are further exposed to lower pHs, reaching a pH of 5 in late endosomes. Based on these two acidic environments in the tumor, various pH-dependent targeting strategies have been employed to release chemotherapy or the combination of chemotherapy and nucleic acids from macromolecules such as the keratin protein or polymeric nanoparticles. We will review these release strategies, including pH-sensitive linkages between the carrier and hydrophobic chemotherapy agent, the protonation and disruption of polymeric nanoparticles, an amalgam of these first two approaches, and the release of polymers shielding drug-loaded nanoparticles. While several pH-sensitive strategies have demonstrated marked antitumor efficacy in preclinical trials, many studies are early in their development with several obstacles that may limit their clinical use.
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Affiliation(s)
- Qixin Leng
- Department of Pathology, University Maryland School of Medicine, University of Maryland, 10 S. Pine St., Baltimore, MD 21201, USA (Z.I.)
| | - Zuha Imtiyaz
- Department of Pathology, University Maryland School of Medicine, University of Maryland, 10 S. Pine St., Baltimore, MD 21201, USA (Z.I.)
| | | | - A. James Mixson
- Department of Pathology, University Maryland School of Medicine, University of Maryland, 10 S. Pine St., Baltimore, MD 21201, USA (Z.I.)
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24
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Lin M, Qi X. Advances and Challenges of Stimuli-Responsive Nucleic Acids Delivery System in Gene Therapy. Pharmaceutics 2023; 15:pharmaceutics15051450. [PMID: 37242692 DOI: 10.3390/pharmaceutics15051450] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 05/04/2023] [Accepted: 05/04/2023] [Indexed: 05/28/2023] Open
Abstract
Gene therapy has emerged as a powerful tool to treat various diseases, such as cardiovascular diseases, neurological diseases, ocular diseases and cancer diseases. In 2018, the FDA approved Patisiran (the siRNA therapeutic) for treating amyloidosis. Compared with traditional drugs, gene therapy can directly correct the disease-related genes at the genetic level, which guarantees a sustained effect. However, nucleic acids are unstable in circulation and have short half-lives. They cannot pass through biological membranes due to their high molecular weight and massive negative charges. To facilitate the delivery of nucleic acids, it is crucial to develop a suitable delivery strategy. The rapid development of delivery systems has brought light to the gene delivery field, which can overcome multiple extracellular and intracellular barriers that prevent the efficient delivery of nucleic acids. Moreover, the emergence of stimuli-responsive delivery systems has made it possible to control the release of nucleic acids in an intelligent manner and to precisely guide the therapeutic nucleic acids to the target site. Considering the unique properties of stimuli-responsive delivery systems, various stimuli-responsive nanocarriers have been developed. For example, taking advantage of the physiological variations of a tumor (pH, redox and enzymes), various biostimuli- or endogenous stimuli-responsive delivery systems have been fabricated to control the gene delivery processes in an intelligent manner. In addition, other external stimuli, such as light, magnetic fields and ultrasound, have also been employed to construct stimuli-responsive nanocarriers. Nevertheless, most stimuli-responsive delivery systems are in the preclinical stage, and some critical issues remain to be solved for advancing the clinical translation of these nanocarriers, such as the unsatisfactory transfection efficiency, safety issues, complexity of manufacturing and off-target effects. The purpose of this review is to elaborate the principles of stimuli-responsive nanocarriers and to emphasize the most influential advances of stimuli-responsive gene delivery systems. Current challenges of their clinical translation and corresponding solutions will also be highlighted, which will accelerate the translation of stimuli-responsive nanocarriers and advance the development of gene therapy.
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Affiliation(s)
- Meng Lin
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610044, China
| | - Xianrong Qi
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China
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Xiu K, Zhang J, Xu J, Chen YE, Ma PX. Recent progress in polymeric gene vectors: Delivery mechanisms, molecular designs, and applications. BIOPHYSICS REVIEWS 2023; 4:011313. [PMID: 37008888 PMCID: PMC10062053 DOI: 10.1063/5.0123664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 03/07/2023] [Indexed: 03/30/2023]
Abstract
Gene therapy and gene delivery have drawn extensive attention in recent years especially when the COVID-19 mRNA vaccines were developed to prevent severe symptoms caused by the corona virus. Delivering genes, such as DNA and RNA into cells, is the crucial step for successful gene therapy and remains a bottleneck. To address this issue, vehicles (vectors) that can load and deliver genes into cells are developed, including viral and non-viral vectors. Although viral gene vectors have considerable transfection efficiency and lipid-based gene vectors become popular since the application of COVID-19 vaccines, their potential issues including immunologic and biological safety concerns limited their applications. Alternatively, polymeric gene vectors are safer, cheaper, and more versatile compared to viral and lipid-based vectors. In recent years, various polymeric gene vectors with well-designed molecules were developed, achieving either high transfection efficiency or showing advantages in certain applications. In this review, we summarize the recent progress in polymeric gene vectors including the transfection mechanisms, molecular designs, and biomedical applications. Commercially available polymeric gene vectors/reagents are also introduced. Researchers in this field have never stopped seeking safe and efficient polymeric gene vectors via rational molecular designs and biomedical evaluations. The achievements in recent years have significantly accelerated the progress of polymeric gene vectors toward clinical applications.
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Affiliation(s)
- Kemao Xiu
- Department of Biologic and Materials Sciences and Prosthodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, USA
| | | | | | | | - Peter X. Ma
- Author to whom correspondence should be addressed:. Tel.: (734) 764-2209
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Jiang Y, Fan M, Yang Z, Liu X, Xu Z, Liu S, Feng G, Tang S, Li Z, Zhang Y, Chen S, Yang C, Law WC, Dong B, Xu G, Yong KT. Recent advances in nanotechnology approaches for non-viral gene therapy. Biomater Sci 2022; 10:6862-6892. [PMID: 36222758 DOI: 10.1039/d2bm01001a] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Gene therapy has shown great potential in the treatment of many diseases by downregulating the expression of certain genes. The development of gene vectors as a vehicle for gene therapy has greatly facilitated the widespread clinical application of nucleic acid materials (DNA, mRNA, siRNA, and miRNA). Currently, both viral and non-viral vectors are used as delivery systems of nucleic acid materials for gene therapy. However, viral vector-based gene therapy has several limitations, including immunogenicity and carcinogenesis caused by the exogenous viral vectors. To address these issues, non-viral nanocarrier-based gene therapy has been explored for superior performance with enhanced gene stability, high treatment efficiency, improved tumor-targeting, and better biocompatibility. In this review, we discuss various non-viral vector-mediated gene therapy approaches using multifunctional biodegradable or non-biodegradable nanocarriers, including polymer-based nanoparticles, lipid-based nanoparticles, carbon nanotubes, gold nanoparticles (AuNPs), quantum dots (QDs), silica nanoparticles, metal-based nanoparticles and two-dimensional nanocarriers. Various strategies to construct non-viral nanocarriers based on their delivery efficiency of targeted genes will be introduced. Subsequently, we discuss the cellular uptake pathways of non-viral nanocarriers. In addition, multifunctional gene therapy based on non-viral nanocarriers is summarized, in which the gene therapy can be combined with other treatments, such as photothermal therapy (PTT), photodynamic therapy (PDT), immunotherapy and chemotherapy. We also provide a comprehensive discussion of the biological toxicity and safety of non-viral vector-based gene therapy. Finally, the present limitations and challenges of non-viral nanocarriers for gene therapy in future clinical research are discussed, to promote wider clinical applications of non-viral vector-based gene therapy.
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Affiliation(s)
- Yihang Jiang
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, Guangdong 518055, China.
| | - Miaozhuang Fan
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, Guangdong 518055, China.
| | - Zhenxu Yang
- School of Biomedical Engineering, The University of Sydney, Sydney, New South Wales 2006, Australia. .,The University of Sydney Nano Institute, The University of Sydney, Sydney, New South Wales 2006, Australia.,The Biophotonics and Mechanobioengineering Laboratory, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Xiaochen Liu
- School of Biomedical Engineering, The University of Sydney, Sydney, New South Wales 2006, Australia. .,The University of Sydney Nano Institute, The University of Sydney, Sydney, New South Wales 2006, Australia.,The Biophotonics and Mechanobioengineering Laboratory, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Zhourui Xu
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, Guangdong 518055, China.
| | - Shikang Liu
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, Guangdong 518055, China.
| | - Gang Feng
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, Guangdong 518055, China.
| | - Shuo Tang
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, Guangdong 518055, China.
| | - Zhengzheng Li
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, Guangdong 518055, China.
| | - Yibin Zhang
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, Guangdong 518055, China.
| | - Shilin Chen
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, Guangdong 518055, China.
| | - Chengbin Yang
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, Guangdong 518055, China.
| | - Wing-Cheung Law
- Department of Industrial and Systems Engineering, The Hong Kong Polytechnic University, Hung Hom, Kowloon 999077, Hong Kong, China
| | - Biqin Dong
- Guangdong Provincial Key Laboratory of Durability for Marine Civil Engineering, College of Civil and Transportation Engineering, Shenzhen University, Shenzhen 518060, China
| | - Gaixia Xu
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, Guangdong 518055, China.
| | - Ken-Tye Yong
- School of Biomedical Engineering, The University of Sydney, Sydney, New South Wales 2006, Australia. .,The University of Sydney Nano Institute, The University of Sydney, Sydney, New South Wales 2006, Australia.,The Biophotonics and Mechanobioengineering Laboratory, The University of Sydney, Sydney, New South Wales 2006, Australia
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Wang J, Zhang Y, Liu C, Zha W, Dong S, Xing H, Li X. Multifunctional Lipid Nanoparticles for Protein Kinase N3 shRNA Delivery and Prostate Cancer Therapy. Mol Pharm 2022; 19:4588-4600. [PMID: 35731922 DOI: 10.1021/acs.molpharmaceut.2c00244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Protein kinase N3 (PKN3), by virtue of its abnormal expression in prostate cells, has been widely used as a target of RNAi (shRNA, siRNA, miRNA) therapy. The major challenges of PKN3 RNAi therapy lie in how to design effective interference sequences and delivery systems. Herein, new PKN3 shRNA sequences (shPKN3-2459 and shPKN3-3357) were designed, and bioreducible, biodegradable, ionizable lipid-based nanoparticles were developed for shPKN3 delivery. First, an ionizable lipid (DDA-SS-DMA) bridged with disulfide bond and ester bonds was synthesized by a three-step reaction and confirmed by MS, 1H NMR, and 13C NMR. The ionizable lipid was mixed with cholesterol, DSPC, PEG-lipid, and shPKN3 by a microfluidic mixer to prepare lipid nanoparticles (LNP-shPKN3) which were characterized by DLS and TEM. Afterward, the pH and glutathione (GSH)-responsiveness of the DDA-SS-DMA based LNP delivery system were investigated by lysosome escape and gel electrophoresis assays. Compared with the commercial transfection reagent Lipo2000, the DDA-SS-DMA based delivery system showed higher transfection efficiency and lower toxicity. Western blot analysis, invasion tests, and migration assays were performed to evaluate the silencing effect of shPKN3 in vitro. In in vivo studies, high tumor suppression (65.8%) and treatment safety were evident in the LNP-shPKN3-2459 treatment group. Taken together, the DDA-SS-DMA based delivery system encapsulating shPKN3-2459 showed significant antitumor efficacy and might be a promising formulation for the treatment of prostate cancer.
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Affiliation(s)
- Ji Wang
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu 214122, PR China
| | - Yanhao Zhang
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu 214122, PR China
| | - Chao Liu
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu 214122, PR China
| | - Wenhui Zha
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu 214122, PR China
| | - Shuo Dong
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu 214122, PR China
| | - Hanlei Xing
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu 214122, PR China
| | - Xinsong Li
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu 214122, PR China
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Eljack S, David S, Faggad A, Chourpa I, Allard-Vannier E. Nanoparticles design considerations to co-deliver nucleic acids and anti-cancer drugs for chemoresistance reversal. Int J Pharm X 2022; 4:100126. [PMID: 36147518 PMCID: PMC9486027 DOI: 10.1016/j.ijpx.2022.100126] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 09/01/2022] [Indexed: 12/24/2022] Open
Abstract
Chemoresistance and hence the consequent treatment failure is considerably challenging in clinical cancer therapeutics. The understanding of the genetic variations in chemoresistance acquisition encouraged the use of gene modulatory approaches to restore anti-cancer drug efficacy. Many smart nanoparticles are designed and optimized to mediate combinational therapy between nucleic acid and anti-cancer drugs. This review aims to define a rational design of such co-loaded nanocarriers with the aim of chemoresistance reversal at various cellular levels to improve the therapeutic outcome of anticancer treatment. Going through the principles of therapeutics loading, physicochemical characteristics tuning, and different nanocarrier modifications, also looking at combination effectiveness on chemosensitivity restoration. Up to now, these emerging nanocarriers are in development status but are expected to introduce outstanding outcomes.
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Imtiyaz Z, He J, Leng Q, Agrawal AK, Mixson AJ. pH-Sensitive Targeting of Tumors with Chemotherapy-Laden Nanoparticles: Progress and Challenges. Pharmaceutics 2022; 14:pharmaceutics14112427. [PMID: 36365245 PMCID: PMC9692785 DOI: 10.3390/pharmaceutics14112427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/03/2022] [Accepted: 11/05/2022] [Indexed: 11/12/2022] Open
Abstract
Accumulating chemotherapeutic drugs such as doxorubicin within a tumor while limiting the drug dose to normal tissues is a central goal of drug delivery with nanoparticles. Liposomal products such as Doxil® represent one of the marked successes of nanoparticle-based strategies. To replicate this success for cancer treatment, many approaches with nanoparticles are being explored in order to direct and release chemotherapeutic agents to achieve higher accumulation in tumors. A promising approach has been stimulus-based therapy, such as the release of chemotherapeutic agents from the nanoparticles in the acidic environments of the tumor matrix or the tumor endosomes. Upon reaching the acidic environments of the tumor, the particles, which are made up of pH-dependent polymers, become charged and release the entrapped chemotherapy agents. This review discusses recent advances in and prospects for pH-dependent histidine-based nanoparticles that deliver chemotherapeutic agents to tumors. The strategies used by investigators include an array of histidine-containing peptides and polymers which form micelles, mixed micelles, nanovesicles, polyplexes, and coat particles. To date, several promising histidine-based nanoparticles have been demonstrated to produce marked inhibition of tumor growth, but challenges remain for successful outcomes in clinical trials. The lessons learned from these histidine-containing particles will provide insight in the development of improved pH-dependent polymeric delivery systems for chemotherapy.
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Affiliation(s)
- Zuha Imtiyaz
- Department of Pathology, University Maryland School of Medicine, 10 S. Pine St., University of Maryland, Baltimore, MD 21201, USA
| | - Jiaxi He
- 20511 Seneca Meadows Pkwy, Suite 260, RNAimmune, Germantown, MD 20876, USA
| | - Qixin Leng
- Department of Pathology, University Maryland School of Medicine, 10 S. Pine St., University of Maryland, Baltimore, MD 21201, USA
| | - Atul K. Agrawal
- Department of Pathology, University Maryland School of Medicine, 10 S. Pine St., University of Maryland, Baltimore, MD 21201, USA
| | - A. James Mixson
- Department of Pathology, University Maryland School of Medicine, 10 S. Pine St., University of Maryland, Baltimore, MD 21201, USA
- Correspondence: ; Tel.: +1-410-706-3223; Fax: +1-410-706-8414
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30
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Liang J, Guo S, Bai M, Huang M, Qu Y, Zhao Y, Song Y. Stimulus-responsive hybrid nanoparticles based on multiple lipids for the co-delivery of doxorubicin and Sphk2-siRNA and breast cancer therapy. Food Chem Toxicol 2022; 171:113532. [DOI: 10.1016/j.fct.2022.113532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 10/03/2022] [Accepted: 11/21/2022] [Indexed: 11/29/2022]
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31
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Zhang Y, Kim I, Lu Y, Xu Y, Yu DG, Song W. Intelligent poly(l-histidine)-based nanovehicles for controlled drug delivery. J Control Release 2022; 349:963-982. [PMID: 35944751 DOI: 10.1016/j.jconrel.2022.08.005] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/04/2022] [Accepted: 08/04/2022] [Indexed: 12/11/2022]
Abstract
Stimuli-responsive drug delivery systems based on polymeric nanovehicles are among the most promising treatment regimens for malignant cancers. Such intelligent systems that release payloads in response to the physiological characteristics of tumor sites have several advantages over conventional drug carriers, offering, in particular, enhanced therapeutic effects and decreased toxicity. The tumor microenvironment (TME) is acidic, suggesting the potential of pH-responsive nanovehicles for enhancing treatment specificity and efficacy. The synthetic polypeptide poly(l-histidine) (PLH) is an appropriate candidate for the preparation of pH-responsive nanovehicles because the pKa of PLH (approximately 6.0) is close to the pH of the acidic TME. In addition, the pendent imidazole rings of PLH yield pH-dependent hydrophobic-to-hydrophilic phase transitions in the acidic TME, triggering the destabilization of nanovehicles and the subsequent release of encapsulated chemotherapeutic agents. Herein, we highlight the state-of-the-art design and construction of pH-responsive nanovehicles based on PLH and discuss the future challenges and perspectives of this fascinating biomaterial for targeted cancer treatment and "benchtop-to-clinic" translation.
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Affiliation(s)
- Yu Zhang
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China.
| | - Il Kim
- School of Chemical Engineering, Pusan National University, Busan 46241, Republic of Korea.
| | - Yiming Lu
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China
| | - Yixin Xu
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China
| | - Deng-Guang Yu
- School of Materials and Chemistry, University of Shanghai for Science and Technology, Shanghai 200093, PR China.
| | - Wenliang Song
- School of Materials and Chemistry, University of Shanghai for Science and Technology, Shanghai 200093, PR China.
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Li Y, Tang K, Zhang X, Pan W, Li N, Tang B. Tumor microenvironment responsive nanocarriers for gene therapy. Chem Commun (Camb) 2022; 58:8754-8765. [PMID: 35880654 DOI: 10.1039/d2cc02759c] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Stimuli responsive nanocarriers are important non-viral gene carriers for gene therapy. We discuss the stimulus conditions and then highlight various stimuli responsive nanocarriers in the tumor microenvironment for cancer gene therapy. We hope that this review will inspire readers to develop more effective stimuli responsive nanocarriers for delivering genes.
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Affiliation(s)
- Yanhua Li
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China.
| | - Kun Tang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China.
| | - Xia Zhang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China.
| | - Wei Pan
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China.
| | - Na Li
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China.
| | - Bo Tang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China.
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Paul A, Muralidharan A, Biswas A, Venkatesh Kamath B, Joseph A, Alex AT. siRNA Therapeutics and its Challenges: Recent Advances in Effective Delivery for Cancer Therapy. OPENNANO 2022. [DOI: 10.1016/j.onano.2022.100063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
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Zhao C, Chen Q, Li W, Zhang J, Yang C, Chen D. Multi-functional platelet membrane-camouflaged nanoparticles reduce neuronal apoptosis and regulate microglial phenotype during ischemic injury. APPLIED MATERIALS TODAY 2022; 27:101412. [DOI: 10.1016/j.apmt.2022.101412] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Affiliation(s)
- Chaoyue Zhao
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China
- Changchun Children's Hospital, 1321Beian Road, Changchun, Jilin 130051, China
| | | | | | | | - Chunrong Yang
- Department of Pharmacy, Shantou University Medical College, 22 Xinling Road, Shantou, Guangdong 515041, China
| | - Dawei Chen
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China
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Development of stimulus-sensitive electrospun membranes based on novel biodegradable segmented polyurethane as triggered delivery system for doxorubicin. BIOMATERIALS ADVANCES 2022; 136:212769. [PMID: 35929309 DOI: 10.1016/j.bioadv.2022.212769] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 03/10/2022] [Accepted: 03/15/2022] [Indexed: 12/19/2022]
Abstract
In this work, redox-sensitive polyurethane urea (PUU) based electrospun membranes have been exploited to chemically tether a pH-sensitive doxorubicin derivative achieved by linking a lipoyl hydrazide to the drug via a hydrazone linkage. First, the lipoyl-hydrazone-doxorubicin derivative labelled as LA-Hy-Doxo has been synthesized and characterized. Then, the molecule has been tethered, via a thiol-disulfide exchange reaction, to the redox-sensitive PUU (PolyCEGS) electrospun membrane. The redox-sensitive PolyCEGS PUU has been produced by using PCL-PEG-PCL polyol and glutathione-tetramethyl ester (GSSG-OMe)4 as a chain extender. The LA-Hy-Doxo tethered electrospun membrane has showed a dually controlled release triggered by acidic and reducing conditions, producing a significant cytotoxic effect in human breast cancer cell lines (MCF-7) which has validated the system for the post-surgical treatment of solid tumors to contrast recurrence.
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Cheng K, Zhou J, Zhao Y, Chen Y, Ming L, Huang D, Yang R, Lin Z, Chen D. pH-responsive and CD44-targeting polymer micelles based on CD44p-conjugated amphiphilic block copolymer PEG- b-HES- b-PLA for delivery of emodin to breast cancer cells. NANOTECHNOLOGY 2022; 33:275604. [PMID: 35313287 DOI: 10.1088/1361-6528/ac5f9a] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 03/17/2022] [Indexed: 06/14/2023]
Abstract
Herein, an amphiphilic block copolymer CD44-targeting peptide-conjugated polyethylene glycol-block-hydroxyethyl starch-block-poly (L-lactic acid) (CD44p-conjugated PEG-b-HES-b-PLA) are synthesized, which could self-assemble into the pH-responsive and CD44-targeting polymer micelles against breast cancer cells MDA-MB-231. Emodin (Emo) is a natural anthraquino with pharmacological activities in anti-tumor effects. However, Emo suffers from poor water solubility, low biocompatibility, rapid systemic elimination, and off-target side effects, resulting in unsatisfactory treatment outcomes. Nanotechnology-based drug delivery systems have proven great potential for cancer chemotherapy. The constructed polymeric micelles Emo@CD44p-PM have exhibited an average size of 154.5 ± 0.9 nm characterized by DLS and TEM. Further, the Emo@CD44p-PM have effective Emo-loading capacity, good thermal stability, and pH responsiveness. Intracellular uptake study shows the enhanced cellular internalization of Emo@CD44p-PM due to the increased exposure of CD44p enhances the cellular internalization of Emo@CD44p-PM effectively. Furthermore, thein vitroresults showed Emo@CD44p-PM has been observed good biocompatibility and anti-tumor effects. Therefore, the polymeric micelles Emo@CD44p-PM provide a promising delivery strategy of targeted therapy for breast cancer.
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Affiliation(s)
- Kai Cheng
- Research Institute for Reproductive Health and Genetic Diseases, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, People's Republic of China
| | - Jie Zhou
- Department of Obstetrics and Gynecology, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, People's Republic of China
| | - Yujie Zhao
- The First Clinical School, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Yu Chen
- Research Institute for Reproductive Health and Genetic Diseases, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, People's Republic of China
| | - Lan Ming
- Research Institute for Reproductive Health and Genetic Diseases, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, People's Republic of China
| | - Da Huang
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, People's Republic of China
| | - Rui Yang
- Research Institute for Reproductive Health and Genetic Diseases, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, People's Republic of China
- Ministry of Education Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection for Food Safety, College of Chemistry, Fuzhou University, Fuzhou, People's Republic of China
| | - Zhenyu Lin
- Ministry of Education Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection for Food Safety, College of Chemistry, Fuzhou University, Fuzhou, People's Republic of China
| | - Daozhen Chen
- Research Institute for Reproductive Health and Genetic Diseases, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, People's Republic of China
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Paskeh MDA, Saebfar H, Mahabady MK, Orouei S, Hushmandi K, Entezari M, Hashemi M, Aref AR, Hamblin MR, Ang HL, Kumar AP, Zarrabi A, Samarghandian S. Overcoming doxorubicin resistance in cancer: siRNA-loaded nanoarchitectures for cancer gene therapy. Life Sci 2022; 298:120463. [DOI: 10.1016/j.lfs.2022.120463] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 02/08/2023]
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Xu X, Jin C, Zhang K, Cao Y, Liu J, Zhang Y, Ran H, Jin Y. Activatable “Matryoshka” nanosystem delivery NgBR siRNA and control drug release for stepwise therapy and evaluate drug resistance cancer. Mater Today Bio 2022; 14:100245. [PMID: 35345559 PMCID: PMC8956824 DOI: 10.1016/j.mtbio.2022.100245] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/02/2022] [Accepted: 03/16/2022] [Indexed: 12/03/2022] Open
Abstract
Drug resistance is always a challenge in conquering breast cancer clinically. Recognition of drug resistance and enhancing the sensitivity of the tumor to chemotherapy is urgent. Herein, a dual-responsive multi-function “Matryoshka" nanosystem is designed, it activates in the tumor microenvironment, decomposes layer by layer, and release gene and drug in sequence. The cell is re-educated by NgBR siRNA first to regain the chemosensitivity through regulating the Akt pathway and inhibit ERα activation, then the drugs loaded in the core are controlled released to killing cells. Carbonized polymer dots are loaded into the nanosystem as an efficient bioimaging probe, due to the GE11 modification, the nanosystem can be a seeker to recognize and evaluate drug-resistance tumors by photoacoustic imaging. In the tumor-bearing mouse, the novel nanosystem firstly enhances the sensitivity to chemotherapy by knockdown NgBR, inducing a much higher reduction in NgBR up to 52.09%, then effectively inhibiting tumor growth by chemotherapy, tumor growth in nude mouse was inhibited by 70.22%. The nanosystem also can inhibit metastasis, prolong survival time, and evaluate tumor drug resistance by real-time imaging. Overall, based on regulating the key molecules of drug resistance, we created visualization nanotechnology and formatted new comprehensive plans with high bio-safety for tumor diagnosis and treatment, providing a personalized strategy to overcome drug resistance clinically.
Knockdown NgBR regulate the Akt pathway and inhibit ERα activate, enhance the sensitivity of chemotherapy. Knockdown of NgBR inhibits metastasis and prolongs survival. Nanosystem can evaluate drug resistance and kill tumors at the same time.
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Zhang C, Zhou X, Zhang H, Han X, Li B, Yang R, Zhou X. Recent Progress of Novel Nanotechnology Challenging the Multidrug Resistance of Cancer. Front Pharmacol 2022; 13:776895. [PMID: 35237155 PMCID: PMC8883114 DOI: 10.3389/fphar.2022.776895] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 01/11/2022] [Indexed: 12/12/2022] Open
Abstract
Multidrug resistance (MDR) of tumors is one of the clinical direct reasons for chemotherapy failure. MDR directly leads to tumor recurrence and metastasis, with extremely grievous mortality. Engineering a novel nano-delivery system for the treatment of MDR tumors has become an important part of nanotechnology. Herein, this review will take those different mechanisms of MDR as the classification standards and systematically summarize the advances in nanotechnology targeting different mechanisms of MDR in recent years. However, it still needs to be seriously considered that there are still some thorny problems in the application of the nano-delivery system against MDR tumors, including the excessive utilization of carrier materials, low drug-loading capacity, relatively narrow targeting mechanism, and so on. It is hoped that through the continuous development of nanotechnology, nano-delivery systems with more universal uses and a simpler preparation process can be obtained, for achieving the goal of defeating cancer MDR and accelerating clinical transformation.
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Affiliation(s)
- Chengyuan Zhang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing, China
| | - Xuemei Zhou
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing, China
| | - Hanyi Zhang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing, China
| | - Xuanliang Han
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing, China
| | - Baijun Li
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing, China
| | - Ran Yang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing, China
| | - Xing Zhou
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing, China
- Department of Pharmacy, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
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Luo J, Zhang S, Zhu P, Liu W, Du J. Fabrication of pH/Redox Dual-Responsive Mixed Polyprodrug Micelles for Improving Cancer Chemotherapy. Front Pharmacol 2022; 12:802785. [PMID: 35185545 PMCID: PMC8850636 DOI: 10.3389/fphar.2021.802785] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/27/2021] [Indexed: 11/18/2022] Open
Abstract
In this work, we prepared pH/redox dual-responsive mixed polyprodrug micelles (MPPMs), which were co-assembled from two polyprodrugs, namely, poly(ethylene glycol) methyl ether-b-poly (β-amino esters) conjugated with doxorubicin (DOX) via redox-sensitive disulfide bonds (mPEG-b-PAE-ss-DOX) and poly(ethylene glycol) methyl ether-b-poly (β-amino esters) conjugated with DOX via pH-sensitive cis-aconityl bonds (mPEG-b-PAE-cis-DOX) for effective anticancer drug delivery with enhanced therapeutic efficacy. The particle size of MPPMs was about 125 nm with low polydispersity index, indicating the reasonable size and uniform dispersion. The particle size, zeta-potential, and critical micelle concentration (CMC) of MPPMs at different mass ratios of the two kinds of polyprodrugs were dependent on pH value and glutathione (GSH) level, suggesting the pH and redox responsiveness. The drug release profiles in vitro of MPPMs at different conditions were further studied, showing the pH—and redox-triggered drug release mechanism. Confocal microscopy study demonstrated that MPPMs can effectively deliver doxorubicin molecules into MDA-MB-231 cells. Cytotoxicity assay in vitro proved that MPPMs possessed high toxic effect against tumor cells including A549 and MDA-MB-231. The results of in vivo experiments demonstrated that MPPMs were able to effectively inhibit the tumor growth with reduced side effect, leading to enhanced survival rate of tumor-bearing mice. Taken together, these findings revealed that this pH/redox dual-responsive MPPMs could be a potential nanomedicine for cancer chemotherapy. Furthermore, it could be a straightforward way to fabricate the multifunctional system basing on single stimuli-responsive polyprodrugs.
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Chen S, Morrison G, Liu W, Kaur A, Chen R. A pH-responsive, endosomolytic liposome functionalized with membrane-anchoring, comb-like pseudopeptides for enhanced intracellular delivery and cancer treatment. Biomater Sci 2022; 10:6718-6730. [DOI: 10.1039/d2bm01087a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Low intracellular delivery efficiency and multidrug resistance are among major barriers to effective cancer therapy.
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Affiliation(s)
- Siyuan Chen
- Department of Chemical Engineering, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK
- Research Institute for Biomaterials, Tech Institute for Advanced Materials, College of Materials Science and Engineering, Suqian Advanced Materials Industry Technology Innovation Center, NJTech-BARTY Joint Research Center for Innovative Medical Technology, Nanjing Tech University, Nanjing 212000, China
| | - Gabriella Morrison
- Department of Chemical Engineering, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK
| | - Wenyuan Liu
- Research Institute for Biomaterials, Tech Institute for Advanced Materials, College of Materials Science and Engineering, Suqian Advanced Materials Industry Technology Innovation Center, NJTech-BARTY Joint Research Center for Innovative Medical Technology, Nanjing Tech University, Nanjing 212000, China
| | - Apanpreet Kaur
- Department of Chemical Engineering, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK
| | - Rongjun Chen
- Department of Chemical Engineering, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK
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42
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Chen M, Wang H, Guo H, Zhang Y, Chen L. Systematic Investigation of Biocompatible Cationic Polymeric Nucleic Acid Carriers for Immunotherapy of Hepatocellular Carcinoma. Cancers (Basel) 2021; 14:85. [PMID: 35008249 PMCID: PMC8750096 DOI: 10.3390/cancers14010085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third-largest cause of cancer death worldwide, while immunotherapy is rapidly being developed to fight HCC with great potential. Nucleic acid drugs are the most important modulators in HCC immunotherapy. To boost the efficacy of therapeutics and amplify the efficiency of genetic materials, biocompatible polymers are commonly used. However, under the strong need of a summary for current developments of biocompatible polymeric nucleic acid carriers for immunotherapy of HCC, there is rare review article specific to this topic to our best knowledge. In this article, we will discuss the current progress of immunotherapy for HCC, biocompatible cationic polymers (BCPs) as nucleic acid carriers used (or potential) to fight HCC, the roles of biocompatible polymeric carriers for nucleic acid delivery, and nucleic acid delivery by biocompatible polymers for immunotherapy. At the end, we will conclude the review and discuss future perspectives. This article discusses biocompatible polymeric nucleic acid carriers for immunotherapy of HCC from multidiscipline perspectives and provides a new insight in this domain. We believe this review will be interesting to polymer chemists, pharmacists, clinic doctors, and PhD students in related disciplines.
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Affiliation(s)
- Mingsheng Chen
- Shanghai Public Health Clinic Center, Fudan University, Shanghai 201508, China; (M.C.); (H.W.); (H.G.)
| | - Hao Wang
- Shanghai Public Health Clinic Center, Fudan University, Shanghai 201508, China; (M.C.); (H.W.); (H.G.)
| | - Hongying Guo
- Shanghai Public Health Clinic Center, Fudan University, Shanghai 201508, China; (M.C.); (H.W.); (H.G.)
| | - Ying Zhang
- School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang 212100, China
| | - Liang Chen
- Shanghai Public Health Clinic Center, Fudan University, Shanghai 201508, China; (M.C.); (H.W.); (H.G.)
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Biomacromolecule-mediated pulmonary delivery of siRNA and anti-sense oligos: challenges and possible solutions. Expert Rev Mol Med 2021; 23:e22. [PMID: 34906269 DOI: 10.1017/erm.2021.25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Biomacromolecules have gained much attention as biomedicine carriers in recent years due to their remarkable biophysical and biochemical properties including sustainability, non-toxicity, biocompatibility, biodegradability, long systemic circulation time and ability to target. Recent developments in a variety of biological functions of biomacromolecules and progress in the study of biological drug carriers suggest that these carriers may have advantages over carriers of synthetic materials in terms of half-life, durability, protection and manufacturing facility. Despite the full pledge advancements in the applications of biomacromolecules, its clinical use is hindered by certain factors that allow the pre-mature release of loaded cargos before reaching the target site. The delivery therapeutics are degraded by systemic nucleases, cleared by reticulo-endothelial system, cleared by pulmonary mucus cilia or engulfed by lysosome during cellular uptake that has led to the failure of clinical therapy. It clearly indicates that there is a wide range of gaps in the results of experimental work and clinical applications of biomacromolecules. This review focuses mainly on the barriers (intracellular/extracellular) and hurdles to the delivery of biomacromolecules with special emphasis on siRNA as well as the delivery of antisense oligos in multiple pulmonary diseases, particularly focusing on lung cancer. Also, the challenges posed to such delivery and possible solutions have been highlighted.
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Gupta P, Neupane YR, Parvez S, Kohli K. Recent advances in targeted nanotherapeutic approaches for breast cancer management. Nanomedicine (Lond) 2021; 16:2605-2631. [PMID: 34854336 DOI: 10.2217/nnm-2021-0281] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most commonly occurring tumor disease worldwide. Breast cancer is currently managed by conventional chemotherapy, which is inadequate in curbing this heterogeneous disease and results in off-site toxic effects, suggesting effective treatment approaches with better therapeutic profiles are needed. This review, therefore, focuses on the recent advancements in delivering therapeutics to the target site using passive and/or active targeted nanodrug-delivery systems to ameliorate endolysosomal escape. In addition, recent strategies in targeting breast cancer stem cells are discussed. The role of naturally cell-secreted nanovesicles (exosomes) in the management of triple-negative breast cancer is also discussed.
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Affiliation(s)
- Priya Gupta
- Department of Pharmaceutics, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India
| | - Yub Raj Neupane
- Department of Pharmacy, National University of Singapore, Singapore, 117559
| | - Suhel Parvez
- Department of Toxicology, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Kanchan Kohli
- Department of Pharmaceutics, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India.,Lloyd Institute of Management & Technology (Pharm.), Plot No. 11, Knowledge Park-II, Greater Noida, 201308, Uttar Pradesh, India
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Cao L, Zhu YQ, Wu ZX, Wang GX, Cheng HW. Engineering nanotheranostic strategies for liver cancer. World J Gastrointest Oncol 2021; 13:1213-1228. [PMID: 34721763 PMCID: PMC8529922 DOI: 10.4251/wjgo.v13.i10.1213] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 06/28/2021] [Accepted: 08/12/2021] [Indexed: 02/06/2023] Open
Abstract
The incidence and mortality of hepatocellular carcinoma have continued to increase over the last few years, and the medicine-based outlook of patients is poor. Given great ideas from the development of nanotechnology in medicine, especially the advantages in the treatments of liver cancer. Some engineering nanoparticles with active targeting, ligand modification, and passive targeting capacity achieve efficient drug delivery to tumor cells. In addition, the behavior of drug release is also applied to the drug loading nanosystem based on the tumor microenvironment. Considering clinical use of local treatment of liver cancer, in situ drug delivery of nanogels is also fully studied in orthotopic chemotherapy, radiotherapy, and ablation therapy. Furthermore, novel therapies including gene therapy, phototherapy, and immunotherapy are also applied as combined therapy for liver cancer. Engineering nonviral polymers to function as gene delivery vectors with increased efficiency and specificity, and strategies of co-delivery of therapeutic genes and drugs show great therapeutic effect against liver tumors, including drug-resistant tumors. Phototherapy is also applied in surgical procedures, chemotherapy, and immunotherapy. Combination strategies significantly enhance therapeutic effects and decrease side effects. Overall, the application of nanotechnology could bring a revolutionary change to the current treatment of liver cancer.
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Affiliation(s)
- Lei Cao
- Department of Pathology, Quanzhou Women's and Children's Hospital, Quanzhou 362000, Fujian Province, China
| | - Yu-Qin Zhu
- Department of Pathology, Quanzhou Women's and Children's Hospital, Quanzhou 362000, Fujian Province, China
| | - Zhi-Xian Wu
- Department of Hepatobiliary Disease, The 900th Hospital of the People’s Liberation Army Joint Service Support Force, Fuzhou 350025, Fujian Province, China
| | - Gao-Xiong Wang
- Department of Pathology, Quanzhou Women's and Children's Hospital, Quanzhou 362000, Fujian Province, China
| | - Hong-Wei Cheng
- School of Public Health, Xiamen University, Xiamen 361002, Fujian Province, China
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Li L, Zhang P, Li C, Guo Y, Sun K. In vitro/vivo antitumor study of modified-chitosan/carboxymethyl chitosan "boosted" charge-reversal nanoformulation. Carbohydr Polym 2021; 269:118268. [PMID: 34294300 DOI: 10.1016/j.carbpol.2021.118268] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/12/2021] [Accepted: 05/26/2021] [Indexed: 12/31/2022]
Abstract
Major obstacles in the development of nanoformulations as efficient drug delivery systems are the rapid clearance from blood circulation and lysosomal entrapment. To overcome these problems, a polysaccharide-based core-shell type charge-switchable nanoformulation (CS-LA-DMMA/CMCS/PAMAM@DOX) is constructed to improve antitumor efficacy of DOX. By applying carboxymethyl chitosan (CMCS) as bridge polymer and negatively charged chitosan-derivative as outer shell, the stability and pH-sensitivity of this nanoformulation is promisingly enhanced. Furthermore, the positively charged PAMAM@DOX could escape from lysosomes via "proton sponge effect" and "cationic-anionic interaction with lysosome membranes". Admirable cellular uptake and high apoptosis/necrosis rate were detected in this study. In vitro assays demonstrate that the CS-LA-DMMA/CMCS/PAMAM@DOX was internalized into HepG2 cells predominantly via the clathrin-mediated endocytosis pathway. Excitingly, in vivo studies showed that high accumulation of CS-LA-DMMA/CMCS/PAMAM@DOX in tumor tissue led to enhanced tumor inhibition. Compared with free DOX, the tumor inhibition rate of nanoformulation was improved up to 226%.
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Affiliation(s)
- Lin Li
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, PR China
| | - Peng Zhang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, PR China.
| | - Congcong Li
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, PR China
| | - Yan Guo
- Department of Development Planning & Discipline Construction, Yantai University, Yantai 264005, PR China
| | - Kaoxiang Sun
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, PR China; State Key Laboratory of Long-Acting and Targeting Drug Delivery System, Shandong Luye Pharmaceutical Co., Ltd, Yantai 264003, PR China.
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Zhang X, Lin ZI, Yang J, Liu GL, Hu Z, Huang H, Li X, Liu Q, Ma M, Xu Z, Xu G, Yong KT, Tsai WC, Tsai TH, Ko BT, Chen CK, Yang C. Carbon Dioxide-Derived Biodegradable and Cationic Polycarbonates as a New siRNA Carrier for Gene Therapy in Pancreatic Cancer. NANOMATERIALS 2021; 11:nano11092312. [PMID: 34578632 PMCID: PMC8472555 DOI: 10.3390/nano11092312] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/18/2021] [Accepted: 09/01/2021] [Indexed: 12/15/2022]
Abstract
Pancreatic cancer is an aggressive malignancy associated with poor prognosis and a high tendency in developing infiltration and metastasis. K-ras mutation is a major genetic disorder in pancreatic cancer patient. RNAi-based therapies can be employed for combating pancreatic cancer by silencing K-ras gene expression. However, the clinical application of RNAi technology is appreciably limited by the lack of a proper siRNA delivery system. To tackle this hurdle, cationic poly (cyclohexene carbonate) s (CPCHCs) using widely sourced CO2 as the monomer are subtly synthesized via ring-opening copolymerization (ROCOP) and thiol-ene functionalization. The developed CPCHCs could effectively encapsulate therapeutic siRNA to form CPCHC/siRNA nanoplexes (NPs). Serving as a siRNA carrier, CPCHC possesses biodegradability, negligible cytotoxicity, and high transfection efficiency. In vitro study shows that CPCHCs are capable of effectively protecting siRNA from being degraded by RNase and promoting a sustained endosomal escape of siRNA. After treatment with CPCHC/siRNA NPs, the K-ras gene expression in both pancreatic cancer cell line (PANC-1 and MiaPaCa-2) are significantly down-regulated. Subsequently, the cell growth and migration are considerably inhibited, and the treated cells are induced into cell apoptotic program. These results demonstrate the promising potential of CPCHC-mediated siRNA therapies in pancreatic cancer treatment.
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Affiliation(s)
- Xinmeng Zhang
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518060, China; (X.Z.); (J.Y.); (Z.H.); (H.H.); (X.L.); (Q.L.); (M.M.); (Z.X.); (G.X.)
| | - Zheng-Ian Lin
- Polymeric Biomaterials Laboratory, Department of Materials and Optoelectronic Science, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan;
| | - Jingyu Yang
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518060, China; (X.Z.); (J.Y.); (Z.H.); (H.H.); (X.L.); (Q.L.); (M.M.); (Z.X.); (G.X.)
| | - Guan-Lin Liu
- Department of Chemistry, National Chung Hsing University, Taichung 402, Taiwan;
| | - Zulu Hu
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518060, China; (X.Z.); (J.Y.); (Z.H.); (H.H.); (X.L.); (Q.L.); (M.M.); (Z.X.); (G.X.)
| | - Haoqiang Huang
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518060, China; (X.Z.); (J.Y.); (Z.H.); (H.H.); (X.L.); (Q.L.); (M.M.); (Z.X.); (G.X.)
| | - Xiang Li
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518060, China; (X.Z.); (J.Y.); (Z.H.); (H.H.); (X.L.); (Q.L.); (M.M.); (Z.X.); (G.X.)
| | - Qiqi Liu
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518060, China; (X.Z.); (J.Y.); (Z.H.); (H.H.); (X.L.); (Q.L.); (M.M.); (Z.X.); (G.X.)
| | - Mingze Ma
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518060, China; (X.Z.); (J.Y.); (Z.H.); (H.H.); (X.L.); (Q.L.); (M.M.); (Z.X.); (G.X.)
- Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen 518055, China
| | - Zhourui Xu
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518060, China; (X.Z.); (J.Y.); (Z.H.); (H.H.); (X.L.); (Q.L.); (M.M.); (Z.X.); (G.X.)
| | - Gaixia Xu
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518060, China; (X.Z.); (J.Y.); (Z.H.); (H.H.); (X.L.); (Q.L.); (M.M.); (Z.X.); (G.X.)
| | - Ken-Tye Yong
- School of Biomedical Engineering, The University of Sydney, Sydney, NSW 2006, Australia;
- The University of Sydney Nano Institute, The University of Sydney, Sydney, NSW 2006, Australia
| | - Wei-Chung Tsai
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan; (W.-C.T.); (T.-H.T.)
| | - Tzu-Hsien Tsai
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan; (W.-C.T.); (T.-H.T.)
| | - Bao-Tsan Ko
- Department of Chemistry, National Chung Hsing University, Taichung 402, Taiwan;
- Correspondence: (B.-T.K.); (C.-K.C.); (C.Y.); Tel.: +886-4-2284-0411 (ext. 715) (B.-T.K.); +886-7-525-2000 (ext. 4060) (C.-K.C.); +86-0755-2693-2683 (C.Y.)
| | - Chih-Kuang Chen
- Polymeric Biomaterials Laboratory, Department of Materials and Optoelectronic Science, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan;
- Correspondence: (B.-T.K.); (C.-K.C.); (C.Y.); Tel.: +886-4-2284-0411 (ext. 715) (B.-T.K.); +886-7-525-2000 (ext. 4060) (C.-K.C.); +86-0755-2693-2683 (C.Y.)
| | - Chengbin Yang
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518060, China; (X.Z.); (J.Y.); (Z.H.); (H.H.); (X.L.); (Q.L.); (M.M.); (Z.X.); (G.X.)
- Correspondence: (B.-T.K.); (C.-K.C.); (C.Y.); Tel.: +886-4-2284-0411 (ext. 715) (B.-T.K.); +886-7-525-2000 (ext. 4060) (C.-K.C.); +86-0755-2693-2683 (C.Y.)
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48
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Cao S, Lin C, Li X, Liang Y, Saw PE. TME-Responsive Multistage Nanoplatform for siRNA Delivery and Effective Cancer Therapy. Int J Nanomedicine 2021; 16:5909-5921. [PMID: 34475756 PMCID: PMC8407678 DOI: 10.2147/ijn.s322901] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 08/09/2021] [Indexed: 12/12/2022] Open
Abstract
Since the discovery of RNA interference (RNAi), RNAi technology has rapidly developed into an efficient tool for post-transcriptional gene silencing, which has been widely used for clinical or preclinical treatment of various diseases including cancer. Small interfering RNA (siRNA) is the effector molecule of RNAi technology. However, as polyanionic macromolecules, naked siRNAs have a short circulatory half-life (<15 min) and is rapidly cleared by renal filtration, which greatly hinders their clinical application. Furthermore, the anionic and macromolecular characteristics of naked siRNAs impede their readiness to cross the cell membrane and therefore delivery vehicles are required to facilitate the cellular uptake and cytosolic delivery of naked siRNAs. In the past decade, numerous nanoparticles (NPs) such as liposomes have been employed for in vivo siRNA delivery, which have achieved favorable therapeutic outcomes in clinical disease treatment. In particular, because tumor microenvironment (TME) or tumor cells show several distinguishing biological/endogenous factors (eg, pH, enzymes, redox, and hypoxia) compared to normal tissues or cells, much attention has recently paid to design and construct TME-responsive NPs for multistaged siRNA delivery, which can respond to biological stimuli to achieve efficient in vivo gene silencing and better anticancer effect. In this review, we summarize recent advances in TME-responsive siRNA delivery systems, especially multistage delivery NPs, and discuss their design principles, functions, effects, and prospects.
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Affiliation(s)
- Shuwen Cao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.,RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Chunhao Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.,RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Xiuling Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.,RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Yixia Liang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.,RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Phei Er Saw
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.,RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
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Yu W, Lin R, He X, Yang X, Zhang H, Hu C, Liu R, Huang Y, Qin Y, Gao H. Self-propelled nanomotor reconstructs tumor microenvironment through synergistic hypoxia alleviation and glycolysis inhibition for promoted anti-metastasis. Acta Pharm Sin B 2021; 11:2924-2936. [PMID: 34589405 PMCID: PMC8463459 DOI: 10.1016/j.apsb.2021.04.006] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/11/2021] [Accepted: 03/29/2021] [Indexed: 12/18/2022] Open
Abstract
Solid tumors always exhibit local hypoxia, resulting in the high metastasis and inertness to chemotherapy. Reconstruction of hypoxic tumor microenvironment (TME) is considered a potential therapy compared to directly killing tumor cells. However, the insufficient oxygen delivery to deep tumor and the confronting “Warburg effect” compromise the efficacy of hypoxia alleviation. Herein, we construct a cascade enzyme-powered nanomotor (NM-si), which can simultaneously provide sufficient oxygen in deep tumor and inhibit the aerobic glycolysis to potentiate anti-metastasis in chemotherapy. Catalase (Cat) and glucose oxidase (GOx) are co-adsorbed on our previously reported CAuNCs@HA to form self-propelled nanomotor (NM), with hexokinase-2 (HK-2) siRNA further condensed (NM-si). The persistent production of oxygen bubbles from the cascade enzymatic reaction propels NM-si to move forward autonomously and in a controllable direction along H2O2 gradient towards deep tumor, with hypoxia successfully alleviated in the meantime. The autonomous movement also facilitates NM-si with lysosome escaping for efficient HK-2 knockdown to inhibit glycolysis. In vivo results demonstrated a promising anti-metastasis effect of commercially available albumin-bound paclitaxel (PTX@HSA) after pre-treated with NM-si for TME reconstruction. This cascade enzyme-powered nanomotor provides a potential prospect in reversing the hypoxic TME and metabolic pathway for reinforced anti-metastasis of chemotherapy.
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Affiliation(s)
- Wenqi Yu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Ruyi Lin
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Xueqin He
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Xiaotong Yang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Huilin Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Chuan Hu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Rui Liu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yuan Huang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yi Qin
- Department of Orthopedics, Zhuhai Hospital, Jinan University, Zhuhai People's Hospital, Guangdong 519000, China
- Corresponding authors.
| | - Huile Gao
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
- Corresponding authors.
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50
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Sun J, Ogunnaike EA, Jiang X, Chen Z. Nanotechnology lights up the antitumor potency by combining chemotherapy with siRNA. J Mater Chem B 2021; 9:7302-7317. [PMID: 34382987 DOI: 10.1039/d1tb01379c] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Nanotechnology-based combination anticancer therapy offers novel approaches to overcome the limitations of single-agent administration. The emerging siRNA technology combined with chemotherapy has shown considerable promise in anticancer therapy. There are three main challenges in the fabrication of siRNA/chemotherapeutic drug co-loaded nanovectors: adequate cargo protection, precise targeted delivery, and site-specific cargo release. This review presents a summary of the nanosystems that have recently been developed for co-delivering siRNA and chemotherapeutic drugs. Their combined therapeutic effects are also discussed.
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Affiliation(s)
- Jian Sun
- College of Nursing, Nanjing University of Chinese Medicine, Nanjing, P. R. China.
| | - Edikan Archibong Ogunnaike
- Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Xing Jiang
- College of Nursing, Nanjing University of Chinese Medicine, Nanjing, P. R. China.
| | - Zhaowei Chen
- Institute of Food Safety and Environment Monitoring, College of Chemistry, Fuzhou University, Fuzhou, P. R. China. and College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China.
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