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Tan K, Zhang H, Yang J, Wang H, Li Y, Ding G, Gu P, Yang S, Li J, Fan X. Organelle-oriented nanomedicines in tumor therapy: Targeting, escaping, or collaborating? Bioact Mater 2025; 49:291-339. [PMID: 40161442 PMCID: PMC11953998 DOI: 10.1016/j.bioactmat.2025.02.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 02/19/2025] [Accepted: 02/25/2025] [Indexed: 04/02/2025] Open
Abstract
Precise tumor therapy is essential for improving treatment specificity, enhancing efficacy, and minimizing side effects. Targeting organelles is a key strategy for achieving this goal and is a frontier research area attracting a considerable amount of attention. The concept of organelle targeting has a significant effect on the structural design of the nanodrugs employed. Most notably, the intricate interactions among different organelles in a tumor cell essentially create a unified system. Unfortunately, this aspect might have been somewhat overlooked when existing organelle-targeting nanodrugs were designed. In this review, we underscore the synergistic relationship among the various organelles and advocate for a holistic view of organelle-targeting design. Through the integration of biology and material science, recent advancements in organelle targeting, escaping, and collaborating are consolidated to offer fresh perspectives for the development of antitumor nanomedicines.
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Affiliation(s)
- Kexin Tan
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, and Center for Basic Medical Research and Innovation in Visual System Diseases of Ministry of Education, Shanghai, 200011, PR China
| | - Haiyang Zhang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, and Center for Basic Medical Research and Innovation in Visual System Diseases of Ministry of Education, Shanghai, 200011, PR China
| | - Jianyuan Yang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, and Center for Basic Medical Research and Innovation in Visual System Diseases of Ministry of Education, Shanghai, 200011, PR China
| | - Hang Wang
- National Key Laboratory of Materials for Integrated Circuits, Joint Laboratory of Graphene Materials and Applications, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, PR China
| | - Yongqiang Li
- National Key Laboratory of Materials for Integrated Circuits, Joint Laboratory of Graphene Materials and Applications, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, PR China
| | - Guqiao Ding
- National Key Laboratory of Materials for Integrated Circuits, Joint Laboratory of Graphene Materials and Applications, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, PR China
| | - Ping Gu
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, and Center for Basic Medical Research and Innovation in Visual System Diseases of Ministry of Education, Shanghai, 200011, PR China
| | - Siwei Yang
- National Key Laboratory of Materials for Integrated Circuits, Joint Laboratory of Graphene Materials and Applications, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, PR China
| | - Jipeng Li
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, and Center for Basic Medical Research and Innovation in Visual System Diseases of Ministry of Education, Shanghai, 200011, PR China
| | - Xianqun Fan
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, and Center for Basic Medical Research and Innovation in Visual System Diseases of Ministry of Education, Shanghai, 200011, PR China
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Obeidat WM, Lahlouh IK. Chitosan Nanoparticles: Approaches to Preparation, Key Properties, Drug Delivery Systems, and Developments in Therapeutic Efficacy. AAPS PharmSciTech 2025; 26:108. [PMID: 40244367 DOI: 10.1208/s12249-025-03100-z] [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: 12/31/2024] [Accepted: 03/27/2025] [Indexed: 04/18/2025] Open
Abstract
The integration of nanotechnology into drug delivery systems holds great promise for enhancing pharmaceutical effectiveness. This approach enables precise targeting, controlled release, improved patient compliance, reduced side effects, and increased bioavailability. Nanoparticles are vital for transporting biomolecules-such as proteins, enzymes, genes, and vaccines-through various administration routes, including oral, intranasal, vaginal, buccal, and pulmonary. Among biodegradable polymers, chitosan, a linear polysaccharide derived from chitin, stands out due to its biocompatibility, safety, biodegradability, mucoadhesive properties, and ability to enhance permeation. Its cationic nature supports strong molecular interactions and provides antimicrobial, anti-inflammatory, and hemostatic benefits. However, its solubility, influenced by pH and ionic sensitivity, poses challenges requiring effective solutions. This review explores chitosan, its modified derivatives and chitosan nanoparticles mainly, focusing on nanoparticles physicochemical properties, drug release mechanisms, preparation methods, and factors affecting their mean hydrodynamic diameter (particle size). It highlights their application in drug delivery systems and disease treatments across various routes. Key considerations include drug loading capacity, zeta potential, and stability, alongside the impact of molecular weight, degree of deacetylation, and drug solubility on nanoparticle properties. Recent advancements and studies underscore chitosan's potential, emphasizing its modified derivatives'versatility in improving therapeutic outcomes.
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Affiliation(s)
- Wasfy M Obeidat
- Jordan University of Science and Technology, 3030, Irbid, 22110, Jordan.
| | - Ishraq K Lahlouh
- Jordan University of Science and Technology, 3030, Irbid, 22110, Jordan
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Dejeu IL, Vicaș LG, Marian E, Ganea M, Frenț OD, Maghiar PB, Bodea FI, Dejeu GE. Innovative Approaches to Enhancing the Biomedical Properties of Liposomes. Pharmaceutics 2024; 16:1525. [PMID: 39771504 PMCID: PMC11728823 DOI: 10.3390/pharmaceutics16121525] [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: 10/13/2024] [Revised: 10/31/2024] [Accepted: 11/25/2024] [Indexed: 01/16/2025] Open
Abstract
Liposomes represent a promising class of drug delivery systems that enhance the therapeutic efficacy and safety of various pharmaceutical agents. Also, they offer numerous advantages compared to traditional drug delivery methods, including targeted delivery to specific sites, controlled release, and fewer side effects. This review meticulously examines the methodologies employed in the preparation and characterization of liposomal formulations. With the rising incidence of adverse drug reactions, there is a pressing need for innovative delivery strategies that prioritize selectivity, specificity, and safety. Nanomedicine promises to revolutionize diagnostics and treatments, addressing current limitations and improving disease management, including cancer, which remains a major global health challenge. This paper aims to conduct a comprehensive study on the interest of biomedical research regarding nanotechnology and its implications for further applications.
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Affiliation(s)
- Ioana Lavinia Dejeu
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 29 Nicolae Jiga Street, 410028 Oradea, Romania; (I.L.D.); (E.M.); (M.G.); (O.D.F.)
| | - Laura Grațiela Vicaș
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 29 Nicolae Jiga Street, 410028 Oradea, Romania; (I.L.D.); (E.M.); (M.G.); (O.D.F.)
| | - Eleonora Marian
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 29 Nicolae Jiga Street, 410028 Oradea, Romania; (I.L.D.); (E.M.); (M.G.); (O.D.F.)
| | - Mariana Ganea
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 29 Nicolae Jiga Street, 410028 Oradea, Romania; (I.L.D.); (E.M.); (M.G.); (O.D.F.)
| | - Olimpia Daniela Frenț
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 29 Nicolae Jiga Street, 410028 Oradea, Romania; (I.L.D.); (E.M.); (M.G.); (O.D.F.)
| | - Paula Bianca Maghiar
- Doctoral School of Biomedical Science, University of Oradea, 1 University Street, 410087 Oradea, Romania; (P.B.M.); (F.I.B.)
| | - Flaviu Ionut Bodea
- Doctoral School of Biomedical Science, University of Oradea, 1 University Street, 410087 Oradea, Romania; (P.B.M.); (F.I.B.)
| | - George Emanuiel Dejeu
- Department of Surgical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 10 Piata 1 Decembrie Street, 410073 Oradea, Romania;
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Wang Y, Liu Y, Long M, Dong Y, Li L, Zhou X. Nanoparticles target M2 macrophages to silence kallikrein-related peptidase 12 for the treatment of tuberculosis and drug-resistant tuberculosis. Acta Biomater 2024; 188:358-373. [PMID: 39305944 DOI: 10.1016/j.actbio.2024.09.026] [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: 05/14/2024] [Revised: 09/08/2024] [Accepted: 09/16/2024] [Indexed: 10/03/2024]
Abstract
Matrix metalloproteinases (MMPs) are involved in the breakdown of lung extracellular matrix and the consequent release of Mycobacterium tuberculosis into the airways. Recent studies indicate that kallikrein-related peptidase 12 (KLK12) regulate MMP-1 and MMP-9, suggesting that targeting the KLK12 gene could be a promising tuberculosis (TB) treatment. To maximise therapeutic potential, this strategy of silencing KLK12 needs to be delivered to the pathogenic cell population while preserving the immunoprotective and tissue homeostatic functions of other lung macrophages. Our research found that KLK12 is highly expressed in M2 macrophages, leading us to design mannose-based bovine serum albumin nanoparticles (MBNPs) for delivering siRNA to silence KLK12 in these cells. The results of in vitro experiments showed that MBNPs could accurately enter M2 macrophages and sustainably release KLK12-siRNA with the help of mannose and mannose receptor targeting. The results of the in vivo experiments showed that MBNPs could reach the lungs within 1 h after intraperitoneal injection and peaked at 6 h. MBNPs increased collagen fibre content in the lungs by decreasing the levels of KLK12/MMPs thereby limiting the progression of TB. Importantly, MBNPs provided greater alleviation of pulmonary TB symptoms and reduced bacterial load in both TB and drug-resistant TB models. These findings provide an alternative and effective option for the treatment of TB, especially when drug resistance occurs. STATEMENT OF SIGNIFICANCE: RNA interference using small interfering RNA (siRNA) can target various genes and has potential for treating diseases such as tuberculosis (TB). However, siRNAs are unstable in the blood and within cells. This study presents bovine serum albumin nanoparticles encapsulating KLK12-siRNA (BNPs) synthesized via desolvation. A mannose layer was added (MBNPs) to target mannose receptors on M2 macrophages, facilitating endocytosis. The low pH-responsive MBNPs enhance lysosomal escape for siRNA delivery, downregulating the KLK12 pathway. Tests confirmed that MBNPs effectively inhibited Mycobacterium bovis proliferation, reduced granulomas, and decreased inflammation in a mouse model. This research aims to reduce antibiotic use, shorten treatment duration, and provide a novel TB treatment option.
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Affiliation(s)
- Yuanzhi Wang
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Yiduo Liu
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Meizhen Long
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Yuhui Dong
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Lin Li
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Xiangmei Zhou
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
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Mainuddin, Kumar A, Ratnesh RK, Singh J, Dumoga S, Sharma N, Jindal A. Physical characterization and bioavailability assessment of 5-fluorouracil-based nanostructured lipid carrier (NLC): In vitro drug release, Hemolysis, and permeability modulation. Med Oncol 2024; 41:95. [PMID: 38526657 DOI: 10.1007/s12032-024-02319-3] [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: 12/13/2023] [Accepted: 01/31/2024] [Indexed: 03/27/2024]
Abstract
5-Fluorouracil (5-FU) is an anticancer agent belonging to BCS Class III that exhibits poor release characteristics and low retention in the biological system. The main objective of this investigation was to develop a drug delivery system, i.e., Nanostructure Lipid Carriers (NLCs) loaded with 5-FU to prolong its biological retention through 5-FU-loaded NLCs (5-FUNLC) were designed to manipulate physicochemical characteristics and assessment of in vitro and in vivo performance. The developed NLCs underwent comprehensive characterization, including assessments for particle size, zeta potential, morphological evaluation, and FT-IR spectroscopy. Additionally, specific evaluations were conducted for 5-FUNLCs, encompassing analyses for encapsulation efficiency of the drug, release characteristics in PBS at pH 6.8, and stability study. The lipophilic character of 5-FUNLC was confirmed through the measurement of the partition coefficient (log P). 5-FUNLCs were observed as spherical-shaped particles with a mean size of 300 ± 25 nm. The encapsulation efficiency was determined to be 89%, indicating effective drug loading within the NLCs. Furthermore, these NLCs exhibited a sustained release nature lasting up to 3-4 h, indicating their potential for controlled drug release over time. Lipid components were biocompatible with the 5-FU to determine thermal transition temperature and show good stability for 30 days. Additionally, an in vitro hemolysis study that confirmed the system did not cause any destruction to the RBCs during intravenous administration. The drug's gut permeability was assessed utilizing the optimized 5-FUNLC (F2) in comparison to 5-FU through the intestine or gut sac model (in the apical to basolateral direction, A → B). The permeability coefficient was measured as 4.91 × 10-5 cm/h with a significant difference. Additionally, the antioxidant potential of the NLCs was demonstrated through the DPPH method. The NLCs' performance was further assessed through in vivo pharmacokinetic studies on Wistar Rats, resulting in a 1.5-fold enhancement in their activity compared to free 5-FU. These NLCs offer improved drug solubility and sustained release, which collectively contribute to enhanced therapeutic outcomes and modulate bioavailability. The study concludes by highlighting the potential of 5-FUNLC as an innovative and efficient drug delivery system. The findings suggest that further preclinical investigations are warranted, indicating a promising avenue for the development of more effective and well-tolerated treatments for cancer.
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Affiliation(s)
- Mainuddin
- Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, NH 58 Near Baghpat Bypass, Meerut, UP, 250005, India
- Department of Pharmaceutics, Amity Institute of Pharmacy, Amity University, Sector 125, Noida, Uttar Pradesh, 201301, India
| | - Anoop Kumar
- Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, NH 58 Near Baghpat Bypass, Meerut, UP, 250005, India
| | - Ratneshwar Kumar Ratnesh
- Department of Electronics and Communication Engineering, Meerut Institute of Engineering and Technology, NH 58 Near Baghpat Bypass, Meerut, UP, 250005, India.
| | - Jay Singh
- Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, UP, 221005, India
| | - Shweta Dumoga
- Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, NH 58 Near Baghpat Bypass, Meerut, UP, 250005, India
| | - Nitin Sharma
- Department of Pharmaceutics, Amity Institute of Pharmacy, Amity University, Sector 125, Noida, Uttar Pradesh, 201301, India
| | - Amulya Jindal
- Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, NH 58 Near Baghpat Bypass, Meerut, UP, 250005, India
- Department of Pharmacy, Meerut Institute of Technology, NH-58 Near Partapur Bypass, Meerut, UP, 250005, India
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Kara G, Ozpolat B. SPIONs: Superparamagnetic iron oxide-based nanoparticles for the delivery of microRNAi-therapeutics in cancer. Biomed Microdevices 2024; 26:16. [PMID: 38324228 DOI: 10.1007/s10544-024-00698-y] [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] [Accepted: 01/05/2024] [Indexed: 02/08/2024]
Abstract
Non-coding RNA (ncRNA)-based therapeutics that induce RNA interference (RNAi), such as microRNAs (miRNAs), have drawn considerable attention as a novel class of targeted cancer therapeutics because of their capacity to specifically target oncogenes/protooncogenes that regulate key signaling pathways involved in carcinogenesis, tumor growth and progression, metastasis, cell survival, proliferation, angiogenesis, and drug resistance. However, clinical translation of miRNA-based therapeutics, in particular, has been challenging due to the ineffective delivery of ncRNA molecules into tumors and their uptake into cancer cells. Recently, superparamagnetic iron oxide-based nanoparticles (SPIONs) have emerged as highly effective and efficient for the delivery of therapeutic RNAs to malignant tissues, as well as theranostic (therapy and diagnostic) applications, due to their excellent biocompatibility, magnetic responsiveness, broad functional surface modification, safety, and biodistribution profiles. This review highlights recent advances in the use of SPIONs for the delivery of ncRNA-based therapeutics with an emphasis on their synthesis and coating strategies. Moreover, the advantages and current limitations of SPIONs and their future perspectives are discussed.
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Affiliation(s)
- Goknur Kara
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, 77030, USA
| | - Bulent Ozpolat
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, 77030, USA.
- Houston Methodist Neal Cancer Center, Houston, TX, 77030, USA.
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7
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Zhang B, Huang S, Meng Y, Chen W. Gold nanoparticles (AuNPs) can rapidly deliver artificial microRNA (AmiRNA)-ATG6 to silence ATG6 expression in Arabidopsis. PLANT CELL REPORTS 2023:10.1007/s00299-023-03026-5. [PMID: 37160448 DOI: 10.1007/s00299-023-03026-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 04/29/2023] [Indexed: 05/11/2023]
Abstract
KEY MESSAGE We establish a fast and efficient transient silencing system that facilitates functional studies of some genes, whose knockout leads to plant lethality. In plants, the generation of loss-of-function mutants is crucial for studying gene function. Artificial microRNA (AmiRNA) technology is a more targeted and effective tool for gene silencing. Gold nanoparticles (AuNPs) can bind nucleic acids and deliver them into animal cells. Here, AuNPs are used in combination with AmiRNA technology in plants. We found that AmiRNA-autophagy-related proteins (ATG6) can be delivered to cells by AuNPs to achieve the effect of ATG6 silencing. It is worth noting that on the 10th day there is still a silencing effect. Similar to the atg5 lines, silencing of ATG6 significantly reduced plant resistance to Pseudomonas syringae pv.maculicola (Psm) ES4326/AvrRpt2. Interestingly, ATG6 silencing and ATG5 mutation in NPR1-GFP (nonexpressor of pathogenesis-related genes) lines significantly reduced plant resistance to Psm ES4326/AvrRpt2, suggesting that autophagy is also involved in NPR1-regulated plant immune responses. In summary, we establish a fast and efficient transient silencing system that facilitates functional studies of some genes, whose knockout leads to plant lethality.
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Affiliation(s)
- Baihong Zhang
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
| | - Shuqin Huang
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
| | - Yixuan Meng
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
| | - Wenli Chen
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
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Huang HJ, Huang SY, Wang TH, Lin TY, Huang NC, Shih O, Jeng US, Chu CY, Chiang WH. Clay nanosheets simultaneously intercalated and stabilized by PEGylated chitosan as drug delivery vehicles for cancer chemotherapy. Carbohydr Polym 2023; 302:120390. [PMID: 36604068 DOI: 10.1016/j.carbpol.2022.120390] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 11/16/2022] [Accepted: 11/20/2022] [Indexed: 11/27/2022]
Abstract
Montmorillonite (MMT) has been frequently utilized as drug vehicles due to its high specific surface area, excellent cation exchange capacity and biocompatibility. However, the significant flocculation of MMT under physiological condition restricted its application to drug delivery. To conquer this problem, the graft-type PEGylated chitosan (PEG-CS) adducts were synthesized as intercalator to stabilize MMT dispersion. Through electrostatic attraction between the chitosan and MMT, the PEG-CS adducts were adsorbed on MMT surfaces and intercalated into MMT. The resulting PEG-CS/MMT nanosheets possessed PEG-rich surfaces, thus showing outstanding dispersion in serum-containing environment. Moreover, the physicochemical characterization revealed that the increased mass ratio of PEG-CS to MMT led to the microstructure transition of PEG-CS/MMT nanosheets from multilayered to exfoliated structure. Interestingly, the PEG-CS/MMT nanosheets with mass ratio of 8.0 in freeze-dried state exhibited a hierarchical lamellar structure organized by the intercalated MMT bundles and unintercalated PEG-CS domains. Notably, the multilayered PEG-CS/MMT nanosheets showed the capability of loading doxorubicin (DOX) superior to the exfoliated counterparts. Importantly, the DOX@PEG-CS/MMT nanosheets endocytosed by TRAMP-C1 cells liberated the drug progressively within acidic organelles, thereby eliciting cell apoptosis. This work provides a new strategy of achieving the controllable dispersion stability of MMT nanoclays towards application potentials in drug delivery.
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Affiliation(s)
- Hsuan-Jung Huang
- Department of Chemical Engineering, National Chung Hsing University, Taichung 402, Taiwan
| | - Shih-Yu Huang
- Department of Chemical Engineering, National Chung Hsing University, Taichung 402, Taiwan
| | - Tzu-Hao Wang
- Department of Chemical Engineering, National Chung Hsing University, Taichung 402, Taiwan
| | - Tzu-Yun Lin
- Department of Chemical Engineering, National Chung Hsing University, Taichung 402, Taiwan
| | - Nan-Ching Huang
- Department of Chemical Engineering, National Chung Hsing University, Taichung 402, Taiwan
| | - Orion Shih
- National Synchrotron Radiation Research Center, Hsinchu 30076, Taiwan
| | - U-Ser Jeng
- National Synchrotron Radiation Research Center, Hsinchu 30076, Taiwan
| | - Che-Yi Chu
- Department of Chemical Engineering, National Chung Hsing University, Taichung 402, Taiwan.
| | - Wen-Hsuan Chiang
- Department of Chemical Engineering, National Chung Hsing University, Taichung 402, Taiwan.
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9
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Mehrabian A, Dadpour S, Mashreghi M, Zarqi J, Askarizadeh A, Badiee A, Arabi L, Moosavian SA, Jaafari MR. The comparison of biodistribution of glutathione PEGylated nanoliposomal doxorubicin formulations prepared by pre-insertion and post-insertion methods for brain delivery in normal mice. IET Nanobiotechnol 2023; 17:112-124. [PMID: 36594666 PMCID: PMC10116028 DOI: 10.1049/nbt2.12111] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 12/14/2022] [Accepted: 12/15/2022] [Indexed: 01/04/2023] Open
Abstract
Several obstacles limit the efficacy of brain tumour treatment, most notably the blood-brain barrier (BBB), which prevents the brain uptake of the majority of accessible medicines due to tight junctions. The presence of glutathione (GSH) receptors on the BBB surface has been demonstrated in numerous papers; consequently, products containing glutathione as a targeting ligand coupled with nanoliposomes are used to enhance drug delivery across the BBB. Here, the 5% pre-inserted PEG2000-GSH PEGylated liposomal doxorubicin was conducted according to 2B3-101 being tested in clinical trials. In addition, PEGylated nanoliposomal doxorubicin connected to the spacer-GSH targeting ligand (GSGGCE) and the PEG3400 was conducted using post-insertion method. Next, in vivo biodistribution of the produced formulations was tested on healthy mice to see if GSGGCE, as the targeted ligand, could cross the BBB compared to 5% pre-inserted PEG2000-GSH and Caelyx® . Compared to the pre-inserted formulation and Caelyx® , the post-inserted formulations' concentration was lower in the heart and higher in brain tissues, resulting in boosting the brain concentration of accumulated doxorubicin with fewer possible side effects, including cardiotoxicity. In comparison to the pre-insertion procedure, the post-insertion method is easier, faster, and more cost-effective. Moreover, employing PEG3400 and the post-insertion approach in the PEG3400-GSGGCE liposomal formulations was found to be effective in crossing the BBB.
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Affiliation(s)
- Amin Mehrabian
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saba Dadpour
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Nanotechnology Research Center, Student Research Committee, Faculty of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Mashreghi
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Javad Zarqi
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Anis Askarizadeh
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Badiee
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Leila Arabi
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyedeh Alia Moosavian
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Reza Jaafari
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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10
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Hoffmann M, Gerlach S, Hoffmann C, Richter N, Hersch N, Csiszár A, Merkel R, Hoffmann B. PEGylation and folic-acid functionalization of cationic lipoplexes-Improved nucleic acid transfer into cancer cells. Front Bioeng Biotechnol 2022; 10:1066887. [PMID: 36619382 PMCID: PMC9811411 DOI: 10.3389/fbioe.2022.1066887] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 12/06/2022] [Indexed: 12/24/2022] Open
Abstract
Efficient and reliable transfer of nucleic acids for therapy applications is a major challenge. Stabilization of lipo- and polyplexes has already been successfully achieved by PEGylation. This modification reduces the interaction with serum proteins and thus prevents the lipoplexes from being cleared by the reticuloendothelial system. Problematically, this stabilization of lipoplexes simultaneously leads to reduced transfer efficiencies compared to non-PEGylated complexes. However, this reduction in transfer efficiency can be used to advantage since additional modification of PEGylated lipoplexes with functional groups enables improved selective transfer into target cells. Cancer cells overexpress folate receptors because of a significantly increased need of folate due to high cell proliferation rates. Thus, additional folate functionalization of PEGylated lipoplexes improves uptake into cancer cells. We demonstrate herein that NHS coupling chemistries can be used to modify two commercially available transfection reagents (Fuse-It-DNA and Lipofectamine® 3000) with NHS-PEG-folate for increased uptake of nucleic acids into cancer cells. Lipoplex characterization and functional analysis in cultures of cancer- and healthy cells clearly demonstrate that functionalization of PEGylated lipoplexes offers a promising method to generate efficient, stable and selective nucleic acid transfer systems.
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Affiliation(s)
| | | | | | | | | | | | | | - Bernd Hoffmann
- Institute of Biological Information Processing, Mechanobiology (IBI-2), Research Center Juelich, Juelich, Germany
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11
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Jalil AR, Tobin MP, Discher DE. Suppressing or Enhancing Macrophage Engulfment through the Use of CD47 and Related Peptides. Bioconjug Chem 2022; 33:1989-1995. [PMID: 35316023 PMCID: PMC9990087 DOI: 10.1021/acs.bioconjchem.2c00019] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Foreign particles and microbes are rapidly cleared by macrophages in vivo, although many key aspects of uptake mechanisms remain unclear. "Self" cells express CD47 which functions as an anti-phagocytic ligand for SIRPα on macrophages, particularly when pro-phagocytic ligands such as antibodies are displayed in parallel. Here, we review CD47 and related "Self" peptides as modulators of macrophage uptake. Nanoparticles conjugated with either CD47 or peptides derived from its SIRPα binding site can suppress phagocytic uptake by macrophages in vitro and in vivo, with similar findings for CD47-displaying viruses. Drugs, dyes, and genes as payloads thus show increased delivery to targeted cells. On the other hand, CD47 expression by cancer cells enables such cells to evade macrophages and immune surveillance. This has motivated development of soluble antagonists to CD47-SIRPα, ranging from blocking antibodies in the clinic to synthetic peptides in preclinical models. CD47 and peptides are thus emerging as dual-use phagocytosis modulators against diseases.
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12
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Yan H, Zhang Y, Zhang Y, Li Y, Kong X, Liu D, Li J, Xi Y, Ji J, Ye L, Zhai G. A ROS-responsive biomimetic nano-platform for enhanced chemo-photodynamic-immunotherapy efficacy. Biomater Sci 2022; 10:6583-6600. [PMID: 36227002 DOI: 10.1039/d2bm01291j] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Due to the complex bloodstream components, tumor microenvironment and tumor heterogeneity, traditional nanoparticles have a limited effect (low drug delivery efficiency and poor penetration to the deeper tumor) on eradicating tumors. To solve these challenges, novel platelet membrane-coated nanoparticles (PCDD NPs) were constructed for combined chemo-photodynamic- and immunotherapy of melanoma. The platelet membrane imparted the PCDD nanoparticles with an excellent long circulation effect and tumor targeting ability, which solved the issues of low drug delivery efficiency. After reaching the tumor cells, it releases the drug-loaded CDD micelles, becoming positively charged and facilitating the deep penetration of tumors. Cytotoxic and apoptosis experiments showed that PCDD nanoparticles have the strongest tumor cell killing ability. Based on the excellent results in vitro, PCDD was used to assess anti-tumor and distal tumor inhibition in rat models. The results revealed that the PCDD combined PDT, immunotherapy and chemotherapy could not only inhibit the primary tumor growth (inhibition rate: 92.0%) but also suppress the distant tumor growth (inhibition rate: 90.7%) and lung metastasis, which is far more effective compared to the commercial Taxotere®. Exploration of the molecular mechanism showed that in vivo immune response induced an increase in positive immune responders, suppressed negative immune suppressors, and established an inflammatory tumor immune environment, leading to excellent results in tumor suppression and lung metastasis. In conclusion, this novel multifunctional PCDD nanoparticle is a promising platform for tumor combined chemotherapy, photodynamic therapy (PDT) and immunotherapy.
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Affiliation(s)
- Huixian Yan
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, P. R. China.
| | - Yanan Zhang
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, P. R. China.
| | - Yu Zhang
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, P. R. China.
| | - Yingying Li
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, P. R. China.
| | - Xinru Kong
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, P. R. China.
| | - Dongzhu Liu
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, P. R. China.
| | - Jin Li
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, P. R. China.
| | - Yanwei Xi
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, P. R. China.
| | - Jianbo Ji
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, P. R. China.
| | - Lei Ye
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, P. R. China.
| | - Guangxi Zhai
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, P. R. China.
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PEGylated Strontium Sulfite Nanoparticles with Spontaneously Formed Surface-Embedded Protein Corona Restrict Off-Target Distribution and Accelerate Breast Tumour-Selective Delivery of siRNA. J Funct Biomater 2022; 13:jfb13040211. [PMID: 36412852 PMCID: PMC9680366 DOI: 10.3390/jfb13040211] [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: 09/06/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022] Open
Abstract
As transporters of RNAi therapeutics in preclinical and clinical studies, the application of nanoparticles is often hindered by their susceptibility to opsonin-mediated clearance, poor biological stability, ineffectual targeting, and undesirable effects on healthy cells. Prolonging the blood circulation time while minimizing the off-target distribution and associated toxicity is indispensable for the establishment of a clinically viable delivery system for therapeutic small interfering RNAs (siRNAs). Herein, we report a scalable and straightforward approach to fabricate non-toxic and biodegradable pH-responsive strontium sulfite nanoparticles (SSNs) wrapped with a hydrophilic coating material, biotinylated PEG to lessen unforeseen biological interactions. Surface functionalization of SSNs with PEG led to the generation of small and uniformly distributed particles with a significant affinity towards siRNAs and augmented internalization into breast cancer cells. A triple quadrupole liquid chromatography-mass spectrometry (LC-MS) was deployed to identify the proteins entrapped onto the SSNs, with the help of SwissProt.Mus_musculus database. The results demonstrated the reduction of opsonin proteins adsorption owing to the stealth effect of PEG. The distribution of PEGylated SSNs in mice after 4 h and 24 h of intravenous administration in breast tumour-bearing mice was found to be significantly less to the organs of the reticuloendothelial system (RES) and augmented accumulation in the tumour region. The anti-EGFR siRNA-loaded PEG-SSNs exerted a significant inhibitory effect on tumour development in the murine breast cancer model without any significant toxicity to healthy tissues. Therefore, PEGylated SSNs open up a new avenue for tumour-selective efficient delivery of siRNAs in managing breast cancer.
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14
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Aram E, Moeni M, Abedizadeh R, Sabour D, Sadeghi-Abandansari H, Gardy J, Hassanpour A. Smart and Multi-Functional Magnetic Nanoparticles for Cancer Treatment Applications: Clinical Challenges and Future Prospects. NANOMATERIALS (BASEL, SWITZERLAND) 2022; 12:nano12203567. [PMID: 36296756 PMCID: PMC9611246 DOI: 10.3390/nano12203567] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/16/2022] [Accepted: 09/27/2022] [Indexed: 05/14/2023]
Abstract
Iron oxide nanoparticle (IONPs) have become a subject of interest in various biomedical fields due to their magnetism and biocompatibility. They can be utilized as heat mediators in magnetic hyperthermia (MHT) or as contrast media in magnetic resonance imaging (MRI), and ultrasound (US). In addition, their high drug-loading capacity enabled them to be therapeutic agent transporters for malignancy treatment. Hence, smartening them allows for an intelligent controlled drug release (CDR) and targeted drug delivery (TDD). Smart magnetic nanoparticles (SMNPs) can overcome the impediments faced by classical chemo-treatment strategies, since they can be navigated and release drug via external or internal stimuli. Recently, they have been synchronized with other modalities, e.g., MRI, MHT, US, and for dual/multimodal theranostic applications in a single platform. Herein, we provide an overview of the attributes of MNPs for cancer theranostic application, fabrication procedures, surface coatings, targeting approaches, and recent advancement of SMNPs. Even though MNPs feature numerous privileges over chemotherapy agents, obstacles remain in clinical usage. This review in particular covers the clinical predicaments faced by SMNPs and future research scopes in the field of SMNPs for cancer theranostics.
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Affiliation(s)
- Elham Aram
- Department of Cancer Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Babol 47138-18981, Iran
- Department of Polymer Engineering, Faculty of Engineering, Golestan University, Gorgan 49188-88369, Iran
| | - Masome Moeni
- School of Chemical and Process Engineering, University of Leeds, Leeds LS2 9JT, UK
| | - Roya Abedizadeh
- Department of Cancer Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Babol 47138-18981, Iran
| | - Davood Sabour
- Department of Cancer Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Babol 47138-18981, Iran
| | - Hamid Sadeghi-Abandansari
- Department of Cancer Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Babol 47138-18981, Iran
- Department of Cell Engineering, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148, Iran
| | - Jabbar Gardy
- School of Chemical and Process Engineering, University of Leeds, Leeds LS2 9JT, UK
- Correspondence: (J.G.); (A.H.)
| | - Ali Hassanpour
- School of Chemical and Process Engineering, University of Leeds, Leeds LS2 9JT, UK
- Correspondence: (J.G.); (A.H.)
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15
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Bocalon LG, Tozatti MG, Januário AH, Pauletti PM, Silva MLA, Rocha LA, Molina EF, Santos MFC, Cunha WR. Incorporation of Betulinic Acid into Silica-Based Nanoparticles for Controlled Phytochemical Release. ANAL LETT 2022. [DOI: 10.1080/00032719.2022.2120491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Affiliation(s)
- Lúzio G. Bocalon
- Research Center in Exact and Technological Sciences, University of Franca, Franca, Brazil
| | - Marcos G. Tozatti
- Research Center in Exact and Technological Sciences, University of Franca, Franca, Brazil
| | - Ana H. Januário
- Research Center in Exact and Technological Sciences, University of Franca, Franca, Brazil
| | - Patrícia M. Pauletti
- Research Center in Exact and Technological Sciences, University of Franca, Franca, Brazil
| | - Márcio L. A. Silva
- Research Center in Exact and Technological Sciences, University of Franca, Franca, Brazil
| | - Lucas A. Rocha
- Research Center in Exact and Technological Sciences, University of Franca, Franca, Brazil
| | - Eduardo F. Molina
- Research Center in Exact and Technological Sciences, University of Franca, Franca, Brazil
| | - Mario F. C. Santos
- Department of Physics and Chemistry, Federal University of Espírito Santo – UFES, Center of Exact, Natural and Health Sciences, Alegre, Brazil
| | - Wilson R. Cunha
- Research Center in Exact and Technological Sciences, University of Franca, Franca, Brazil
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16
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Ali LMA, Gary-Bobo M. Photochemical Internalization of siRNA for Cancer Therapy. Cancers (Basel) 2022; 14:cancers14153597. [PMID: 35892854 PMCID: PMC9331967 DOI: 10.3390/cancers14153597] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/14/2022] [Accepted: 07/19/2022] [Indexed: 01/27/2023] Open
Abstract
Simple Summary The objective of this review is to focus on the different nanovectors capable of transporting genetic material such as small-interfering RNA (siRNA) in order to block the expression of genes responsible for the development of cancer. Usually, these nanovectors are internalized by cancer cells via the endo-lysosomal pathway. To increase the lysosomal cargo escape, excitation using a lamp or a laser, can be applied to induce a more efficient leakage of siRNA to the cytoplasm, which is the site of action of the siRNA to block the translation of RNA into proteins. This is the mechanism of photochemical internalization. Abstract In the race to design ever more effective therapy with ever more focused and controlled actions, nanomedicine and phototherapy seem to be two allies of choice. Indeed, the use of nanovectors making it possible to transport and protect genetic material is becoming increasingly important. In addition, the use of a method allowing the release of genetic material in a controlled way in space and time is also a strategy increasingly studied thanks to the use of lasers. In parallel, the use of interfering RNA and, more particularly, of small-interfering RNA (siRNA) has demonstrated significant potential for gene therapy. In this review, we focused on the design of the different nanovectors capable of transporting siRNAs and releasing them so that they can turn off the expression of deregulated genes in cancers through controlled photoexcitation with high precision. This mechanism, called photochemical internalization (PCI), corresponds to the lysosomal leakage of the cargo (siRNA in this case) after destabilization of the lysosomal membrane under light excitation.
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Affiliation(s)
- Lamiaa Mohamed Ahmed Ali
- IBMM, University Montpellier, CNRS, ENSCM, 34093 Montpellier, France;
- Department of Biochemistry, Medical Research Institute, University of Alexandria, Alexandria 21561, Egypt
- Correspondence:
| | - Magali Gary-Bobo
- IBMM, University Montpellier, CNRS, ENSCM, 34093 Montpellier, France;
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17
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Poonaki E, Nickel AC, Shafiee Ardestani M, Rademacher L, Kaul M, Apartsin E, Meuth SG, Gorji A, Janiak C, Kahlert UD. CD133-Functionalized Gold Nanoparticles as a Carrier Platform for Telaglenastat (CB-839) against Tumor Stem Cells. Int J Mol Sci 2022; 23:5479. [PMID: 35628289 PMCID: PMC9141725 DOI: 10.3390/ijms23105479] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/04/2022] [Accepted: 05/09/2022] [Indexed: 01/01/2023] Open
Abstract
The failure of a long-lasting curative therapeutic benefit of currently applied chemotherapies against malignant cancers is suggested to be caused by the ineffectiveness of such interventions on cancer stem cells (CSCs). CD133/AC133 is a cell surface protein previously shown to have potential to identify CSCs in various tumors, including brain tumors. Moreover, an increase in the rate of cellular metabolism of glutamine and glucose are contributors to the fast cellular proliferation of some high-grade malignancies. Inhibition of glutaminolysis by utilizing pharmacological inhibitors of the enzyme glutaminase 1 (GLS1) can be an effective anti-CSC strategy. In this study, the clinical-stage GLS1 inhibitor Telaglenastat (CB-839) was loaded into PEGylated gold nanoparticles equipped with the covalently conjugated CD133 aptamer (Au-PEG-CD133-CB-839) and exposed to a collection of CD133-positive brain tumor models in vitro. Our results show that Au-PEG-CD133-CB-839 significantly decreased the viability of CD133-postive cancer cells in a dose-dependent manner, which was higher as compared to the effects of treatment of the cells with the individual components of the assembled nanodrug. Interestingly, the treatment effect was observed in glioblastoma stem cells modeling different transcriptomic subtypes of the disease. The presented platform is the fundament for subsequent target specificity characterization and in vivo application.
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Affiliation(s)
- Elham Poonaki
- Department of Neurology, Faculty of Medicine, Heinrich-Heine-University, 40225 Düsseldorf, Germany; (E.P.); (S.G.M.)
- Institut für Anorganische Chemie und Strukturchemie, Heinrich-Heine-University, 40204 Düsseldorf, Germany; (L.R.); (M.K.)
- Molecular and Experimental Surgery, University Clinic for General-, Visceral-, Vascular- and Transplantation Surgery, Faculty of Medicine, Otto-von-Guericke-University, 39120 Magdeburg, Germany
| | - Ann-Christin Nickel
- Clinic for Neurosurgery, Heinrich-Heine-University, 40225 Düsseldorf, Germany;
| | - Mehdi Shafiee Ardestani
- Department of Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 1416634793, Iran;
| | - Lars Rademacher
- Institut für Anorganische Chemie und Strukturchemie, Heinrich-Heine-University, 40204 Düsseldorf, Germany; (L.R.); (M.K.)
| | - Marilyn Kaul
- Institut für Anorganische Chemie und Strukturchemie, Heinrich-Heine-University, 40204 Düsseldorf, Germany; (L.R.); (M.K.)
| | - Evgeny Apartsin
- Institute of Chemical Biology and Fundamental Medicine SB RAS, 630090 Novosibirsk, Russia;
- Laboratoire de Chimie de Coordination CNRS, 31400 Toulouse, France
| | - Sven G. Meuth
- Department of Neurology, Faculty of Medicine, Heinrich-Heine-University, 40225 Düsseldorf, Germany; (E.P.); (S.G.M.)
| | - Ali Gorji
- Epilepsy Research Center, Department of Neurosurgery and Department of Neurology, Westfälische Wilhelms-Universität, 48149 Münster, Germany;
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran 9815733169, Iran
| | - Christoph Janiak
- Institut für Anorganische Chemie und Strukturchemie, Heinrich-Heine-University, 40204 Düsseldorf, Germany; (L.R.); (M.K.)
| | - Ulf Dietrich Kahlert
- Molecular and Experimental Surgery, University Clinic for General-, Visceral-, Vascular- and Transplantation Surgery, Faculty of Medicine, Otto-von-Guericke-University, 39120 Magdeburg, Germany
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18
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Liu S, Wang X, Yu X, Cheng Q, Johnson LT, Chatterjee S, Zhang D, Lee SM, Sun Y, Lin TC, Liu JL, Siegwart DJ. Zwitterionic Phospholipidation of Cationic Polymers Facilitates Systemic mRNA Delivery to Spleen and Lymph Nodes. J Am Chem Soc 2021; 143:21321-21330. [PMID: 34878786 PMCID: PMC9437927 DOI: 10.1021/jacs.1c09822] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Polymers represent a promising therapeutic platform for extrahepatic messenger RNA (mRNA) delivery but are hampered by low in vivo efficacy due to polyplex serum instability and inadequate endosomal escape following systemic administration. Here, we report the rational design and combinatorial synthesis of zwitterionic phospholipidated polymers (ZPPs) via cationic polymer postmodification by alkylated dioxaphospholane oxides to deliver mRNA to spleen and lymph nodes in vivo. This modular postmodification approach readily produces tunable zwitterionic species for serum resistance and introduces alkyl chains simultaneously to enhance endosomal escape, thereby transforming deficient cationic polymers to efficacious zwitterionic mRNA carriers without the need to elaborately synthesize functional monomers. ZPPs mediated up to 39 500-fold higher protein expression than their parent cationic counterparts in vitro and enabled efficacious mRNA delivery selectively in spleen and lymph nodes following intravenous administration in vivo. This zwitterionic phospholipidation methodology provides a versatile and generalizable postmodification strategy to introduce zwitterions into the side chains of cationic polymers, extending the utility of cationic polymer families for precise mRNA delivery and demonstrating substantial potential for immunotherapeutic applications.
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Affiliation(s)
- Shuai Liu
- Department of Biochemistry, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Xu Wang
- Department of Biochemistry, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Xueliang Yu
- Department of Biochemistry, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Qiang Cheng
- Department of Biochemistry, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Lindsay T. Johnson
- Department of Biochemistry, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Sumanta Chatterjee
- Department of Biochemistry, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Di Zhang
- Department of Biochemistry, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Sang M. Lee
- Department of Biochemistry, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Yehui Sun
- Department of Biochemistry, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Ting-Chih Lin
- Department of Biochemistry, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - John L. Liu
- Department of Biochemistry, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Daniel J. Siegwart
- Department of Biochemistry, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
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Synthesis and Evaluation of High Functionality and Quality Cell-penetrating Peptide Conjugated Lipid for Octaarginine Modified PEGylated Liposomes In U251 and U87 Glioma Cells. J Pharm Sci 2021; 111:1719-1727. [PMID: 34863974 DOI: 10.1016/j.xphs.2021.11.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 11/27/2021] [Accepted: 11/28/2021] [Indexed: 11/20/2022]
Abstract
The use of peptide ligand modified PEGylated liposomes has been widely investigated for tumor targeting. Peptides are mainly inserted in the liposomal lipid bilayer using PEG2K-lipid spacer (Peptide-PEG2K-DSPE). However, a lower cellular uptake from longer nonlinear PEG2K spacer was reported, we here synthesized a high functionality and quality (HFQ) lipid with a short, linear serine-glycine repeated peptide [(SG)5] spacer. The objective of the current study is to develop novel octaarginine (R8) peptide-HFQ lipid grafted PEGylated liposomes for glioma cells targeting. In vitro liposomes characterization showed that the mean particle size of all liposomal formulations was in the nano-scale range < 120 nm, with a small PDI value (i.e. ∼0.2) and had a spherical shape under Transmission Electron Microscope, indicating a homogenous particle size distribution. The flow cytometry in vitro cellular association data with U251 MG and U87 cells revealed that 1.5% R8-(SG)5-lipid-PEGylated liposomes exhibited significantly higher cellular association of ∼15.87 and 7.59-fold than the conventional R8-PEG2K-lipid-PEGylated liposomes (10.4 and 6.19-fold), respectively, relative to the unmodified PEGylated liposomes. Moreover, intracellular distribution studies using confocal laser scanning microscopy (CLSM) corroborated the results of the in vitro cell association. The use of ligand-HFQ-lipid liposomes could be a potential alternative to ligand-PEG2K-lipid-modified liposomes as a drug delivery system for tumor targeting.
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20
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Drug Release Kinetics of DOX-Loaded Graphene-Based Nanocarriers for Ovarian and Breast Cancer Therapeutics. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app112311151] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cancer remains one of the leading causes of death worldwide despite extensive efforts at developing curative treatments. Chemotherapy, one of the most common forms of treatment, lacks specificity and can induce collateral damages to healthy surrounding tissues/cells and elicit off-target toxic side effects. The carbon-based nanomaterial graphene, can load aromatic drugs with high efficiency, has good biocompatibility, and can be easily functionalised with targeting ligands, antibodies, and biomolecules to increase the accuracy of targeting specific areas; graphene has therefore been explored as a nanocarrier for classical chemotherapy drugs. In this work, seventeen publications that report the release of doxorubicin (DOX) from 2D graphene-based nanohybrids (graphene oxide and reduced graphene oxide) for the treatment of breast and ovarian cancers have been identified based on a range of inclusion and exclusion criteria. To aid in the clinical translation of proof-of-concept studies, this work identifies the pre-clinical experimental protocols and analyses the release kinetics of these publications. Fifteen of the papers utilised a change in pH as the stimulus for drug release, and two utilised either near infrared (NIR) or ultrasound as the stimulus. The extracted drug release data from these publications were fit to four known kinetic models. It was found that the majority of these data best fit the Weibull kinetic model. The agreement between the kinetic data in previously published literature provides a predictable estimation of DOX release from graphene-based nanocarriers. This study demonstrates the potential conjugation of graphene and DOX in drug delivery applications, and this knowledge can help improve to the design and formulation of future graphene-based nanocarriers. In addition, the use of further experimental testing and the standardisation of experimental protocols will be beneficial for future work. The incorporation of computational modelling prior to pre-clinical testing will also aid in the development of controlled and sustained DOX release systems that offer efficient and efficacious results.
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21
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The Evolution and Future of Targeted Cancer Therapy: From Nanoparticles, Oncolytic Viruses, and Oncolytic Bacteria to the Treatment of Solid Tumors. NANOMATERIALS 2021; 11:nano11113018. [PMID: 34835785 PMCID: PMC8623458 DOI: 10.3390/nano11113018] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/28/2021] [Accepted: 11/01/2021] [Indexed: 02/07/2023]
Abstract
While many classes of chemotherapeutic agents exist to treat solid tumors, few can generate a lasting response without substantial off-target toxicity despite significant scientific advancements and investments. In this review, the paths of development for nanoparticles, oncolytic viruses, and oncolytic bacteria over the last 20 years of research towards clinical translation and acceptance as novel cancer therapeutics are compared. Novel nanoparticle, oncolytic virus, and oncolytic bacteria therapies all start with a common goal of accomplishing therapeutic drug activity or delivery to a specific site while avoiding off-target effects, with overlapping methodology between all three modalities. Indeed, the degree of overlap is substantial enough that breakthroughs in one therapeutic could have considerable implications on the progression of the other two. Each oncotherapeutic modality has accomplished clinical translation, successfully overcoming the potential pitfalls promising therapeutics face. However, once studies enter clinical trials, the data all but disappears, leaving pre-clinical researchers largely in the dark. Overall, the creativity, flexibility, and innovation of these modalities for solid tumor treatments are greatly encouraging, and usher in a new age of pharmaceutical development.
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Tracey SR, Smyth P, Barelle CJ, Scott CJ. Development of next generation nanomedicine-based approaches for the treatment of cancer: we've barely scratched the surface. Biochem Soc Trans 2021; 49:2253-2269. [PMID: 34709394 PMCID: PMC8589425 DOI: 10.1042/bst20210343] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/23/2021] [Accepted: 10/07/2021] [Indexed: 12/15/2022]
Abstract
Interest in nanomedicines has grown rapidly over the past two decades, owing to the promising therapeutic applications they may provide, particularly for the treatment of cancer. Personalised medicine and 'smart' actively targeted nanoparticles represent an opportunity to deliver therapies directly to cancer cells and provide sustained drug release, in turn providing overall lower off-target toxicity and increased therapeutic efficacy. However, the successful translation of nanomedicines from encouraging pre-clinical findings to the clinic has, to date, proven arduous. In this review, we will discuss the use of nanomedicines for the treatment of cancer, with a specific focus on the use of polymeric and lipid nanoparticle delivery systems. In particular, we examine approaches exploring the surface functionalisation of nanomedicines to elicit active targeting and therapeutic effects as well as challenges and future directions for nanoparticles in cancer treatment.
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Affiliation(s)
- Shannon R. Tracey
- The Patrick G Johnston Centre for Cancer Research, Queen's University, 97 Lisburn Road, Belfast BT9 7AE, U.K
| | - Peter Smyth
- The Patrick G Johnston Centre for Cancer Research, Queen's University, 97 Lisburn Road, Belfast BT9 7AE, U.K
| | - Caroline J. Barelle
- Elasmogen Ltd, Liberty Building, Foresterhill Health Campus, Aberdeen AB25 2ZP, U.K
| | - Christopher J. Scott
- The Patrick G Johnston Centre for Cancer Research, Queen's University, 97 Lisburn Road, Belfast BT9 7AE, U.K
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23
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Jeong SG, Ryu YC, Hwang BH. Synergistic gene delivery by self-assembled nanocomplexes using fusion peptide and calcium phosphate. J Control Release 2021; 338:284-294. [PMID: 34425165 DOI: 10.1016/j.jconrel.2021.08.034] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 08/12/2021] [Accepted: 08/18/2021] [Indexed: 11/29/2022]
Abstract
Gene therapy can be a promising therapeutic approach to cure the fundamental causes of incurable genetic diseases. Because virus carriers are costly and can cause inflammation and immunogenicity, efficient non-viral carriers need to be developed for broader gene therapy applications. Therefore, we designed novel synergistic nanocomplexes for efficient transfection incorporated by the fusion of nuclear localization signal and cell-penetrating peptides with calcium phosphate. Fusion peptides were able to package large plasmid DNAs into nanocomplexes spontaneously and efficiently. After optimization, S-R/CaP or S-S/CaP nanocomplexes significantly improved specific luciferase expression up to 2-fold compared to Lipofectamine® 2000. In addition, the large Cas9-encoding plasmids were transfected into HEK293T cells more efficiently than Lipofectamine® 2000. Furthermore, subcutaneously injected cells to mice maintained more stable protein expression until 10 days than Lipofectamine® 2000. Moreover, the biocompatibility was revealed by observing negligible cytotoxicity, histological difference, and inflammatory cytokine release. Consequently, the new chimeric strategy will be an efficient and safe gene carrier into cells and tissues to treat various genetic diseases through gene therapy.
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Affiliation(s)
- Soon Gil Jeong
- Department of Bioengineering and Nano-bioengineering, Incheon National University, Incheon 22012, Republic of Korea
| | - Yeong Chae Ryu
- Department of Bioengineering and Nano-bioengineering, Incheon National University, Incheon 22012, Republic of Korea
| | - Byeong Hee Hwang
- Department of Bioengineering and Nano-bioengineering, Incheon National University, Incheon 22012, Republic of Korea; Division of Bioengineering, Incheon National University, Incheon 22012, Republic of Korea; Institute for New Drug Development, Incheon National University, Incheon 22012, Republic of Korea.
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24
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Domb AJ, Sharifzadeh G, Nahum V, Hosseinkhani H. Safety Evaluation of Nanotechnology Products. Pharmaceutics 2021; 13:pharmaceutics13101615. [PMID: 34683908 PMCID: PMC8539492 DOI: 10.3390/pharmaceutics13101615] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 09/21/2021] [Accepted: 09/23/2021] [Indexed: 01/11/2023] Open
Abstract
Nanomaterials are now being used in a wide variety of biomedical applications. Medical and health-related issues, however, have raised major concerns, in view of the potential risks of these materials against tissue, cells, and/or organs and these are still poorly understood. These particles are able to interact with the body in countless ways, and they can cause unexpected and hazardous toxicities, especially at cellular levels. Therefore, undertaking in vitro and in vivo experiments is vital to establish their toxicity with natural tissues. In this review, we discuss the underlying mechanisms of nanotoxicity and provide an overview on in vitro characterizations and cytotoxicity assays, as well as in vivo studies that emphasize blood circulation and the in vivo fate of nanomaterials. Our focus is on understanding the role that the physicochemical properties of nanomaterials play in determining their toxicity.
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Affiliation(s)
- Abraham J. Domb
- The Centers for Nanoscience and Nanotechnology, Alex Grass Center for Drug Design and Synthesis and Cannabinoids Research, School of Pharmacy, Faculty of Medicine, Institute of Drug Research, The Hebrew University of Jerusalem, Jerusalem 91120, Israel;
- Correspondence: (A.J.D.); (H.H.)
| | - Ghorbanali Sharifzadeh
- Department of Polymer Engineering, School of Chemical Engineering, Universiti Teknologi Malaysia, Johor Bahru 81310, Malaysia;
| | - Victoria Nahum
- The Centers for Nanoscience and Nanotechnology, Alex Grass Center for Drug Design and Synthesis and Cannabinoids Research, School of Pharmacy, Faculty of Medicine, Institute of Drug Research, The Hebrew University of Jerusalem, Jerusalem 91120, Israel;
| | - Hossein Hosseinkhani
- Innovation Center for Advanced Technology, Matrix, Inc., New York, NY 10029, USA
- Correspondence: (A.J.D.); (H.H.)
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25
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Jiang X, Fu J, Zhong J, Li X, Wang H, Zhong S, Wei Y, Zhao X, Chen X, Zhou Y, Du L, Ye G, Zhao J, Huang Y. Guanidinylated Cyclic Synthetic Polypeptides Can Effectively Deliver siRNA by Mimicking the Biofunctions of Both Cell-Penetrating Peptides and Nuclear Localization Signal Peptides. ACS Macro Lett 2021; 10:767-773. [PMID: 35549206 DOI: 10.1021/acsmacrolett.1c00236] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Preventing endosomal entrapment of gene/vector nanocomplexes (NCs) remains a challenge for highly effective siRNA delivery. To address this problem, guanidinylated cyclic synthetic polypeptides (GCSPs) were synthesized using an efficient and easy method. GCSPs can condense siRNAs into NCs with an encapsulation efficiency of approximately 90%, over twice the effectiveness of Lipofectamine2000 (Lipo2000). The NCs can also mediate luciferase knockdown in HeLa cells with a silencing efficiency of 80%, nearly 2- and 1.1-fold that of Lipo2000 and PEI, respectively. More importantly, the NCs can enter cells by mimicking the bioactivity of cell-penetrating peptides (CPPs). NCs can also exert a nuclear localized function similar to nuclear localization signal peptides (NLSPs). Both biofunctions are helpful for preventing the common endosomal entrapment of NCs and greatly enhance the efficiency of siRNA delivery.
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Affiliation(s)
- Xinlin Jiang
- The Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Jijun Fu
- The Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Junyang Zhong
- The Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Xin Li
- The Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - He Wang
- Center of Cancer Research, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
| | - Songjing Zhong
- The Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Yinhui Wei
- The Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Xiaoya Zhao
- The Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Xing Chen
- School of Public Health, Guangxi Medical University, Nanning 530021, China
| | - Yi Zhou
- The Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Lingran Du
- The Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Guodong Ye
- The Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Jing Zhao
- The Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Yugang Huang
- The Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
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26
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Russo E, Spallarossa A, Tasso B, Villa C, Brullo C. Nanotechnology of Tyrosine Kinase Inhibitors in Cancer Therapy: A Perspective. Int J Mol Sci 2021; 22:6538. [PMID: 34207175 PMCID: PMC8235113 DOI: 10.3390/ijms22126538] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 12/23/2022] Open
Abstract
Nanotechnology is an important application in modern cancer therapy. In comparison with conventional drug formulations, nanoparticles ensure better penetration into the tumor mass by exploiting the enhanced permeability and retention effect, longer blood circulation times by a reduced renal excretion and a decrease in side effects and drug accumulation in healthy tissues. The most significant classes of nanoparticles (i.e., liposomes, inorganic and organic nanoparticles) are here discussed with a particular focus on their use as delivery systems for small molecule tyrosine kinase inhibitors (TKIs). A number of these new compounds (e.g., Imatinib, Dasatinib, Ponatinib) have been approved as first-line therapy in different cancer types but their clinical use is limited by poor solubility and oral bioavailability. Consequently, new nanoparticle systems are necessary to ameliorate formulations and reduce toxicity. In this review, some of the most important TKIs are reported, focusing on ongoing clinical studies, and the recent drug delivery systems for these molecules are investigated.
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Affiliation(s)
- Eleonora Russo
- Section of Medicinal and Cosmetic Chemistry, Department of Pharmacy, University of Genova, Viale Benedetto XV, 3-16132 Genova, Italy; (A.S.); (B.T.); (C.V.)
| | | | | | | | - Chiara Brullo
- Section of Medicinal and Cosmetic Chemistry, Department of Pharmacy, University of Genova, Viale Benedetto XV, 3-16132 Genova, Italy; (A.S.); (B.T.); (C.V.)
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27
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Kumar R, Santa Chalarca CF, Bockman MR, Bruggen CV, Grimme CJ, Dalal RJ, Hanson MG, Hexum JK, Reineke TM. Polymeric Delivery of Therapeutic Nucleic Acids. Chem Rev 2021; 121:11527-11652. [PMID: 33939409 DOI: 10.1021/acs.chemrev.0c00997] [Citation(s) in RCA: 198] [Impact Index Per Article: 49.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The advent of genome editing has transformed the therapeutic landscape for several debilitating diseases, and the clinical outlook for gene therapeutics has never been more promising. The therapeutic potential of nucleic acids has been limited by a reliance on engineered viral vectors for delivery. Chemically defined polymers can remediate technological, regulatory, and clinical challenges associated with viral modes of gene delivery. Because of their scalability, versatility, and exquisite tunability, polymers are ideal biomaterial platforms for delivering nucleic acid payloads efficiently while minimizing immune response and cellular toxicity. While polymeric gene delivery has progressed significantly in the past four decades, clinical translation of polymeric vehicles faces several formidable challenges. The aim of our Account is to illustrate diverse concepts in designing polymeric vectors towards meeting therapeutic goals of in vivo and ex vivo gene therapy. Here, we highlight several classes of polymers employed in gene delivery and summarize the recent work on understanding the contributions of chemical and architectural design parameters. We touch upon characterization methods used to visualize and understand events transpiring at the interfaces between polymer, nucleic acids, and the physiological environment. We conclude that interdisciplinary approaches and methodologies motivated by fundamental questions are key to designing high-performing polymeric vehicles for gene therapy.
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Affiliation(s)
- Ramya Kumar
- Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | | | - Matthew R Bockman
- Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Craig Van Bruggen
- Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Christian J Grimme
- Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Rishad J Dalal
- Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Mckenna G Hanson
- Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Joseph K Hexum
- Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Theresa M Reineke
- Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
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28
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Huang Z, Kłodzińska SN, Wan F, Nielsen HM. Nanoparticle-mediated pulmonary drug delivery: state of the art towards efficient treatment of recalcitrant respiratory tract bacterial infections. Drug Deliv Transl Res 2021; 11:1634-1654. [PMID: 33694082 PMCID: PMC7945609 DOI: 10.1007/s13346-021-00954-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/01/2021] [Indexed: 12/16/2022]
Abstract
Recalcitrant respiratory tract infections caused by bacteria have emerged as one of the greatest health challenges worldwide. Aerosolized antimicrobial therapy is becoming increasingly attractive to combat such infections, as it allows targeted delivery of high drug concentrations to the infected organ while limiting systemic exposure. However, successful aerosolized antimicrobial therapy is still challenged by the diverse biological barriers in infected lungs. Nanoparticle-mediated pulmonary drug delivery is gaining increasing attention as a means to overcome the biological barriers and accomplish site-specific drug delivery by controlling release of the loaded drug(s) at the target site. With the aim to summarize emerging efforts in combating respiratory tract infections by using nanoparticle-mediated pulmonary delivery strategies, this review provides a brief introduction to the bacterial infection-related pulmonary diseases and the biological barriers for effective treatment of recalcitrant respiratory tract infections. This is followed by a summary of recent advances in design of inhalable nanoparticle-based drug delivery systems that overcome the biological barriers and increase drug bioavailability. Finally, challenges for the translation from exploratory laboratory research to clinical application are also discussed and potential solutions proposed.
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Affiliation(s)
- Zheng Huang
- Center for Biopharmaceuticals and Biobarriers in Drug Delivery, Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen Ø, Denmark
| | - Sylvia Natalie Kłodzińska
- Center for Biopharmaceuticals and Biobarriers in Drug Delivery, Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen Ø, Denmark
| | - Feng Wan
- Center for Biopharmaceuticals and Biobarriers in Drug Delivery, Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen Ø, Denmark.
| | - Hanne Mørck Nielsen
- Center for Biopharmaceuticals and Biobarriers in Drug Delivery, Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen Ø, Denmark.
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29
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Biosca A, Cabanach P, Abdulkarim M, Gumbleton M, Gómez-Canela C, Ramírez M, Bouzón-Arnáiz I, Avalos-Padilla Y, Borros S, Fernàndez-Busquets X. Zwitterionic self-assembled nanoparticles as carriers for Plasmodium targeting in malaria oral treatment. J Control Release 2021; 331:364-375. [PMID: 33497747 DOI: 10.1016/j.jconrel.2021.01.028] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 01/13/2021] [Accepted: 01/19/2021] [Indexed: 11/15/2022]
Abstract
The current decline in antimalarial drug efficacy due to the evolution of resistant Plasmodium strains calls for new strategies capable of improving the bioavailability of antimalarials, especially of those whose lipophilic character imparts them a low solubility in biological fluids. Here we have designed, synthesized and characterized amphiphilic zwitterionic block copolymers forming nanoparticles capable of penetrating the intestinal epithelium that can be used for oral administration. Poly(butyl methacrylate-co-morpholinoethyl sulfobetaine methacrylate) (PBMA-MESBMA)-based nanoparticles exhibited a specific targeting to Plasmodium falciparum-infected vs. parasite-free red blood cells (74.8%/0.8% respectively), which was maintained upon encapsulation of the lipophilic antimalarial drug curcumin (82.6%/0.3%). The in vitro efficacy of curcumin upon encapsulation was maintained relative to the free compound, with an IC50 around 5 μM. In vivo assays indicated a significantly increased curcumin concentration in the blood of mice one hour after being orally fed PBMA-MESBMA-curcumin in comparison to the administration of free drug (18.7 vs. 2.1 ng/ml, respectively). At longer times, however, plasma curcumin concentration equaled between free and encapsulated drug, which was reflected in similar in vivo antimalarial activities in Plasmodium yoelii yoelii-infected mice. Microscopic analysis in blood samples of fluorescently labeled PBMA-MESBMA revealed the presence of the polymer inside P. yoelii yoelii-parasitized erythrocytes one hour after oral administration to infected animals.
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Affiliation(s)
- Arnau Biosca
- Barcelona Institute for Global Health (ISGlobal, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, ES-08036 Barcelona, Spain; Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, ES-08028 Barcelona, Spain; Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, ES-08028 Barcelona, Spain
| | - Pol Cabanach
- Grup d'Enginyeria de Materials (GEMAT), Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, 08017 Barcelona, Spain
| | - Muthanna Abdulkarim
- School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Cardiff, UK
| | - Mark Gumbleton
- School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Cardiff, UK
| | - Cristian Gómez-Canela
- Departament de Química Analítica, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, 08017 Barcelona, Spain
| | - Miriam Ramírez
- Barcelona Institute for Global Health (ISGlobal, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, ES-08036 Barcelona, Spain
| | - Inés Bouzón-Arnáiz
- Barcelona Institute for Global Health (ISGlobal, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, ES-08036 Barcelona, Spain; Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, ES-08028 Barcelona, Spain; Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, ES-08028 Barcelona, Spain
| | - Yunuen Avalos-Padilla
- Barcelona Institute for Global Health (ISGlobal, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, ES-08036 Barcelona, Spain; Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, ES-08028 Barcelona, Spain; Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, ES-08028 Barcelona, Spain
| | - Salvador Borros
- Grup d'Enginyeria de Materials (GEMAT), Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, 08017 Barcelona, Spain
| | - Xavier Fernàndez-Busquets
- Barcelona Institute for Global Health (ISGlobal, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, ES-08036 Barcelona, Spain; Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, ES-08028 Barcelona, Spain; Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, ES-08028 Barcelona, Spain.
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30
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Gräfe C, Müller EK, Gresing L, Weidner A, Radon P, Friedrich RP, Alexiou C, Wiekhorst F, Dutz S, Clement JH. Magnetic hybrid materials interact with biological matrices. PHYSICAL SCIENCES REVIEWS 2020. [DOI: 10.1515/psr-2019-0114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Abstract
Magnetic hybrid materials are a promising group of substances. Their interaction with matrices is challenging with regard to the underlying physical and chemical mechanisms. But thinking matrices as biological membranes or even structured cell layers they become interesting with regard to potential biomedical applications. Therefore, we established in vitro blood-organ barrier models to study the interaction and processing of superparamagnetic iron oxide nanoparticles (SPIONs) with these cellular structures in the presence of a magnetic field gradient. A one-cell-type–based blood-brain barrier model was used to investigate the attachment and uptake mechanisms of differentially charged magnetic hybrid materials. Inhibition of clathrin-dependent endocytosis and F-actin depolymerization led to a dramatic reduction of cellular uptake. Furthermore, the subsequent transportation of SPIONs through the barrier and the ability to detect these particles was of interest. Negatively charged SPIONs could be detected behind the barrier as well as in a reporter cell line. These observations could be confirmed with a two-cell-type–based blood-placenta barrier model. While positively charged SPIONs heavily interact with the apical cell layer, neutrally charged SPIONs showed a retarded interaction behavior. Behind the blood-placenta barrier, negatively charged SPIONs could be clearly detected. Finally, the transfer of the in vitro blood-placenta model in a microfluidic biochip allows the integration of shear stress into the system. Even without particle accumulation in a magnetic field gradient, the negatively charged SPIONs were detectable behind the barrier. In conclusion, in vitro blood-organ barrier models allow the broad investigation of magnetic hybrid materials with regard to biocompatibility, cell interaction, and transfer through cell layers on their way to biomedical application.
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Affiliation(s)
- Christine Gräfe
- Department of Internal Medicine II, Hematology and Medical Oncology , Jena University Hospital , Jena , Germany
| | - Elena K. Müller
- Department of Internal Medicine II, Hematology and Medical Oncology , Jena University Hospital , Jena , Germany
| | - Lennart Gresing
- Department of Internal Medicine II, Hematology and Medical Oncology , Jena University Hospital , Jena , Germany
| | - Andreas Weidner
- Institute of Biomedical Engineering and Informatics (BMTI), Technische Universität Ilmenau , Ilmenau , Germany
| | - Patricia Radon
- Physikalisch-Technische Bundesanstalt , Berlin , Germany
| | - Ralf P. Friedrich
- Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON) , Else Kröner-Fresenius-Stiftung-Professorship, Universitätsklinikum Erlangen , Erlangen , Germany
| | - Christoph Alexiou
- Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON) , Else Kröner-Fresenius-Stiftung-Professorship, Universitätsklinikum Erlangen , Erlangen , Germany
| | | | - Silvio Dutz
- Institute of Biomedical Engineering and Informatics (BMTI), Technische Universität Ilmenau , Ilmenau , Germany
| | - Joachim H. Clement
- Department of Internal Medicine II, Hematology and Medical Oncology , Jena University Hospital , Jena , Germany
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31
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Yoon S, Kim Y, Youn YS, Oh KT, Kim D, Lee ES. Transferrin-Conjugated pH-Responsive γ-Cyclodextrin Nanoparticles for Antitumoral Topotecan Delivery. Pharmaceutics 2020; 12:pharmaceutics12111109. [PMID: 33218116 PMCID: PMC7698888 DOI: 10.3390/pharmaceutics12111109] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 11/17/2020] [Accepted: 11/17/2020] [Indexed: 02/06/2023] Open
Abstract
In this study, we developed γ-cyclodextrin-based multifunctional nanoparticles (NPs) for tumor-targeted therapy. The NPs were self-assembled using a γ-cyclodextrin (γCD) coupled with phenylacetic acid (PA), 2,3-dimethylmaleic anhydride (DMA), poly(ethylene glycol) (PEG), and transferrin (Tf), termed γCDP-(DMA/PEG-Tf) NPs. These γCDP-(DMA/PEG-Tf) NPs are effective in entrapping topotecan (TPT, as a model antitumor drug) resulting from the ionic interaction between pH-responsive DMA and TPT or the host–guest interaction between γCDP and TPT. More importantly, the γCDP-(DMA/PEG-Tf) NPs can induce ionic repulsion at an endosomal pH (~6.0) resulting from the chemical detachment of DMA from γCDP, which is followed by extensive TPT release. We demonstrated that γCDP-(DMA/PEG-Tf) NPs led to a significant increase in cellular uptake and MDA-MB-231 tumor cell death. In vivo animal studies using an MDA-MB-231 tumor xenografted mice model supported the finding that γCDP-(DMA/PEG-Tf) NPs are effective carriers of TPT to Tf receptor-positive MDA-MB-231 tumor cells, promoting drug uptake into the tumors through the Tf ligand-mediated endocytic pathway and increasing their toxicity due to DMA-mediated cytosolic TPT delivery.
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Affiliation(s)
- Seonyoung Yoon
- Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Bucheon-si, Gyeonggi-do 14662, Korea; (S.Y.); (Y.K.)
| | - Yoonyoung Kim
- Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Bucheon-si, Gyeonggi-do 14662, Korea; (S.Y.); (Y.K.)
| | - Yu Seok Youn
- School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do 16419, Korea;
| | - Kyung Taek Oh
- College of Pharmacy, Chung-Ang University, 221 Heukseok dong, Dongjak-gu, Seoul 06974, Korea;
| | - Dongin Kim
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, 1110 N Stonewall Ave, Oklahoma City, OK 73117, USA;
| | - Eun Seong Lee
- Department of Biomedical-Chemical Engineering, The Catholic University of Korea, 43 Jibong-ro, Bucheon-si, Gyeonggi-do 14662, Korea
- Correspondence: ; Tel.: +82-2-2164-4921
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32
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Jarak I, Varela CL, Tavares da Silva E, Roleira FFM, Veiga F, Figueiras A. Pluronic-based nanovehicles: Recent advances in anticancer therapeutic applications. Eur J Med Chem 2020; 206:112526. [PMID: 32971442 DOI: 10.1016/j.ejmech.2020.112526] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 05/27/2020] [Accepted: 06/01/2020] [Indexed: 02/06/2023]
Abstract
Pluronics are a class of amphiphilic tri-block copolymers with wide pharmaceutical applicability. In the past decades, the ability to form biocompatible nanosized micelles was exploited to formulate stable drug nanovehicles with potential use in antitumor therapy. Due to the great potential for tuning physical and structural properties of Pluronic unimers, a panoply of drug or polynucleotide-loaded micelles was prepared and tested for their antitumoral activity. The attractive inherent antitumor properties of Pluronic polymers in combination with cell targeting and stimuli-responsive ligands greatly improved antitumoral therapeutic effects of tested drugs. In spite of that, the extraordinary complexity of biological challenges in the delivery of micellar drug payload makes their therapeutic potential still not exploited to the fullest. In this review paper we attempt to present the latest developments in the field of Pluronic based nanovehicles and their application in anticancer therapy with an overview of the chemistry involved in the preparation of these nanovehicles.
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Affiliation(s)
- Ivana Jarak
- Univ. Coimbra, Department of Pharmaceutical Technology, Faculty of Pharmacy, Azinhaga de Santa Comba, Pólo III - Pólo das Ciências da Saúde, 3000-548, Coimbra, Portugal
| | - Carla L Varela
- Univ. Coimbra, CIEPQPF, FFUC, Laboratory of Pharmaceutical Chemistry, Azinhaga de Santa Comba, Pólo III - Pólo das Ciências da Saúde, 3000-548, Coimbra, Portugal
| | - Elisiário Tavares da Silva
- Univ. Coimbra, CIEPQPF, FFUC, Laboratory of Pharmaceutical Chemistry, Azinhaga de Santa Comba, Pólo III - Pólo das Ciências da Saúde, 3000-548, Coimbra, Portugal
| | - Fernanda F M Roleira
- Univ. Coimbra, CIEPQPF, FFUC, Laboratory of Pharmaceutical Chemistry, Azinhaga de Santa Comba, Pólo III - Pólo das Ciências da Saúde, 3000-548, Coimbra, Portugal
| | - Francisco Veiga
- Univ. Coimbra, Department of Pharmaceutical Technology, Faculty of Pharmacy, Azinhaga de Santa Comba, Pólo III - Pólo das Ciências da Saúde, 3000-548, Coimbra, Portugal; Univ. Coimbra, REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, Azinhaga de Santa Comba, Pólo III - Pólo das Ciências da Saúde, 3000-548, Coimbra, Portugal
| | - Ana Figueiras
- Univ. Coimbra, Department of Pharmaceutical Technology, Faculty of Pharmacy, Azinhaga de Santa Comba, Pólo III - Pólo das Ciências da Saúde, 3000-548, Coimbra, Portugal; Univ. Coimbra, REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, Azinhaga de Santa Comba, Pólo III - Pólo das Ciências da Saúde, 3000-548, Coimbra, Portugal.
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Kashapov R, Gaynanova G, Gabdrakhmanov D, Kuznetsov D, Pavlov R, Petrov K, Zakharova L, Sinyashin O. Self-Assembly of Amphiphilic Compounds as a Versatile Tool for Construction of Nanoscale Drug Carriers. Int J Mol Sci 2020; 21:E6961. [PMID: 32971917 PMCID: PMC7555343 DOI: 10.3390/ijms21186961] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/18/2020] [Accepted: 09/19/2020] [Indexed: 12/12/2022] Open
Abstract
This review focuses on synthetic and natural amphiphilic systems prepared from straight-chain and macrocyclic compounds capable of self-assembly with the formation of nanoscale aggregates of different morphology and their application as drug carriers. Since numerous biological species (lipid membrane, bacterial cell wall, mucous membrane, corneal epithelium, biopolymers, e.g., proteins, nucleic acids) bear negatively charged fragments, much attention is paid to cationic carriers providing high affinity for encapsulated drugs to targeted cells. First part of the review is devoted to self-assembling and functional properties of surfactant systems, with special attention focusing on cationic amphiphiles, including those bearing natural or cleavable fragments. Further, lipid formulations, especially liposomes, are discussed in terms of their fabrication and application for intracellular drug delivery. This section highlights several features of these carriers, including noncovalent modification of lipid formulations by cationic surfactants, pH-responsive properties, endosomal escape, etc. Third part of the review deals with nanocarriers based on macrocyclic compounds, with such important characteristics as mucoadhesive properties emphasized. In this section, different combinations of cyclodextrin platform conjugated with polymers is considered as drug delivery systems with synergetic effect that improves solubility, targeting and biocompatibility of formulations.
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Affiliation(s)
- Ruslan Kashapov
- A.E. Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov street 8, Kazan 420088, Russia; (G.G.); (D.G.); (D.K.); (R.P.); (K.P.); (L.Z.); (O.S.)
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Chilug LE, Niculae D, Leonte RA, Nan A, Turcu R, Mustaciosu C, Serban RM, Lavric V, Manda G. Preclinical Evaluation of NHS-Activated Gold Nanoparticles Functionalized with Bombesin or Neurotensin-Like Peptides for Targeting Colon and Prostate Tumours. Molecules 2020; 25:E3363. [PMID: 32722221 PMCID: PMC7435928 DOI: 10.3390/molecules25153363] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/13/2020] [Accepted: 07/22/2020] [Indexed: 11/17/2022] Open
Abstract
Recent advances and large-scale use of hybrid imaging modalities like PET-CT have led to the necessity of improving nano-drug carriers that can facilitate both functional and metabolic screening in nuclear medicine applications. In this study, we focused on the evaluation of four potential imaging nanoparticle structures labelled with the 68Ga positron emitter. For this purpose, we functionalized NHS-activated PEG-gold nanoparticles with 68Ga-DOTA-Neuromedin B, 68Ga-DOTA-PEG(4)-BBN(7-14), 68Ga-DOTA-NT and 68Ga-DOTA-Neuromedin N. In vitro binding kinetics and specific binding to human HT-29 colon carcinoma cells and DU-145 prostate carcinoma cells respectively were assessed, over 75% retention being obtained in the case of 68Ga-DOTA-PEG(4)-BBN(7-14)-AuNP in prostate tumour cells and over 50% in colon carcinoma cells. Biodistribution in NU/J mice highlighted a three-fold uptake increase in tumours at 30 min post-injection of 68Ga-DOTA-NT-AuNP and 68Ga-DOTA-PEG(4)-BBN(7-14)-AuNP compared to 68Ga-DOTA-NT and 68Ga-DOTA-PEG(4)-BBN(7-14) respectively, therewith fast distribution in prostate and colon tumours and minimum accumulation in non-targeted tissues.
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Affiliation(s)
- Livia Elena Chilug
- Radiopharmaceutical Research Centre, Horia Hulubei National Institute for R&D in Physics and Nuclear Engineering, 30 Reactorului Street, Magurele, 077125 Ilfov, Romania; (L.E.C.); (R.A.L.); (C.M.); (R.M.S.)
- Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, 1–7 Polizu Street, 011061 Bucharest, Romania;
| | - Dana Niculae
- Radiopharmaceutical Research Centre, Horia Hulubei National Institute for R&D in Physics and Nuclear Engineering, 30 Reactorului Street, Magurele, 077125 Ilfov, Romania; (L.E.C.); (R.A.L.); (C.M.); (R.M.S.)
| | - Radu Anton Leonte
- Radiopharmaceutical Research Centre, Horia Hulubei National Institute for R&D in Physics and Nuclear Engineering, 30 Reactorului Street, Magurele, 077125 Ilfov, Romania; (L.E.C.); (R.A.L.); (C.M.); (R.M.S.)
| | - Alexandrina Nan
- National Institute for Research and Development of Isotopic and Molecular Technologies, 67–103 Donat Street, 400293 Cluj-Napoca, Romania; (A.N.); (R.T.)
| | - Rodica Turcu
- National Institute for Research and Development of Isotopic and Molecular Technologies, 67–103 Donat Street, 400293 Cluj-Napoca, Romania; (A.N.); (R.T.)
| | - Cosmin Mustaciosu
- Radiopharmaceutical Research Centre, Horia Hulubei National Institute for R&D in Physics and Nuclear Engineering, 30 Reactorului Street, Magurele, 077125 Ilfov, Romania; (L.E.C.); (R.A.L.); (C.M.); (R.M.S.)
- Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, 1–7 Polizu Street, 011061 Bucharest, Romania;
| | - Radu Marian Serban
- Radiopharmaceutical Research Centre, Horia Hulubei National Institute for R&D in Physics and Nuclear Engineering, 30 Reactorului Street, Magurele, 077125 Ilfov, Romania; (L.E.C.); (R.A.L.); (C.M.); (R.M.S.)
- Faculty of Biology, University of Bucharest, 91–95 Splaiul Independentei Street, 050095 Bucharest, Romania
| | - Vasile Lavric
- Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, 1–7 Polizu Street, 011061 Bucharest, Romania;
| | - Gina Manda
- Victor Babes National Institute of Pathology, 99–101 Splaiul Independentei Street, 050096 Bucharest, Romania;
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Shetab Boushehri MA, Dietrich D, Lamprecht A. Nanotechnology as a Platform for the Development of Injectable Parenteral Formulations: A Comprehensive Review of the Know-Hows and State of the Art. Pharmaceutics 2020; 12:pharmaceutics12060510. [PMID: 32503171 PMCID: PMC7356945 DOI: 10.3390/pharmaceutics12060510] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 05/24/2020] [Indexed: 12/11/2022] Open
Abstract
Within recent decades, the development of nanotechnology has made a significant contribution to the progress of various fields of study, including the domains of medical and pharmaceutical sciences. A substantially transformed arena within the context of the latter is the development and production of various injectable parenteral formulations. Indeed, recent decades have witnessed a rapid growth of the marketed and pipeline nanotechnology-based injectable products, which is a testimony to the remarkability of the aforementioned contribution. Adjunct to the ability of nanomaterials to deliver the incorporated payloads to many different targets of interest, nanotechnology has substantially assisted to the development of many further facets of the art. Such contributions include the enhancement of the drug solubility, development of long-acting locally and systemically injectable formulations, tuning the onset of the drug’s release through the endowment of sensitivity to various internal or external stimuli, as well as adjuvancy and immune activation, which is a desirable component for injectable vaccines and immunotherapeutic formulations. The current work seeks to provide a comprehensive review of all the abovementioned contributions, along with the most recent advances made within each domain. Furthermore, recent developments within the domains of passive and active targeting will be briefly debated.
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Affiliation(s)
- Maryam A. Shetab Boushehri
- Department of Pharmaceutics, Faculty of Pharmacy, University of Bonn, 53121 Bonn, Germany;
- Correspondence: ; Tel.: +49-228-736428; Fax: +49-228-735268
| | - Dirk Dietrich
- Department of Neurosurgery, University Clinic of Bonn, 53105 Bonn, Germany;
| | - Alf Lamprecht
- Department of Pharmaceutics, Faculty of Pharmacy, University of Bonn, 53121 Bonn, Germany;
- PEPITE EA4267, Institute of Pharmacy, University Bourgogne Franche-Comté, 25000 Besançon, France
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36
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Xu Y, Wei L, Wang H. Progress and perspectives on nanoplatforms for drug delivery to the brain. J Drug Deliv Sci Technol 2020. [DOI: 10.1016/j.jddst.2020.101636] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Zhang J, Shen H, Xu J, Liu L, Tan J, Li M, Xu N, Luo S, Wang J, Yang F, Tang J, Li Q, Wang Y, Yu L, Yan Z. Liver-Targeted siRNA Lipid Nanoparticles Treat Hepatic Cirrhosis by Dual Antifibrotic and Anti-inflammatory Activities. ACS NANO 2020; 14:6305-6322. [PMID: 32378877 DOI: 10.1021/acsnano.0c02633] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Previous studies on the treatment of hepatic cirrhosis have been focusing on how to inhibit liver fibrosis, while ignoring liver inflammation, a key and underlying factor that promotes cirrhosis. High mobility group box-1 (HMGB1) protein, a pro-inflammatory factor and fibroblast chemokine, can promote the proliferation of hepatic stellate cells (HSCs) and the development of hepatic inflammation and fibrosis, playing a key role in cirrhosis formation. In this study, we prepared pPB peptide (C*SRNLIDC*)-modified and HMGB1-siRNA-loaded stable nucleic acid lipid nanoparticles (HMGB1-siRNA@SNALP-pPB) to effectively treat hepatic cirrhosis by their dual antifibrotic and anti-inflammatory activities. The pPB peptide-modified and heat shock protein 47 (HSP47)-siRNA-loaded stable nucleic acid lipid nanoparticles (HSP47-siRNA@SNALP-pPB), which have only an antifibrotic effect without an anti-inflammatory effect, was used as control. The results demonstrated that HMGB1-siRNA@SNALP-pPB were actively targeted to HSCs by the mediation of pPB peptide, effectively silenced the HMGB1 gene, inhibited the activation and proliferation of HSCs, reduced the release of HMGB1 protein, inhibited collagen deposition and fibrosis formation in the liver, and significantly prolonged the survival time of cirrhotic mice models. HMGB1-siRNA@SNALP-pPB showed a stronger therapeutic effect on liver cirrhosis than HSP47-siRNA@SNALP-pPB. This study provides an actively targeted siRNA delivery system for cirrhosis treatment based on the dual antifibrotic and anti-inflammatory effects. In addition, this study clarified the role of inflammatory problems in cirrhosis treatment in addition to liver fibrosis, providing a useful idea and scientific basis for the development of cirrhosis treatment strategies in the future.
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Affiliation(s)
- Jinfang Zhang
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, People's Republic of China
| | - Hongwei Shen
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, People's Republic of China
| | - Jiaojiao Xu
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, People's Republic of China
| | - Li Liu
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, People's Republic of China
| | - Jingwen Tan
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, People's Republic of China
| | - Minghao Li
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, People's Republic of China
| | - Nan Xu
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, People's Republic of China
| | - Shenggen Luo
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, People's Republic of China
| | - Jing Wang
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, People's Republic of China
| | - Fan Yang
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, People's Republic of China
| | - Jie Tang
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, People's Republic of China
| | - Qinghua Li
- Department of Hepatology and Pancreatology, Shanghai East Hospital, Tongji University, Shanghai 200120, People's Republic of China
| | - Yiting Wang
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, People's Republic of China
| | - Lei Yu
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, People's Republic of China
| | - Zhiqiang Yan
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, People's Republic of China
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38
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Wu PH, Opadele AE, Onodera Y, Nam JM. Targeting Integrins in Cancer Nanomedicine: Applications in Cancer Diagnosis and Therapy. Cancers (Basel) 2019; 11:E1783. [PMID: 31766201 PMCID: PMC6895796 DOI: 10.3390/cancers11111783] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 02/08/2023] Open
Abstract
Due to advancements in nanotechnology, the application of nanosized materials (nanomaterials) in cancer diagnostics and therapeutics has become a leading area in cancer research. The decoration of nanomaterial surfaces with biological ligands is a major strategy for directing the actions of nanomaterials specifically to cancer cells. These ligands can bind to specific receptors on the cell surface and enable nanomaterials to actively target cancer cells. Integrins are one of the cell surface receptors that regulate the communication between cells and their microenvironment. Several integrins are overexpressed in many types of cancer cells and the tumor microvasculature and function in the mediation of various cellular events. Therefore, the surface modification of nanomaterials with integrin-specific ligands not only increases their binding affinity to cancer cells but also enhances the cellular uptake of nanomaterials through the intracellular trafficking of integrins. Moreover, the integrin-specific ligands themselves interfere with cancer migration and invasion by interacting with integrins, and this finding provides a novel direction for new treatment approaches in cancer nanomedicine. This article reviews the integrin-specific ligands that have been used in cancer nanomedicine and provides an overview of the recent progress in cancer diagnostics and therapeutic strategies involving the use of integrin-targeted nanomaterials.
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Affiliation(s)
- Ping-Hsiu Wu
- Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo 060-8638, Hokkaido, Japan
| | - Abayomi Emmanuel Opadele
- Molecular and Cellular Dynamics Research, Graduate School of Biomedical Science and Engineering, Hokkaido University, Sapporo 060-8638, Hokkaido, Japan;
| | - Yasuhito Onodera
- Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo 060-8638, Hokkaido, Japan
- Department of Molecular Biology, Faculty of Medicine, Hokkaido University, Sapporo 060-8638, Hokkaido, Japan
| | - Jin-Min Nam
- Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo 060-8638, Hokkaido, Japan
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Das M, Huang L. Liposomal Nanostructures for Drug Delivery in Gastrointestinal Cancers. J Pharmacol Exp Ther 2019; 370:647-656. [PMID: 30541917 PMCID: PMC6812858 DOI: 10.1124/jpet.118.254797] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 12/11/2018] [Indexed: 12/19/2022] Open
Abstract
Gastrointestinal (GI) cancers like liver, pancreatic, colorectal, and gastric cancer remain some of the most difficult and aggressive cancers. Nanoparticles like liposomes had been approved in the clinic for cancer therapy dating as far back as 1995. Over the years, liposomal formulations have come a long way, facing several roadblocks and failures, and advancing by optimizing formulations and incorporating novel design approaches to navigate therapeutic delivery challenges. The first liposomal formulation for a GI cancer drug was approved recently in 2015, setting the stage for further clinical developments of liposome-based delivery systems for therapies against GI malignancies. This article reviews the design considerations and strategies that can be used to deliver drugs to GI tumors, the wide range of therapeutic agents that have been explored in preclinical as well as clinical studies, and the current therapies that are being investigated in the clinic against GI malignancies.
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Affiliation(s)
- Manisit Das
- Division of Pharmacoengineering and Molecular Pharmaceutics, and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Leaf Huang
- Division of Pharmacoengineering and Molecular Pharmaceutics, and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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40
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Rathore B, Sunwoo K, Jangili P, Kim J, Kim JH, Huang M, Xiong J, Sharma A, Yang Z, Qu J, Kim JS. Nanomaterial designing strategies related to cell lysosome and their biomedical applications: A review. Biomaterials 2019; 211:25-47. [DOI: 10.1016/j.biomaterials.2019.05.002] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 05/01/2019] [Accepted: 05/02/2019] [Indexed: 01/04/2023]
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41
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Arabipour I, Amani J, Mirhosseini SA, Salimian J. The study of genes and signal transduction pathways involved in mustard lung injury: A gene therapy approach. Gene 2019; 714:143968. [PMID: 31323308 DOI: 10.1016/j.gene.2019.143968] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Revised: 07/06/2019] [Accepted: 07/08/2019] [Indexed: 02/06/2023]
Abstract
Sulfur mustard (SM) is a destructive and harmful chemical agent for the eyes, skin and lungs that causes short-term and long-term lesions and was widely used in Iraq war against Iran (1980-1988). SM causes DNA damages, oxidative stress, and Inflammation. Considering the similarities between SM and COPD (Chronic Obstructive Pulmonary Disease) pathogens and limited available treatments, a novel therapeutic approach is not developed. Gene therapy is a novel therapeutic approach that uses genetic engineering science in treatment of most diseases including chronic obstructive pulmonary disease. In this review, attempts to presenting a comprehensive study of mustard lung and introducing the genes therapy involved in chronic obstructive pulmonary disease and emphasizing the pathways and genes involved in the pathology and pathogenesis of sulfur Mustard. It seems that, given the high potential of gene therapy and the fact that this experimental technique is a candidate for the treatment of pulmonary diseases, further study of genes, vectors and gene transfer systems can draw a very positive perspective of gene therapy in near future.
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Affiliation(s)
- Iman Arabipour
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Jafar Amani
- Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Seyed Ali Mirhosseini
- Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Jafar Salimian
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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42
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Du M, Ouyang Y, Meng F, Ma Q, Liu H, Zhuang Y, Pang M, Cai T, Cai Y. Nanotargeted agents: an emerging therapeutic strategy for breast cancer. Nanomedicine (Lond) 2019; 14:1771-1786. [PMID: 31298065 DOI: 10.2217/nnm-2018-0481] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Breast cancer is the most common female cancer worldwide and represents 12% of all cancer cases. Improvements in survival rates are largely attributed to improved screening and diagnosis. Conventional chemotherapy remains an important treatment option but it is beset with poor cell selectivity, serious side effects and resistance. Nanoparticle drug delivery systems bring promising opportunities to breast cancer treatment. They may improve chemotherapy by targeting drugs to tumors, generating high drug concentrations at tumors providing slow release of the drug, increased drug stability and concomitant reductions in side effects. The nanotechnology-based drug delivery approaches and the current research and application status of nano-targeted agents for breast cancer are discussed in this review to provide a basis for further study on targeted drug delivery systems.
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Affiliation(s)
- Manling Du
- College of Pharmacy, Jinan University, Guangzhou 510632, PR China
| | - Yong Ouyang
- Guangzhou Hospital of Integrated Traditional Chinese & Western Medicine, Guangzhou 510800, PR China
| | - Fansu Meng
- Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of TCM, Zhongshan, Guangdong 528400, PR China
| | - Qianqian Ma
- College of Pharmacy, Jinan University, Guangzhou 510632, PR China
| | - Hui Liu
- College of Pharmacy, Jinan University, Guangzhou 510632, PR China
| | - Yong Zhuang
- College of Pharmacy, Jinan University, Guangzhou 510632, PR China
| | - Mujuan Pang
- College of Pharmacy, Jinan University, Guangzhou 510632, PR China
| | - Tiange Cai
- College of Life Sciences, Liaoning University, Shenyang 110036, PR China
| | - Yu Cai
- College of Pharmacy, Jinan University, Guangzhou 510632, PR China.,Cancer Research Institute of Jinan University, Guangzhou 510632, PR China
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Chen HJ, Hang T, Yang C, Liu D, Su C, Xiao S, Liu C, Lin DA, Zhang T, Jin Q, Tao J, Wu MX, Wang J, Xie X. Functionalized Spiky Particles for Intracellular Biomolecular Delivery. ACS CENTRAL SCIENCE 2019; 5:960-969. [PMID: 31263755 PMCID: PMC6598163 DOI: 10.1021/acscentsci.8b00749] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Indexed: 05/08/2023]
Abstract
The intracellular delivery of biomolecules is of significant importance yet challenging. In addition to the conventional delivery of nanomaterials that rely on biochemical pathways, vertical nanowires have been recently proposed to physically penetrate the cell membrane, thus enabling the direct release of biomolecules into the cytoplasm circumventing endosomal routes. However, due to the inherent attachment of the nanowires to a planar 2D substrate, nanowire cell penetrations are restricted to in vitro applications, and they are incapable of providing solution-based delivery. To overcome this structural limitation, we created polyethylenimine-functionalized microparticles covered with nanospikes, namely, "spiky particles", to deliver biomolecules by utilizing the nanospikes to penetrate the cell membrane. The nanospikes might penetrate the cell membrane during particle engulfment, and this enables the bound biomolecules to be released directly into the cytosol. TiO2 spiky particles were fabricated through hydrothermal routes, and they were demonstrated to be biocompatible with HeLa cells, macrophage-like RAW cells, and fibroblast-like 3T3-L1 cells. The polyethylenimine-functionalized spiky particles provided direct delivery of fluorescent siRNA into cell cytosol and functional siRNA for gene knockdown as well as successful DNA plasmid transfection which were difficult to achieve by using microparticles without nanospikes. The spiky particles presented a unique direct cell membrane penetrant vehicle to introduce biomolecules into cell cytosol, where the biomolecules might bypass conventional endocytic degradation routes.
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Affiliation(s)
- Hui-Jiuan Chen
- The
First Affiliated Hospital of Sun Yat-Sen University; State Key Laboratory
of Optoelectronic Materials and Technologies, School of Electronics
and Information Technology, Sun Yat-Sen
University, Guangzhou 510275, China
| | - Tian Hang
- The
First Affiliated Hospital of Sun Yat-Sen University; State Key Laboratory
of Optoelectronic Materials and Technologies, School of Electronics
and Information Technology, Sun Yat-Sen
University, Guangzhou 510275, China
| | - Chengduan Yang
- The
First Affiliated Hospital of Sun Yat-Sen University; State Key Laboratory
of Optoelectronic Materials and Technologies, School of Electronics
and Information Technology, Sun Yat-Sen
University, Guangzhou 510275, China
| | - Di Liu
- Pritzker
School of Medicine, University of Chicago, Chicago, Illinois 60637, United States
| | - Chen Su
- The
First Affiliated Hospital of Sun Yat-Sen University; State Key Laboratory
of Optoelectronic Materials and Technologies, School of Electronics
and Information Technology, Sun Yat-Sen
University, Guangzhou 510275, China
| | - Shuai Xiao
- The
First Affiliated Hospital of Sun Yat-Sen University; State Key Laboratory
of Optoelectronic Materials and Technologies, School of Electronics
and Information Technology, Sun Yat-Sen
University, Guangzhou 510275, China
| | - Chenglin Liu
- The
First Affiliated Hospital of Sun Yat-Sen University; State Key Laboratory
of Optoelectronic Materials and Technologies, School of Electronics
and Information Technology, Sun Yat-Sen
University, Guangzhou 510275, China
| | - Di-an Lin
- The
First Affiliated Hospital of Sun Yat-Sen University; State Key Laboratory
of Optoelectronic Materials and Technologies, School of Electronics
and Information Technology, Sun Yat-Sen
University, Guangzhou 510275, China
| | - Tao Zhang
- The
First Affiliated Hospital of Sun Yat-Sen University; State Key Laboratory
of Optoelectronic Materials and Technologies, School of Electronics
and Information Technology, Sun Yat-Sen
University, Guangzhou 510275, China
- College
of Electrical and Information Engineering, Huaihua University, Huaihua 418000, China
| | - Quanchang Jin
- The
First Affiliated Hospital of Sun Yat-Sen University; State Key Laboratory
of Optoelectronic Materials and Technologies, School of Electronics
and Information Technology, Sun Yat-Sen
University, Guangzhou 510275, China
| | - Jun Tao
- The
First Affiliated Hospital of Sun Yat-Sen University; State Key Laboratory
of Optoelectronic Materials and Technologies, School of Electronics
and Information Technology, Sun Yat-Sen
University, Guangzhou 510275, China
| | - Mei X. Wu
- Department
of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Ji Wang
- The
First Affiliated Hospital of Sun Yat-Sen University; State Key Laboratory
of Optoelectronic Materials and Technologies, School of Electronics
and Information Technology, Sun Yat-Sen
University, Guangzhou 510275, China
- Department
of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Xi Xie
- The
First Affiliated Hospital of Sun Yat-Sen University; State Key Laboratory
of Optoelectronic Materials and Technologies, School of Electronics
and Information Technology, Sun Yat-Sen
University, Guangzhou 510275, China
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Amiri S, Dastghaib S, Ahmadi M, Mehrbod P, Khadem F, Behrouj H, Aghanoori MR, Machaj F, Ghamsari M, Rosik J, Hudecki A, Afkhami A, Hashemi M, Los MJ, Mokarram P, Madrakian T, Ghavami S. Betulin and its derivatives as novel compounds with different pharmacological effects. Biotechnol Adv 2019; 38:107409. [PMID: 31220568 DOI: 10.1016/j.biotechadv.2019.06.008] [Citation(s) in RCA: 128] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Revised: 05/30/2019] [Accepted: 06/13/2019] [Indexed: 02/07/2023]
Abstract
Betulin (B) and Betulinic acid (BA) are natural pentacyclic lupane-structure triterpenoids which possess a wide range of pharmacological activities. Recent evidence indicates that B and BA have several properties useful for the treatment of metabolic disorders, infectious diseases, cardiovascular disorders, and neurological disorders. In the current review, we discuss B and BA structures and derivatives and then comprehensively explain their pharmacological effects in relation to various diseases. We also explain antiviral, antibacterial and anti-cancer effects of B and BA. Finally, we discuss the delivery methods, in which these compounds most effectively target different systems.
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Affiliation(s)
- Shayan Amiri
- Department of Human Anatomy and Cell Science, Rady College of Medicine, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
| | - Sanaz Dastghaib
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mazaher Ahmadi
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Parvaneh Mehrbod
- Influenza and Respiratory Viruses Department, Pasteur Institute of IRAN, Tehran, Iran
| | - Forough Khadem
- Department of Immunology, Rady College of Medicine, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
| | - Hamid Behrouj
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohamad-Reza Aghanoori
- Division of Neurodegenerative Disorders, St Boniface Hospital Albrechtsen Research Centre, Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada
| | - Filip Machaj
- Department of Pathology, Pomeranian Medical University, ul. Unii Lubelskiej 1, 71-344 Szczecin, Poland
| | - Mahdi Ghamsari
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Jakub Rosik
- Department of Pathology, Pomeranian Medical University, ul. Unii Lubelskiej 1, 71-344 Szczecin, Poland
| | - Andrzej Hudecki
- Institue of Non-Ferrous Metals, ul. Sowińskiego 5, 44-100 Gliwice, Poland
| | - Abbas Afkhami
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Mohammad Hashemi
- Department of Clinical Biochemistry, Zahedan University of Medical Science, Zahedan, Iran
| | - Marek J Los
- Biotechnology Center, Silesian University of Technology, ul Bolesława Krzywoustego 8, Gliwice, Poland; Linkocare Life Sciences AB, Teknikringen 10, Plan 3, 583 30 Linköping, Sweden
| | - Pooneh Mokarram
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tayyebeh Madrakian
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Rady College of Medicine, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada; Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran; Research Institute of Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada.
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Suicide Gene Therapy By Amphiphilic Copolymer Nanocarrier for Spinal Cord Tumor. NANOMATERIALS 2019; 9:nano9040573. [PMID: 30965667 PMCID: PMC6523721 DOI: 10.3390/nano9040573] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 03/30/2019] [Accepted: 03/30/2019] [Indexed: 02/06/2023]
Abstract
Spinal cord tumors (SCT) are uncommon neoplasms characterized by irregular growth of tissue inside the spinal cord that can result in non-mechanical back pain. Current treatments for SCT include surgery, radiation therapy, and chemotherapy, but these conventional therapies have many limitations. Suicide gene therapy using plasmid encoding herpes simplex virus-thymidine kinase (pHSV-TK) and ganciclovir (GCV) has been an alternative approach to overcome the limitations of current therapies. However, there is a need to develop a carrier that can deliver both pHSV-TK and GCV for improving therapeutic efficacy. Our group developed a cationic, amphiphilic copolymer, poly (lactide-co-glycolide) -graft-polyethylenimine (PgP), and demonstrated its efficacy as a drug and gene carrier in both cell culture studies and animal models. In this study, we evaluated PgP as a gene carrier and demonstrate that PgP can efficiently deliver reporter genes, pGFP in rat glioma (C6) cells in vitro, and pβ-gal in a rat T5 SCT model in vivo. We also show that PgP/pHSV-TK with GCV treatment showed significantly higher anticancer activity in C6 cells compared to PgP/pHSV-TK without GCV treatment. Finally, we demonstrate that PgP/pHSV-TK with GCV treatment increases the suicide effect and apoptosis of tumor cells and reduces tumor size in a rat T5 SCT model.
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Zang X, Zhang X, Zhao X, Hu H, Qiao M, Deng Y, Chen D. Targeted Delivery of miRNA 155 to Tumor Associated Macrophages for Tumor Immunotherapy. Mol Pharm 2019; 16:1714-1722. [DOI: 10.1021/acs.molpharmaceut.9b00065] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Xinlong Zang
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China
| | - Xiaoxu Zhang
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China
| | - Xiuli Zhao
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China
| | - Haiyang Hu
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China
| | - Mingxi Qiao
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China
| | - Yihui Deng
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China
| | - Dawei Chen
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China
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47
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Sangsuwan R, Tachachartvanich P, Francis MB. Cytosolic Delivery of Proteins Using Amphiphilic Polymers with 2-Pyridinecarboxaldehyde Groups for Site-Selective Attachment. J Am Chem Soc 2019; 141:2376-2383. [DOI: 10.1021/jacs.8b10947] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
| | | | - Matthew B. Francis
- Materials Sciences Division, Lawrence Berkeley National Laboratories, Berkeley, California 94720, United States
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48
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Chandela A, Ueno Y. Systemic Delivery of Small Interfering RNA Therapeutics: Obstacles and Advances. ACTA ACUST UNITED AC 2019. [DOI: 10.7831/ras.7.10] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Akash Chandela
- United Graduate School of Agricultural Science, Gifu University
| | - Yoshihito Ueno
- United Graduate School of Agricultural Science, Gifu University
- Course of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University
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50
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Kefayat A, Ghahremani F, Motaghi H, Amouheidari A. Ultra-small but ultra-effective: Folic acid-targeted gold nanoclusters for enhancement of intracranial glioma tumors' radiation therapy efficacy. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2018; 16:173-184. [PMID: 30594659 DOI: 10.1016/j.nano.2018.12.007] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2018] [Revised: 12/12/2018] [Accepted: 12/14/2018] [Indexed: 12/31/2022]
Abstract
The aim of the present study is to investigate folic acid and BSA decorated gold nanoclusters (FA-AuNCs) effect on the enhancement of intracranial C6 glioma tumors radiation therapy (RT) efficacy. Inductively coupled plasma optical emission spectrometry (ICP-OES) measurements exhibited about 2.5 times more FA-AuNCs uptake by C6 cancer cells (32.8 ng/106 cells) than the normal cells. FA-AuNCs had significantly higher concentration in the brain tumors (8.1 μg/mg) in comparison with surrounding normal brain tissue (4.3 μg/mg). Moreover, FA-AuNCs exhibited dose enhancement factor (DEF) of 1.6. The glioma-bearing rats' survival times were almost doubled at radiation therapy + FA-AuNCs (25.0 ± 1.5 days) in comparison with no-treatment group (12.8 ± 0.7 days). The Ki-67 labeling index was 48.89% ± 9.93 for control, 29.98% ± 8.32 for RT, and 11.53% ± 7.65 for RT + FA-AuNCs. Therefore, FA-AuNCs can be effective radiosensitizers for intracranial glioma tumors RT.
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Affiliation(s)
- Amirhosein Kefayat
- Department of Oncology, Cancer Prevention Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fatemeh Ghahremani
- Department of Medical Physics and Radiotherapy, Arak University of Medical Sciences, Arak, Iran..
| | - Hasan Motaghi
- Department of Science, Farhangian University, Tehran, Iran
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