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Abdelhamid MS, Wadan AHS, Saad HA, El-Dakroury WA, Hageen AW, Mohammed DH, Mourad S, Mohammed OA, Abdel-Reheim MA, Doghish AS. Nanoparticle innovations in targeted cancer therapy: advancements in antibody-drug conjugates. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:6369-6389. [PMID: 39825965 DOI: 10.1007/s00210-024-03764-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Accepted: 12/23/2024] [Indexed: 01/20/2025]
Abstract
Antibody-drug conjugates (ADCs) have emerged as a promising strategy in targeted cancer therapy, enabling the precise delivery of cytotoxic agents to tumor sites while minimizing systemic toxicity. However, traditional ADCs face significant limitations, including restricted drug loading capacity, where an optimal drug-to-antibody ratio (DAR) is crucial; low DARs may lead to insufficient potency, while high DARs can cause rapid clearance and increased toxicity. Additionally, ADCs often suffer from instability in circulation due to the potential for premature release of cytotoxic agents, resulting in off-target effects and reduced therapeutic efficacy. Furthermore, their large size can impede adequate penetration into solid tumors, particularly in heterogeneous environments with varying antigen expressions. This review explores the innovative use of nanoparticles as carriers for ADCs, which offers a multifaceted approach to enhance therapeutic efficacy. By leveraging the unique properties of nanoparticles, such as their small size and ability to exploit the enhanced permeability and retention (EPR) effect, researchers can improve drug stability, prolong circulation time, and achieve more effective tumor targeting. Recent studies demonstrate that nanoparticle-encapsulated ADCs can significantly enhance treatment outcomes while reducing off-target effects, as evidenced by improved targeting capabilities and reduced toxicity in preclinical models. Despite the promising advancements, challenges remain, including potential nanoparticle toxicity and manufacturing complexities. This review aims to provide a comprehensive overview of the current research on nanoparticle-encapsulated ADCs. It highlights their potential to transform cancer treatment and offers insights into future directions for optimizing these advanced therapeutic strategies.
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Affiliation(s)
| | - Al-Hassan Soliman Wadan
- Oral Biology Department, Faculty of Dentistry, Galala University, Galala Plateau, Attaka, 15888, Suez Governorate, Egypt
| | - Hager Adel Saad
- Faculty of Pharmacy, German University in Cairo (GUC), New Cairo, 11835, Cairo, Egypt
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Ahmed W Hageen
- Faculty of Medicine, Tanta University, Tanta, 31527, Egypt
| | | | - Sohaila Mourad
- Faculty of Medicine, Alexandria University, Alexandria, 21526, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, 61922, Bisha, Saudi Arabia
| | | | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt.
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt.
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Abbas SJ, Yesmin S, Vittala SK, Sepay N, Xia F, Ali SI, Chang WC, Hung YC, Ma WL. Target Bioconjugation of Protein Through Chemical, Molecular Dynamics, and Artificial Intelligence Approaches. Metabolites 2024; 14:668. [PMID: 39728449 DOI: 10.3390/metabo14120668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 11/18/2024] [Accepted: 11/22/2024] [Indexed: 12/28/2024] Open
Abstract
Covalent modification of proteins at specific, predetermined sites is essential for advancing biological and biopharmaceutical applications. Site-selective labeling techniques for protein modification allow us to effectively track biological function, intracellular dynamics, and localization. Despite numerous reports on modifying target proteins with functional chemical probes, unique organic reactions that achieve site-selective integration without compromising native functional properties remain a significant challenge. In this review, we delve into site-selective protein modification using synthetic probes, highlighting both chemical and computational methodologies for chemo- and regioselective modifications of naturally occurring amino acids, as well as proximity-driven protein-selective chemical modifications. We also underline recent traceless affinity labeling strategies that involve exchange/cleavage reactions and catalyst tethering modifications. The rapid development of computational infrastructure and methods has made the bioconjugation of proteins more accessible, enabling precise predictions of structural changes due to protein modifications. Hence, we discuss bioconjugational computational approaches, including molecular dynamics and artificial intelligence, underscoring their potential applications in enhancing our understanding of cellular biology and addressing current challenges in the field.
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Affiliation(s)
- Sk Jahir Abbas
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
- Department of Obstetrics and Gynecology, Asia University Hospital, Taichung 41354, Taiwan
| | - Sabina Yesmin
- Institute of Chemistry, Academia Sinica, Taipei 115201, Taiwan
- Department of Physics, National Dong Hwa University, Hualien 97401, Taiwan
| | - Sandeepa K Vittala
- Leiden Institute of Chemistry, Leiden University, 2300 RA Leiden, The Netherlands
| | - Nayim Sepay
- Department of Chemistry, Lady Brabourne College, Kolkata 700017, India
| | - Fangfang Xia
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Centre, Houston, TX 77030, USA
| | - Sk Imran Ali
- Department of Chemistry, University of Kalyani, Kalyani 741235, India
| | - Wei-Chun Chang
- Ph.D. Program for Health Science and Industry, China Medical University, Taichung 40402, Taiwan
- Department of Medical Research, Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung 40402, Taiwan
| | - Yao-Ching Hung
- Department of Obstetrics and Gynecology, Asia University Hospital, Taichung 41354, Taiwan
| | - Wen-Lung Ma
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
- Department of Medical Research, Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung 40402, Taiwan
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Park DD, Park SS, Dai E, Haller CA, Wong DJ, Wever WJ, Cummings RD, Chaikof EL. Intact quantitation and evaluation of a PEG-glycosulfopeptide as a therapeutic P-selectin antagonist. RSC Adv 2024; 14:34090-34099. [PMID: 39469021 PMCID: PMC11513618 DOI: 10.1039/d4ra05000b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 10/20/2024] [Indexed: 10/30/2024] Open
Abstract
Peptide-based therapeutics are recognized as potent and selective molecules but are often limited by short circulating half-lives, instability towards enzymatic degradation, and immunogenicity. To address these limitations and improve their pharmacological properties, peptides are commonly modified by the covalent attachment of polyethylene glycol (PEG). However, the large molecular weight and polydispersity of PEG chains complicate the interpretation of the full structure of PEGylated peptide therapeutics using standard analytical techniques. Here, we developed a mass spectrometric-based workflow in negative ion mode to identify and quantify GSnP-6, a P-selectin antagonist, with a linear 10 kDa PEG (PEG10) attached at the N-terminus of the glycopeptide. Intact mass analysis with multiple microscans allowed accurate measurements of precursor ions in complex biological mixtures with baseline resolution. Utilizing stepped collision energies improved sequence coverage and enabled identification of key amino acid modifications. We show the utility of this approach in evaluating the properties of PEG10-GSnP-6 in vitro and in vivo. Inhibitory capacity was preserved while extending the half-life of this glycopeptide, as shown by the reduction of P-selectin/PSGL-1 binding. By sustaining effective circulating concentrations, PEG conjugation of a P-selectin glycopeptide antagonist represents a promising therapeutic strategy to target diseases linked to inflammatory processes.
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Affiliation(s)
- Diane D Park
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School 110 Francis Street, Suite 9F, 330 Brookline Ave Boston MA 02215 USA +1-617-632-9581 +1-617-632-9701
- Wyss Institute for Biologically Inspired Engineering, Harvard University 3 Blackfan Circle Boston MA 02115 USA
| | - Simon S Park
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School 110 Francis Street, Suite 9F, 330 Brookline Ave Boston MA 02215 USA +1-617-632-9581 +1-617-632-9701
- Wyss Institute for Biologically Inspired Engineering, Harvard University 3 Blackfan Circle Boston MA 02115 USA
| | - Erbin Dai
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School 110 Francis Street, Suite 9F, 330 Brookline Ave Boston MA 02215 USA +1-617-632-9581 +1-617-632-9701
- Wyss Institute for Biologically Inspired Engineering, Harvard University 3 Blackfan Circle Boston MA 02115 USA
| | - Carolyn A Haller
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School 110 Francis Street, Suite 9F, 330 Brookline Ave Boston MA 02215 USA +1-617-632-9581 +1-617-632-9701
- Wyss Institute for Biologically Inspired Engineering, Harvard University 3 Blackfan Circle Boston MA 02115 USA
| | - Daniel J Wong
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School 110 Francis Street, Suite 9F, 330 Brookline Ave Boston MA 02215 USA +1-617-632-9581 +1-617-632-9701
- Wyss Institute for Biologically Inspired Engineering, Harvard University 3 Blackfan Circle Boston MA 02115 USA
| | - Walter J Wever
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School 110 Francis Street, Suite 9F, 330 Brookline Ave Boston MA 02215 USA +1-617-632-9581 +1-617-632-9701
- Wyss Institute for Biologically Inspired Engineering, Harvard University 3 Blackfan Circle Boston MA 02115 USA
| | - Richard D Cummings
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School 110 Francis Street, Suite 9F, 330 Brookline Ave Boston MA 02215 USA +1-617-632-9581 +1-617-632-9701
- Harvard Medical School Center for Glycoscience, Harvard Medical School Boston MA 02215 USA
| | - Elliot L Chaikof
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School 110 Francis Street, Suite 9F, 330 Brookline Ave Boston MA 02215 USA +1-617-632-9581 +1-617-632-9701
- Wyss Institute for Biologically Inspired Engineering, Harvard University 3 Blackfan Circle Boston MA 02115 USA
- Harvard Medical School Center for Glycoscience, Harvard Medical School Boston MA 02215 USA
- Division of Health Sciences and Technology, Massachusetts Institute of Technology Cambridge MA 02139 USA
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Vonderohe C, Stoll B, Didelija I, Nguyen T, Mohammad M, Jones-Hall Y, Cruz MA, Marini J, Burrin D. Citrulline and ADI-PEG20 reduce inflammation in a juvenile porcine model of acute endotoxemia. Front Immunol 2024; 15:1400574. [PMID: 39176089 PMCID: PMC11338849 DOI: 10.3389/fimmu.2024.1400574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 07/15/2024] [Indexed: 08/24/2024] Open
Abstract
Background Arginine is a conditionally essential amino acid that is depleted in critically ill or surgical patients. In pediatric and adult patients, sepsis results in an arginine-deficient state, and the depletion of plasma arginine is associated with greater mortality. However, direct supplementation of arginine can result in the excessive production of nitric oxide (NO), which can contribute to the hypotension and macrovascular hypo-reactivity observed in septic shock. Pegylated arginine deiminase (ADI-PEG20, pegargiminase) reduces plasma arginine and generates citrulline that can be transported intracellularly to generate local arginine and NO, without resulting in hypotension, while maintaining microvascular patency. The objective of this study was to assess the efficacy of ADI-PEG20 with and without supplemental intravenous citrulline in mitigating hypovolemic shock, maintaining tissue levels of arginine, and reducing systemic inflammation in an endotoxemic pediatric pig model. Methods Twenty 3-week-old crossbred piglets were implanted with jugular and carotid catheters as well as telemetry devices in the femoral artery to measure blood pressure, body temperature, heart rate, and respiration rate. The piglets were assigned to one of three treatments before undergoing a 5 h lipopolysaccharide (LPS) infusion protocol. Twenty-four hours before LPS infusion, control pigs (LPS; n=6) received saline, ADI-PEG20 pigs (n=7) received an injection of ADI-PEG20, and seven pigs (ADI-PEG20 + CIT pigs [n=7]) received ADI-PEG20 and 250 mg/kg citrulline intravenously. Pigs were monitored throughout LPS infusion and tissue was harvested at the end of the protocol. Results Plasma arginine levels decreased and remained low in ADI-PEG20 + CIT and ADI-PEG20 pigs compared with LPS pigs but tissue arginine levels in the liver and kidney were similar across all treatments. Mean arterial pressure in all groups decreased from 90 mmHg to 60 mmHg within 1 h of LPS infusion but there were no significant differences between treatment groups. ADI-PEG20 and ADI-PEG20 + CIT pigs had less CD45+ infiltrate in the liver and lung and lower levels of pro-inflammatory cytokines in the plasma. Conclusion ADI-PEG20 and citrulline supplementation failed to ameliorate the hypotension associated with acute endotoxic sepsis in pigs but reduced systemic and local inflammation in the lung and liver.
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Affiliation(s)
- Caitlin Vonderohe
- USDA-ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| | - Barbara Stoll
- USDA-ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| | - Inka Didelija
- USDA-ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| | - Trung Nguyen
- Pediatric Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veteran Administration Medical Center, Houston, TX, United States
| | - Mahmoud Mohammad
- USDA-ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| | - Yava Jones-Hall
- Department of Pathobiology, Texas A&M College of Veterinary Medicine and Biomedical Science, College Station, TX, United States
| | - Miguel A. Cruz
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veteran Administration Medical Center, Houston, TX, United States
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Juan Marini
- USDA-ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
- Pediatric Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| | - Douglas Burrin
- USDA-ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
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Hnamte L, Vanlallawmzuali, Kumar A, Yadav MK, Zothanpuia, Singh PK. An updated view of bacterial endophytes as antimicrobial agents against plant and human pathogens. CURRENT RESEARCH IN MICROBIAL SCIENCES 2024; 7:100241. [PMID: 39091295 PMCID: PMC11292266 DOI: 10.1016/j.crmicr.2024.100241] [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] [Indexed: 08/04/2024] Open
Abstract
Bacterial endophytes are a crucial component of the phytomicrobiome, playing an essential role in agriculture and industries. Endophytes are a rich source of bioactive compounds, serving as natural antibiotics that can be effective in combating antibiotic resistance in pathogens. These bacteria interact with host plants through various processes such as quorum sensing, chemotaxis, antibiosis, and enzymatic activity. The current paper focuses on how plants benefit extensively from endophytic bacteria and their symbiotic relationship in which the microbes enhance plant growth, nitrogen fixation, increase nutrient uptake, improve defense mechanisms, and act as antimicrobial agents against pathogens. Moreover, it highlights some of the bioactive compounds produced by endophytes.
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Affiliation(s)
- Lalhmangaihmawia Hnamte
- Department of Biotechnology/Life Sciences, Pachhunga University College (A Constituent College of Mizoram University), Aizawl-796001, Mizoram, India
| | - Vanlallawmzuali
- Department of Biotechnology/Life Sciences, Pachhunga University College (A Constituent College of Mizoram University), Aizawl-796001, Mizoram, India
| | - Ajay Kumar
- Amity institute of Biotechnology, Amity University, Noida-201313, India
| | - Mukesh Kumar Yadav
- Department of Microbiology, Central University of Punjab, Bathinda, Punjab, India
| | - Zothanpuia
- Department of Biotechnology/Life Sciences, Pachhunga University College (A Constituent College of Mizoram University), Aizawl-796001, Mizoram, India
| | - Prashant Kumar Singh
- Department of Biotechnology/Life Sciences, Pachhunga University College (A Constituent College of Mizoram University), Aizawl-796001, Mizoram, India
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Gong K, Jiao J, Wu Z, Wang Q, Liao J, Duan Y, Lin J, Yu J, Sun Y, Zhang Y, Duan Y. Nanosystem Delivers Senescence Activators and Immunomodulators to Combat Liver Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2308310. [PMID: 38520730 PMCID: PMC11132057 DOI: 10.1002/advs.202308310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 02/28/2024] [Indexed: 03/25/2024]
Abstract
CD47 blockade has emerged as a promising immunotherapy against liver cancer. However, the optimization of its antitumor effectiveness using efficient drug delivery systems or combinations of therapeutic agents remains largely incomplete. Here, patients with liver cancer co-expressing CD47 and CDC7 (cell division cycle 7, a negative senescence-related gene) are found to have the worst prognosis. Moreover, CD47 is highly expressed, and senescence is inhibited after the development of chemoresistance, suggesting that combination therapy targeting CD47 and CDC7 to inhibit CD47 and induce senescence may be a promising strategy for liver cancer. The efficacy of intravenously administered CDC7 and CD47 inhibitors is limited by low uptake and short circulation times. Here, inhibitors are coloaded into a dual-targeted nanosystem. The sequential release of the inhibitors from the nanosystem under acidic conditions first induces cellular senescence and then promotes immune responses. In an in situ liver cancer mouse model and a chemotherapy-resistant mouse model, the nanosystem effectively inhibited tumor growth by 90.33% and 85.15%, respectively. Overall, the nanosystem in this work achieved the sequential release of CDC7 and CD47 inhibitors in situ to trigger senescence and induce immunotherapy, effectively combating liver cancer and overcoming chemoresistance.
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Affiliation(s)
- Ke Gong
- State Key Laboratory of Systems Medicine for CancerShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200032P. R. China
| | - Juyang Jiao
- Department of Bone and Joint SurgeryDepartment of OrthopedicsRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200001P. R. China
| | - Zhihua Wu
- State Key Laboratory of Systems Medicine for CancerShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200032P. R. China
| | - Quan Wang
- State Key Laboratory of Systems Medicine for CancerShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200032P. R. China
| | - Jinghan Liao
- State Key Laboratory of Systems Medicine for CancerShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200032P. R. China
| | - Yi Duan
- State Key Laboratory of Systems Medicine for CancerShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200032P. R. China
| | - Jiangtao Lin
- State Key Laboratory of Systems Medicine for CancerShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200032P. R. China
| | - Jian Yu
- State Key Laboratory of Systems Medicine for CancerShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200032P. R. China
| | - Ying Sun
- State Key Laboratory of Systems Medicine for CancerShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200032P. R. China
| | - Yong Zhang
- School of Chemistry and Chemical EngineeringShanghai Key Laboratory of Electrical Insulation and Thermal AgingShanghai Jiao Tong UniversityShanghai200240P. R. China
| | - Yourong Duan
- State Key Laboratory of Systems Medicine for CancerShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200032P. R. China
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Li C, Li T, Tian X, An W, Wang Z, Han B, Tao H, Wang J, Wang X. Research progress on the PEGylation of therapeutic proteins and peptides (TPPs). Front Pharmacol 2024; 15:1353626. [PMID: 38523641 PMCID: PMC10960368 DOI: 10.3389/fphar.2024.1353626] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 02/22/2024] [Indexed: 03/26/2024] Open
Abstract
With the rapid advancement of genetic and protein engineering, proteins and peptides have emerged as promising drug molecules for therapeutic applications. Consequently, there has been a growing interest in the field of chemical modification technology to address challenges associated with their clinical use, including rapid clearance from circulation, immunogenicity, physical and chemical instabilities (such as aggregation, adsorption, deamination, clipping, oxidation, etc.), and enzymatic degradation. Polyethylene glycol (PEG) modification offers an effective solution to these issues due to its favorable properties. This review presents recent progress in the development and application of PEGylated therapeutic proteins and peptides (TPPs). For this purpose, firstly, the physical and chemical properties as well as classification of PEG and its derivatives are described. Subsequently, a detailed summary is provided on the main sites of PEGylated TPPs and the factors that influence their PEGylation. Furthermore, notable instances of PEG-modified TPPs (including antimicrobial peptides (AMPs), interferon, asparaginase and antibodies) are highlighted. Finally, we propose the chemical modification of TPPs with PEG, followed by an analysis of the current development status and future prospects of PEGylated TPPs. This work provides a comprehensive literature review in this promising field while facilitating researchers in utilizing PEG polymers to modify TPPs for disease treatment.
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Affiliation(s)
- Chunxiao Li
- Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, China
- Key Laboratory of Feed Biotechnology, Ministry of Agriculture and Rural Affairs, Beijing, China
| | - Ting Li
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China
| | - Xinya Tian
- Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, China
- Key Laboratory of Feed Biotechnology, Ministry of Agriculture and Rural Affairs, Beijing, China
| | - Wei An
- Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, China
- Key Laboratory of Feed Biotechnology, Ministry of Agriculture and Rural Affairs, Beijing, China
| | - Zhenlong Wang
- Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, China
- Key Laboratory of Feed Biotechnology, Ministry of Agriculture and Rural Affairs, Beijing, China
| | - Bing Han
- Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, China
- Key Laboratory of Feed Biotechnology, Ministry of Agriculture and Rural Affairs, Beijing, China
| | - Hui Tao
- Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, China
- Key Laboratory of Feed Biotechnology, Ministry of Agriculture and Rural Affairs, Beijing, China
| | - Jinquan Wang
- Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, China
- Key Laboratory of Feed Biotechnology, Ministry of Agriculture and Rural Affairs, Beijing, China
| | - Xiumin Wang
- Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, China
- Key Laboratory of Feed Biotechnology, Ministry of Agriculture and Rural Affairs, Beijing, China
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Qi J, Guo Z, Zhu S, Jiang X, Wu Y, Chen Y, Hu F, Xiong J, Wu Y, Ye X, Liang X. Therapeutic effect of long-acting FGF21 with controlled site-specific modification on nonalcoholic steatohepatitis. Int J Biol Macromol 2024; 261:129797. [PMID: 38290625 DOI: 10.1016/j.ijbiomac.2024.129797] [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: 08/15/2023] [Revised: 01/25/2024] [Accepted: 01/25/2024] [Indexed: 02/01/2024]
Abstract
FGF21 plays an active role in the treatment of type 2 diabetes, obesity, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). However, the short half-life and poor stability of wild-type FGF21 limit its clinical application. Previous studies found that PEGylation can significantly increase the stability of FGF21. However, the uneven distribution of PEGylation sites in FGF21 makes it difficult to purify PEG-FGF21, thereby affecting its yield, purity, and activity. To obtain long-acting FGF21 with controlled site-specific modification, we mutated lysine residues in FGF21, resulting in PEGylation only at the N-terminus of FGF21 (mFGF21). In addition, we modified mFGF21 molecules with different PEG molecules and selected the PEG-mFGF21 moiety with the highest activity. The yield of PEG-mFGF21 in this study reached 1 g/L (purity >99 %), and the purification process was simple and efficient with strong quality controllability. The half-life of PEG-mFGF21 in rats reached 40.5-67.4 h. Pharmacodynamic evaluation in mice with high-fat, high-cholesterol- and methionine and choline deficiency-induced NASH illustrated that PEG-mFGF21 exhibited long-term efficacy in improving liver steatosis and reducing liver cell damage, inflammation, and fibrosis. Taken together, PEG-mFGF21 could represent a potential therapeutic drug for the treatment of NASH.
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Affiliation(s)
- Jianying Qi
- National Research Centre for Carbohydrate Synthesis, Jiangxi Normal University, 99 Ziyang Avenue, Nanchang 330022, China
| | - Zhimou Guo
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China; Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road 457, Dalian 116023, China
| | - Shenglong Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China
| | - Xuan Jiang
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China
| | - Yuanyuan Wu
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China
| | - Yingli Chen
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China
| | - Fei Hu
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China
| | - Jingjing Xiong
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China
| | - YunZhou Wu
- College of Life Science, Northeast Agricultural University, Harbin 150030, China.
| | - Xianlong Ye
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China.
| | - Xinmiao Liang
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China; Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road 457, Dalian 116023, China
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9
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Fu Y, Kong Y, Li X, Cheng D, Hou Y, Li Y, Li T, Xiao Y, Zhang Q, Rong R. Novel Pt(IV) prodrug self-assembled nanoparticles with enhanced blood circulation stability and improved antitumor capacity of oxaliplatin for cancer therapy. Drug Deliv 2023; 30:2171158. [PMID: 36744299 PMCID: PMC9904295 DOI: 10.1080/10717544.2023.2171158] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Pt(IV) compounds are regarded as prodrugs of active Pt(II) drugs (i.e. cisplatin, carboplatin, and oxaliplatin) and burgeoned as the most ideal candidates to substitute Pt(II) anticancer drugs with severe side effects. Nanoparticle drug delivery systems have been widely introduced to deliver Pt(IV) prodrugs more effectively and safely to tumors, but clinical outcomes were unpredictable owing to limited in vivo pharmacokinetics understanding. Herein, a novel Pt(IV) prodrug of oxaliplatin(OXA) was synthesized and prepared as self-assembled micellar nanoparticles(PEG-OXA NPs). In vitro, PEG-OXA NPs rapidly released biologically active OXA within 5 min in tumor cells while remaining extremely stable in whole blood or plasma. Importantly, the pharmacokinetic results showed that the AUC0-∞, and t1/2 values of PEG-OXA NPs were 1994 ± 117 h·µg/mL and 3.28 ± 0.28 h, respectively, which were much higher than that of free OXA solution (2.03 ± 0.55 h·µg/mL and 0.16 ± 0.07 h), indicating the longer drug circulation of PEG-OXA NPs in vivo. The altered pharmacokinetic behavior of PEG-OXA NPs remarkably contributed to improve antitumor efficacy, decrease systemic toxicity and increase tumor growth inhibition compared to free OXA. These findings establish that PEG-OXA NPs have the potential to offer a desirable self-delivery platform of platinum drugs for anticancer therapeutics.
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Affiliation(s)
- Yuanlei Fu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, China,Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, Shandong, China,Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China
| | - Ying Kong
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, Shandong, China,Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China
| | - Xiangping Li
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, Shandong, China,Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China
| | - Dongfang Cheng
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, Shandong, China,Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China
| | - Yuqian Hou
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, Shandong, China,Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China
| | - Yan Li
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, Shandong, China,Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China
| | - Tongfang Li
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, Shandong, China,Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China
| | - Yani Xiao
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, Shandong, China,Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China
| | - Qiuyan Zhang
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, Shandong, China,Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China,CONTACT Qiuyan Zhang
| | - Rong Rong
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, Shandong, China,Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China,Rong Rong
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10
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Grigoletto A, Marotti V, Tedeschini T, Campara B, Marigo I, Ingangi V, Pasut G. Improving the Therapeutic Potential of G-CSF through Compact Circular PEGylation Based on Orthogonal Conjugations. Biomacromolecules 2023; 24:4229-4239. [PMID: 37638739 PMCID: PMC10498445 DOI: 10.1021/acs.biomac.3c00543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 08/08/2023] [Indexed: 08/29/2023]
Abstract
In this study, a circular conjugate of granulocyte colony-stimulating factor (G-CSF) was prepared by conjugating the two end-chains of poly(ethylene glycol) (PEG) to two different sites of the protein. For the orthogonal conjugation, a heterobifunctional PEG chain was designed and synthesized, bearing the dipeptide ZGln-Gly (ZQG) at one end-chain, for transglutaminase (TGase) enzymatic selective conjugation at Lys41 of G-CSF, and an aldehyde group at the opposite end-chain, for N-terminal selective reductive alkylation of the protein. The cPEG-Nter/K41-G-CSF circular conjugate was characterized by physicochemical methods and compared with native G-CSF and the corresponding linear monoconjugates of G-CSF, PEG-Nter-G-CSF, and PEG-K41-G-CSF. The results demonstrated that the circular conjugate had improved physicochemical and thermal stability, prolonged pharmacokinetic interaction, and retained the biological activity of G-CSF. The PEGylation strategy employed in this study has potential applications in the design of novel protein-based therapeutics.
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Affiliation(s)
- Antonella Grigoletto
- Department
of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy
| | - Valentina Marotti
- Department
of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy
| | - Tommaso Tedeschini
- Department
of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy
| | - Benedetta Campara
- Department
of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy
| | - Ilaria Marigo
- Department
of Surgery, Oncology and Gastroenterology, University of Padova, 35131 Padova, Italy
- Istituto
Oncologico Veneto IOV − IRCCS, Via Gattamelata 64, 35128 Padova, Italy
| | - Vincenzo Ingangi
- Istituto
Oncologico Veneto IOV − IRCCS, Via Gattamelata 64, 35128 Padova, Italy
| | - Gianfranco Pasut
- Department
of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy
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11
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Song S, Sun D, Wang H, Wang J, Yan H, Zhao X, Fawcett JP, Xu X, Cai D, Gu J. Full-profile pharmacokinetics, anticancer activity and toxicity of an extended release trivalent PEGylated irinotecan prodrug. Acta Pharm Sin B 2023; 13:3444-3453. [PMID: 37655324 PMCID: PMC10466002 DOI: 10.1016/j.apsb.2023.01.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 11/22/2022] [Accepted: 12/03/2022] [Indexed: 01/12/2023] Open
Abstract
Irinotecan is an anticancer topoisomerase I inhibitor that acts as a prodrug of the active metabolite, SN-38. Unfortunately, the limited utility of irinotecan is attributed to its pH-dependent stability, short half-life and dose-limiting toxicity. To address this problem, a novel trivalent PEGylated prodrug (PEG-[Irinotecan]3) has been synthesized and its full-profile pharmacokinetics, antitumor activity and toxicity compared with those of irinotecan. The results show that after intravenous administration to rats, PEG-[Irinotecan]3 undergoes stepwise loss of irinotecan to form PEG-[Irinotecan]3‒x (x = 1,2) and PEG-[linker] during which time the released irinotecan undergoes conversion to SN-38. As compared with conventional irinotecan, PEG-[Irinotecan]3 displays extended release of irinotecan and efficient formation of SN-38 with significantly improved AUC and half-life. In a colorectal cancer-bearing model in nude mice, the tumor concentrations of irinotecan and SN-38 produced by PEG-[Irinotecan]3 were respectively 86.2 and 2293 times higher at 48 h than produced by irinotecan. In summary, PEG-[Irinotecan]3 displays superior pharmacokinetic characteristics and antitumor activity with lower toxicity than irinotecan. This supports the view that PEG-[Irinotecan]3 is a superior anticancer drug to irinotecan and it has entered the phase II trial stage.
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Affiliation(s)
- Shiwen Song
- Research Center for Drug Metabolism, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Dong Sun
- Research Center for Drug Metabolism, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Hong Wang
- Research Center for Drug Metabolism, School of Life Sciences, Jilin University, Changchun 130012, China
- Center for Food and Drug Inspection of NMPA, Changchun 130012, China
| | | | - Huijing Yan
- JenKem Technology Co., Ltd., Tianjin 300450, China
| | - Xuan Zhao
- JenKem Technology Co., Ltd., Tianjin 300450, China
| | - John Paul Fawcett
- Research Center for Drug Metabolism, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Xin Xu
- Research Center for Drug Metabolism, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Deqi Cai
- Research Center for Drug Metabolism, School of Life Sciences, Jilin University, Changchun 130012, China
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, China
| | - Jingkai Gu
- Research Center for Drug Metabolism, School of Life Sciences, Jilin University, Changchun 130012, China
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, China
- Beijing Institute of Drug Metabolism, Beijing 102209, China
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12
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Ma N, Kwon MH, Palanisamy S, Ge Y, Zhang Y, Kou F, Dae-Hee L, Lee DJ, Shin IS, You S. A novel sulfated mannan-carboxymethyl-5-fluorouracil-folic acid conjugates for targeted anticancer drug delivery. Carbohydr Polym 2023; 304:120454. [PMID: 36641184 DOI: 10.1016/j.carbpol.2022.120454] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 12/06/2022] [Accepted: 12/07/2022] [Indexed: 12/15/2022]
Abstract
CFP2 is a sulfated polysaccharide isolated from Codium fragile that shows excellent immunomodulatory activity. To reduce the side effects of 5-fluorouracil (5-FU), CFP2 was used as a macromolecular carrier to react with carboxymethyl-5-fluorouracil (C-5-FU) to form CFP2-C-5-FU, which further reacted with folic acid (FA) via an ester bond to form novel conjugates (CFP2-C-5-FU-FA). CFP2-C-5-FU-FA was confirmed by nuclear magnetic resonance (NMR) analysis. In vitro drug release results showed that the cumulative release rate of C-5-FU was 49.9% in phosphate buffer (pH 7.4) after 96 h, which was much higher than that of the other groups, indicating that CFP2-C-5-FU-FA showed controlled drug release behavior. CFP2-C-5-FU-FA also exhibited enhanced apoptosis and cellular uptake in vitro. Further, intravenous administration of CFP2-C-5-FU-FA in an HCT-116 cell-bearing xenograft mouse showed that the conjugates were safe and effective drug delivery systems. These results suggest that folate-targeted conjugates can be used effectively for efficient chemotherapy of colorectal cancer.
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Affiliation(s)
- Nan Ma
- Department of Marine Food Science and Technology, Gangneung-Wonju National University, 120 Gangneung, Gangwon 210-702, Republic of Korea
| | - Mi-Hye Kwon
- Department of Marine Food Science and Technology, Gangneung-Wonju National University, 120 Gangneung, Gangwon 210-702, Republic of Korea; East Coast Research Institute of Life Science, Gangneung-Wonju National University, 120 Gangneung, Gangwon 210-702, Republic of Korea
| | - Subramanian Palanisamy
- Department of Marine Food Science and Technology, Gangneung-Wonju National University, 120 Gangneung, Gangwon 210-702, Republic of Korea; East Coast Research Institute of Life Science, Gangneung-Wonju National University, 120 Gangneung, Gangwon 210-702, Republic of Korea
| | - Yunfei Ge
- Department of Marine Food Science and Technology, Gangneung-Wonju National University, 120 Gangneung, Gangwon 210-702, Republic of Korea
| | - Yutong Zhang
- Department of Marine Food Science and Technology, Gangneung-Wonju National University, 120 Gangneung, Gangwon 210-702, Republic of Korea
| | - Fang Kou
- Department of Marine Food Science and Technology, Gangneung-Wonju National University, 120 Gangneung, Gangwon 210-702, Republic of Korea
| | - Lee Dae-Hee
- Department of Marine Food Science and Technology, Gangneung-Wonju National University, 120 Gangneung, Gangwon 210-702, Republic of Korea; East Coast Research Institute of Life Science, Gangneung-Wonju National University, 120 Gangneung, Gangwon 210-702, Republic of Korea
| | - Dong-Jin Lee
- Department of Food and Bioproduct Sciences, University of Saskatchewan, Saskatoon, SK S7N 5A8, Canada
| | - Il-Shik Shin
- Department of Marine Food Science and Technology, Gangneung-Wonju National University, 120 Gangneung, Gangwon 210-702, Republic of Korea; East Coast Research Institute of Life Science, Gangneung-Wonju National University, 120 Gangneung, Gangwon 210-702, Republic of Korea
| | - SangGuan You
- Department of Marine Food Science and Technology, Gangneung-Wonju National University, 120 Gangneung, Gangwon 210-702, Republic of Korea; East Coast Research Institute of Life Science, Gangneung-Wonju National University, 120 Gangneung, Gangwon 210-702, Republic of Korea.
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13
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Xi Y, Wang W, Ma L, Xu N, Shi C, Xu G, He H, Pan W. Alendronate modified mPEG-PLGA nano-micelle drug delivery system loaded with astragaloside has anti-osteoporotic effect in rats. Drug Deliv 2022; 29:2386-2402. [PMID: 35869674 PMCID: PMC9310824 DOI: 10.1080/10717544.2022.2086942] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Astragaloside (AS) has an anti-osteoporotic effect, but its poor water solubility and low bioavailability limit its application. In this study, a novel nano-carrier with bone targeting was prepared by modifying mPEG-PLGA with alendronate (AL) before incorporation into astragaloside nano-micelles (AS-AL-mPEG-PLGA) to enhance the oral bioavailability, bone targeting and anti-osteoporosis effect of AS. The release behavior of AS-AL-mPEG-PLGA in vitro was investigated via dialysis. The pharmacokinetics of AS-AL-mPEG-PLGA was studied in Sprague-Dawley (SD) rats. The cytotoxicity of AS-AL-mPEG-PLGA in vitro (via MTT method), coupled with bone targeting ability in vitro and in vivo were evaluated. The therapeutic effects of free AS and AS-AL-mPEG-PLGA (ELISA, micro-CT, H&E staining) were compared in osteoporotic rats. AS-AL-mPEG-PLGA with smaller particle size (45.3 ± 3.8 nm) and high absolute zeta potential (−23.02 ± 0.51 mV) were successfully prepared, wherein it demonstrated higher entrapment efficiency (96.16 ± 0.18%), a significant sustained-release effect for 96 h and acceptable safety within 10–200 μg/mL. AS-AL-mPEG-PLGA could enhance the hydroxyapatite affinity and bone tissue concentration of AS. The relative bioavailability of AS-AL-mPEG-PLGA was 233.90% compared with free AS. In addition, the effect of AS in reducing serum levels of bone metabolism-related indicators, restoring the bone microarchitecture and improving bone injury could be enhanced by AS-AL-mPEG-PLGA. AS-AL-mPEG-PLGA with small particle size, good stability, remarkable sustained-release effect, safety and bone targeting was successfully constructed in this experiment to potentially improve the oral bioavailability and anti-osteoporosis effect of AS. Thus, AS-AL-mPEG-PLGA may be a promising strategy to prevent and treat osteoporosis.
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Affiliation(s)
- Yanhai Xi
- Department of Orthopedics, Spine Surgery, The Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Weiheng Wang
- Department of Orthopedics, Spine Surgery, The Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Liang Ma
- Minimally invasive Spinal Surgery department, The Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Ning Xu
- Department of Orthopedics, Spine Surgery, The Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Changgui Shi
- Department of Orthopedics, Spine Surgery, The Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Guohua Xu
- Department of Orthopedics, Spine Surgery, The Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Hailong He
- Department of Orthopedics, Spine Surgery, The Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Wenming Pan
- Department of Spine Surgery, The Affiliated Changshu Hospital of Xuzhou Medical School, The Second People's Hospital of Changshu, Changshu, China
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14
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Liu C, Liu C, Bai Y, Wang J, Tian W. Drug Self-Delivery Systems: Molecule Design, Construction Strategy, and Biological Application. Adv Healthc Mater 2022; 12:e2202769. [PMID: 36538727 DOI: 10.1002/adhm.202202769] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 11/29/2022] [Indexed: 02/01/2023]
Abstract
Drug self-delivery systems (DSDSs) offer new ways to create novel drug delivery systems (DDSs). In typical DSDSs, therapeutic reagents are not considered passive cargos but active delivery agents of actionable targets. As an advanced drug delivery strategy, DSDSs with positive cooperativity of both free drugs and nanocarriers exhibit the clear merits of unprecedented drug-loading capacity, minimized systemic toxicity, and flexible preparation of nanoscale deliverables for passive targeted therapy. This review highlights the recent advances and future trends in DSDSs on the basis of two differently constructed structures: covalent and noncovalent bond-based DSDSs. Specifically, various chemical and architectural designs, fabrication strategies, and responsive and functional features are comprehensively discussed for these two types of DSDSs. In addition, additional comments on the current development status of DSDSs and the potential applications of their molecular designs are presented in the corresponding discussion. Finally, the promising potential of DSDSs in biological applications is revealed and the relationship between preliminary molecular design of DSDSs and therapeutic effects of subsequent DSDSs biological applications is clarified.
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Affiliation(s)
- Chengfei Liu
- Shaanxi Key Laboratory of Macromolecular Science and Technology, MOE Key Laboratory of Material Physics and Chemistry under Extraordinary Conditions, School of Chemistry and Chemical Engineering, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China
| | - Caiping Liu
- Shaanxi Key Laboratory of Chemical Additives for Industry, College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an, Shaanxi, 710021, China
| | - Yang Bai
- Shaanxi Key Laboratory of Chemical Additives for Industry, College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an, Shaanxi, 710021, China
| | - Jingxia Wang
- Shaanxi Key Laboratory of Macromolecular Science and Technology, MOE Key Laboratory of Material Physics and Chemistry under Extraordinary Conditions, School of Chemistry and Chemical Engineering, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China
| | - Wei Tian
- Shaanxi Key Laboratory of Macromolecular Science and Technology, MOE Key Laboratory of Material Physics and Chemistry under Extraordinary Conditions, School of Chemistry and Chemical Engineering, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China
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15
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Tasdemiroglu Y, Gourdie RG, He JQ. In vivo degradation forms, anti-degradation strategies, and clinical applications of therapeutic peptides in non-infectious chronic diseases. Eur J Pharmacol 2022; 932:175192. [PMID: 35981605 DOI: 10.1016/j.ejphar.2022.175192] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 08/01/2022] [Accepted: 08/05/2022] [Indexed: 11/03/2022]
Abstract
Current medicinal treatments for diseases comprise largely of two categories: small molecular (chemical) (e.g., aspirin) and larger molecular (peptides/proteins, e.g., insulin) drugs. Whilst both types of therapeutics can effectively treat different diseases, ranging from well-understood (in view of pathogenesis and treatment) examples (e.g., flu), to less-understood chronic diseases (e.g., diabetes), classical small molecule drugs often possess significant side-effects (a major cause of drug withdrawal from market) due to their low- or non-specific targeting. By contrast, therapeutic peptides, which comprise short sequences from naturally occurring peptides/proteins, commonly demonstrate high target specificity, well-characterized modes-of-action, and low or non-toxicity in vivo. Unfortunately, due to their small size, linear permutation, and lack of tertiary structure, peptidic drugs are easily subject to rapid degradation or loss in vivo through chemical and physical routines, thus resulting in a short half-life and reduced therapeutic efficacy, a major drawback that can reduce therapeutic efficiency. However, recent studies demonstrate that the short half-life of peptidic drugs can be significantly extended by various means, including use of enantiomeric or non-natural amino acids (AAs) (e.g., L-AAs replacement with D-AAs), chemical conjugation [e.g., with polyethylene glycol], and encapsulation (e.g., in exosomes). In this context, we provide an overview of the major in vivo degradation forms of small therapeutic peptides in the plasma and anti-degradation strategies. We also update on the progress of small peptide therapeutics that are either currently in clinical trials or are being successfully used in clinical therapies for patients with non-infectious diseases, such as diabetes, multiple sclerosis, and cancer.
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Affiliation(s)
- Yagmur Tasdemiroglu
- Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, USA
| | - Robert G Gourdie
- Center for Vascular and Heart Research, Fralin Biomedical Research Institute, Virginia Tech, Roanoke, VA, 24016, USA
| | - Jia-Qiang He
- Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, USA.
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16
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Lin Q, Xia X, Li J, Zhou Z, Chen Y. Site-specific N-terminal PEGylation-based controlled release of biotherapeutics: An application for GLP-1 delivery to improve pharmacokinetics and prolong hypoglycemic effects. Eur J Med Chem 2022; 242:114672. [PMID: 35973313 DOI: 10.1016/j.ejmech.2022.114672] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 08/05/2022] [Accepted: 08/07/2022] [Indexed: 11/30/2022]
Abstract
PEGylation is a well-established technology for half-life extension in drug delivery. In this study, we aimed to develop a site-specific N-terminal PEGylation for biotherapeutics to achieve controlled release, using GLP-1 as a model. An additional threonine was introduced at N-terminal GLP-1. Followed by periodate oxidation, hydrazide-based PEGylation was achieved in a site-selective manner under reductive condition. Two homogenous monovalent mPEG5k-GLP-1 (peptide 4) and mPEG20k-GLP-1 (peptide 5) were successfully constructed. After PEGylation, the degradation by DPP-IV and rat plasma was obviously reduced. Their pharmacokinetic performances were enhanced at the expense of impaired GLP-1R stimulating potency, and their hypoglycemic effects were improved in different degrees. Compared with conventional strategies, this approach is devoid of the restriction and alteration of native peptide sequences, and can produce utterly homogenous conjugates with excellent selectivity and efficiency. It provides a practical controlled release approach for peptides by site-specific modification to achieve better pharmacological and therapeutic properties.
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Affiliation(s)
- Qianmeng Lin
- Department of Oncology, Department of Pathology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Xuan Xia
- Department of Oncology, Department of Pathology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Jun Li
- Department of Oncology, Department of Pathology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Zhan Zhou
- Research Center for Molecular Metabolomics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
| | - Yongheng Chen
- Department of Oncology, Department of Pathology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
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17
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Wang S, Cheng K, Chen K, Xu C, Ma P, Dang G, Yang Y, Lei Q, Huang H, Yu Y, Fang Y, Tang Q, Jiang N, Miao H, Liu F, Zhao X, Li N. Nanoparticle-based medicines in clinical cancer therapy. NANO TODAY 2022; 45:101512. [DOI: 10.1016/j.nantod.2022.101512] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2024]
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18
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McDougall RM, Cahill HF, Power ME, MacCormack TJ, Meli MV, Rourke JL. Multiparametric cytotoxicity assessment: the effect of gold nanoparticle ligand functionalization on SKOV3 ovarian carcinoma cell death. Nanotoxicology 2022; 16:355-374. [PMID: 35787735 DOI: 10.1080/17435390.2022.2095312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Gold nanoparticles (AuNP) are promising anti-cancer agents because of their modifiable properties and high biocompatibility. This study used multiple parallel analyses to investigate the cytotoxic properties of 5 nm AuNP conjugated to four different ligands with distinct surface chemistry: polyethylene glycol (PEG), trimethylammonium bromide (TMAB), 4-dimethylaminopyridine (DMAP), and carboxyl (COOH). We used a range of biochemical and high-content microscopy methods to evaluate the metabolic function, oxidative stress, cell health, cell viability, and cell morphology in SKOV3 ovarian cancer cells. Each AuNP displayed a distinct cytotoxicity profile. All AuNP species assessed exhibited signs of dose-dependent cytotoxicity when morphology, clonogenic survival, lysosomal uptake, or cell number were measured as the marker of toxicity. All particles except for AuNP-COOH increased SKOV3 apoptosis. In contrast, AuNP-TMAB was the only particle that did not alter the metabolic function or induce significant signs of oxidative stress. These results demonstrate that AuNP surface chemistry impacts the magnitude and mechanism of SKOV3 cell death. Together, these findings reinforce the important role for multiparametric cytotoxicity characterization when considering the utility of novel particles and surface chemistries.
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Affiliation(s)
- Rachel M McDougall
- Department of Chemistry and Biochemistry, Mount Allison University, Sackville, Canada
| | - Hannah F Cahill
- Department of Chemistry and Biochemistry, Mount Allison University, Sackville, Canada
| | - Madeline E Power
- Department of Chemistry and Biochemistry, Mount Allison University, Sackville, Canada
| | - Tyson J MacCormack
- Department of Chemistry and Biochemistry, Mount Allison University, Sackville, Canada
| | - M-Vicki Meli
- Department of Chemistry and Biochemistry, Mount Allison University, Sackville, Canada
| | - Jillian L Rourke
- Department of Chemistry and Biochemistry, Mount Allison University, Sackville, Canada
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19
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Zhao M, Jiang W, Xie X, Jaiswal Y, Williams L, Wei M, Mo Y, Guan Y, Yang H. Preparation and Release of pH-Sensitive β-Cyclodextrin Derivative Micelles Loaded with Paclitaxel. Polymers (Basel) 2022; 14:polym14122482. [PMID: 35746058 PMCID: PMC9227914 DOI: 10.3390/polym14122482] [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: 05/16/2022] [Revised: 06/08/2022] [Accepted: 06/15/2022] [Indexed: 11/16/2022] Open
Abstract
In this paper, a new amphiphilic mono-6-β-cyclodextrin octadecylimine (6-β-CD-N-ODMA) copolymer was synthesized based on β-cyclodextrin and octadecylamine, which can self-assemble to form polymeric micelles. Drug-loaded micelles (a new drug carrier) were obtained using 6-β-CD-N-ODMA and paclitaxel (PTX) by the dialysis method. Orthogonal experiments were used to optimize the preparation method of the drug-loaded micelles. The drug-loading content of the carrier prepared by the optimized method was 1.97%. The physicochemical properties of blank micelles and drug-loaded micelles were evaluated by the fluorescence probe method, infrared spectra, dynamic light scattering, and scanning electron microscopy. The release properties of the carrier were investigated. The carrier has good pH sensitivity and the cumulative release rate after 96 h was 88% in PBS (pH = 5.0). The Ritger–Peppas equation is the optimal model for PTX released at pH 5.0, implying that the hydrolysis effect of 6-β-CD-N-ODMA is the main reason for PTX release. The results indicate that the developed carrier can increase the solubility of PTX and possess potential for increased clinical efficacy of PTX.
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Affiliation(s)
- Meirong Zhao
- School of Chemistry and Chemical Engineering, Guangxi Minzu University, Nanning 530006, China; (M.Z.); (X.X.)
- Department of Pharmacy, Guangxi Agricultural Vocational University, Nanning 530021, China; (M.W.); (Y.M.)
| | - Weiwei Jiang
- College of Medicine, Guangxi University, Nanning 530004, China;
| | - Xinrong Xie
- School of Chemistry and Chemical Engineering, Guangxi Minzu University, Nanning 530006, China; (M.Z.); (X.X.)
| | - Yogini Jaiswal
- Center for Excellence in Post-Harvest Technologies, North Carolina A&T State University, The North Carolina Research Campus, 500 Laureate Way, Kannapolis, NC 2802, USA; (Y.J.); (L.W.)
| | - Leonard Williams
- Center for Excellence in Post-Harvest Technologies, North Carolina A&T State University, The North Carolina Research Campus, 500 Laureate Way, Kannapolis, NC 2802, USA; (Y.J.); (L.W.)
| | - Mei Wei
- Department of Pharmacy, Guangxi Agricultural Vocational University, Nanning 530021, China; (M.W.); (Y.M.)
| | - Ying Mo
- Department of Pharmacy, Guangxi Agricultural Vocational University, Nanning 530021, China; (M.W.); (Y.M.)
| | - Yifu Guan
- School of Chemistry and Chemical Engineering, Guangxi Minzu University, Nanning 530006, China; (M.Z.); (X.X.)
- Correspondence: (Y.G.); (H.Y.)
| | - Hua Yang
- College of Medicine, Guangxi University, Nanning 530004, China;
- Correspondence: (Y.G.); (H.Y.)
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20
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Hu Z, Cao X, Zhang X, Wu B, Luo W, Huang H, Li L, Chen Y. Catalytically Controlled Ring-Opening Polymerization of 2-Oxo-15-crown-5 for Degradable and Recyclable PEG-Like Polyesters. ACS Macro Lett 2022; 11:792-798. [PMID: 35653639 DOI: 10.1021/acsmacrolett.2c00210] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Poly(ethylene glycol) (PEG) has been extensively used in diverse applications. However, it is not biodegradable and shows abnormal immune responses. Herein, a fast, controlled, ring-opening polymerization (ROP) of 2-oxo-15-crown-5 (O-15C5) is reported to prepare well-defined PEG-like polyesters, poly(O-15C5). This approach relies on a coordination between the macrocyclic monomer and Na+ that increases the electrophilicity of the carbonyl group of O-15C5 and leads to a fast controlled ROP (dispersity, ĐM < 1.2). Both computational and mechanistic studies show that the selective Na+ binding to the monomer over poly(O-15C5) allows the ring-opening initiation and propagation to be more energetically favorable than side transesterifications. This is the key to control the challenging entropy-driven ROP of O-15C5. Moreover, with the aid of Na+ and organic base, poly(O-15C5) depolymerized readily into O-15C5 in 2 h. Also, it degraded in a buffer of pH 7.4 by hydrolysis.
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Affiliation(s)
- Zhitao Hu
- School of Materials Science and Engineering, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, China
- Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, China
| | - Xiaohui Cao
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Xiaohui Zhang
- School of Chemistry, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, China
| | - Bin Wu
- School of Chemistry, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, China
| | - Wenjun Luo
- School of Chemistry, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, China
| | - Huahua Huang
- School of Materials Science and Engineering, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, China
- Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, China
| | - Le Li
- School of Chemistry, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, China
- Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, China
| | - Yongming Chen
- School of Materials Science and Engineering, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, China
- Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, China
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21
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Zhong W, Zhang X, Duan X, Liu H, Fang Y, Luo M, Fang Z, Miao C, Lin D, Wu J. Redox-responsive self-assembled polymeric nanoprodrug for delivery of gemcitabine in B-cell lymphoma therapy. Acta Biomater 2022; 144:67-80. [PMID: 35331940 DOI: 10.1016/j.actbio.2022.03.035] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 03/08/2022] [Accepted: 03/18/2022] [Indexed: 12/30/2022]
Abstract
Gemcitabine, as a standard and classic strategy for B-cell lymphoma in the clinic, is limited by its poor pharmacodynamics. Although stimuli-responsive polymeric nanodelivery systems have been widely investigated in the past decade, issues such as complicated procedures, low loading capacity, and uncontrollable release kinetics still hinder their clinical translation. In view of the above considerations, we attempt to construct hyperbranched polyprodrug micelles with considerable drug loading via simple procedures and make use of the particularity of the tumor microenvironment to ensure that the micelles are "inactivated" in normal tissues and "activated" in the tumor microenvironment. Hence, in this work, a redox-responsive polymeric gemcitabine-prodrug (GEM-S-S-PEG) was one-pot synthesized via facile esterification and acylation. The self-assembled subsize (< 100 nm) GEM-S-S-PEG (GSP NPs) with considerable loading capacity (≈ 24.6%) exhibited on-demand and accurate control of gemcitabine release under a simulated tumor microenvironment and thus significantly induced the apoptosis of B-cell lymphoma in vitro. Moreover, in the A20 tumor xenograft murine model, GSP NPs efficiently decreased the expansion of tumor tissues with minimal systemic toxicity. In summary, these redox-responsive and self-assembling GSP NPs with a facile one-pot synthesis procedure may hold great potency in clinical translation for enhanced chemotherapy of B-cell lymphoma. STATEMENT OF SIGNIFICANCE: A redox-responsive polymeric gemcitabine-prodrug (GEM-S-S-PEG) was one-pot synthesized via facile esterification and acylation. The self-assembled subsize (< 100 nm) GEM-S-S-PEG (GSP NPs) exhibited significant tumor therapeutic effects in vitro and in vivo. The polyprodrug GEM-S-S-PEG prepared in this study shows the great potential of redox-responsive nanodrugs for antitumor activity, which provides a reference value for the optimization of the design of functional polyprodrugs.
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Affiliation(s)
- Wenhao Zhong
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Xinyu Zhang
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Xiao Duan
- Department of Reproductive Genetics, Heping Hospital of Changzhi Medical College, The Stem Cell and Tissue Engineering Research Center, Changzhi Medical College, Changzhi, Shanxi 046000, China
| | - Hengyu Liu
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Yifen Fang
- The Affiliated TCM Hospital of Guangzhou Medical University, Guangzhou, 511436, China
| | - Moucheng Luo
- School of Biomedical Engineering, Sun Yat-sen University, Shenzhen, 518107, China
| | - Zhengwen Fang
- School of Biomedical Engineering, Sun Yat-sen University, Shenzhen, 518107, China
| | - Congxiu Miao
- Department of Reproductive Genetics, Heping Hospital of Changzhi Medical College, The Stem Cell and Tissue Engineering Research Center, Changzhi Medical College, Changzhi, Shanxi 046000, China.
| | - Dongjun Lin
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
| | - Jun Wu
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China; School of Biomedical Engineering, Sun Yat-sen University, Shenzhen, 518107, China.
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22
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Sarwar S, Abdul Qadir M, Alharthy RD, Ahmed M, Ahmad S, Vanmeert M, Mirza MU, Hameed A. Folate Conjugated Polyethylene Glycol Probe for Tumor-Targeted Drug Delivery of 5-Fluorouracil. Molecules 2022; 27:1780. [PMID: 35335144 PMCID: PMC8954791 DOI: 10.3390/molecules27061780] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/25/2022] [Accepted: 03/04/2022] [Indexed: 01/01/2023] Open
Abstract
A targeted delivery system is primarily intended to carry a potent anticancer drug to specific tumor sites within the bodily tissues. In the present study, a carrier system has been designed using folic acid (FA), bis-amine polyethylene glycol (PEG), and an anticancer drug, 5-fluorouracil (5-FU). FA and PEG were joined via an amide bond, and the resulting FA-PEG-NH2 was coupled to 5-FU producing folate-polyethylene glycol conjugated 5-fluorouracil (FA-PEG-5-FU). Spectroscopic techniques (UV-Vis, 1HNMR, FTIR, and HPLC) were used for the characterization of products. Prodrug (FA-PEG-5-FU) was analyzed for drug release profile (in vitro) up to 10 days and compared to a standard anticancer drug (5-FU). Folate conjugate was also analyzed to study its folate receptors (FR) mediated transport and in vitro cytotoxicity assays using HeLa cancer cells/Vero cells, respectively, and antitumor activity in tumor-bearing mice models. Folate conjugate showed steady drug release patterns and improved uptake in the HeLa cancer cells than Vero cells. Folate conjugate treated mice group showed smaller tumor volumes; specifically after the 15th day post-treatment, tumor sizes were decreased significantly compared to the standard drug group (5-FU). Molecular docking findings demonstrated importance of Trp138, Trp140, and Lys136 in the stabilization of flexible loop flanking the active site. The folic acid conjugated probe has shown the potential of targeted drug delivery and sustained release of anticancer drug to tumor lesions with intact antitumor efficacy.
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Affiliation(s)
- Shabnam Sarwar
- School of Chemistry, University of the Punjab, Lahore 54590, Pakistan; (M.A.Q.); (S.A.)
| | - Muhammad Abdul Qadir
- School of Chemistry, University of the Punjab, Lahore 54590, Pakistan; (M.A.Q.); (S.A.)
| | - Rima D. Alharthy
- Chemistry Department, Faculty of Science and Arts, King Abdulaziz University, Rabigh 21911, Saudi Arabia
| | - Mahmood Ahmed
- Department of Chemistry, Division of Science and Technology, University of Education, College Road, Lahore 54770, Pakistan
| | - Saghir Ahmad
- School of Chemistry, University of the Punjab, Lahore 54590, Pakistan; (M.A.Q.); (S.A.)
| | - Michiel Vanmeert
- Medicinal Chemistry, Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium; (M.V.); (M.U.M.)
| | - Muhammad Usman Mirza
- Medicinal Chemistry, Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium; (M.V.); (M.U.M.)
- Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada
| | - Abdul Hameed
- Department of Chemistry, University of Sahiwal, Sahiwal 57000, Pakistan;
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23
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Ashrafizadeh M, Saebfar H, Gholami MH, Hushmandi K, Zabolian A, Bikarannejad P, Hashemi M, Daneshi S, Mirzaei S, Sharifi E, Kumar AP, Khan H, Heydari Sheikh Hossein H, Vosough M, Rabiee N, Thakur Kumar V, Makvandi P, Mishra YK, Tay FR, Wang Y, Zarrabi A, Orive G, Mostafavi E. Doxorubicin-loaded graphene oxide nanocomposites in cancer medicine: Stimuli-responsive carriers, co-delivery and suppressing resistance. Expert Opin Drug Deliv 2022; 19:355-382. [PMID: 35152815 DOI: 10.1080/17425247.2022.2041598] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION The application of doxorubicin (DOX) in cancer therapy has been limited due to its drug resistance and poor internalization. Graphene oxide (GO) nanostructures have the capacity for DOX delivery while promoting its cytotoxicity in cancer. AREAS COVERED The favorable characteristics of GO nanocomposites, preparation method, and application in cancer therapy are described. Then, DOX resistance in cancer is discussed. The GO-mediated photothermal therapy and DOX delivery for cancer suppression are described. Preparation of stimuli-responsive GO nanocomposites, surface functionalization, hybrid nanoparticles, and theranostic applications are emphasized in DOX chemotherapy. EXPERT OPINION Graphene oxide nanoparticle-based photothermal therapy maximizes the anti-cancer activity of DOX against cancer cells. Apart from DOX delivery, GO nanomaterials are capable of loading anti-cancer agents and genetic tools to minimize drug resistance and enhance the cytolytic impact of DOX in cancer eradication. To enhance DOX accumulation in cancer cells, stimuli-responsive (redox-, light-, enzyme- and pH-sensitive) GO nanoparticles have been developed for DOX delivery. Further development of targeted delivery of DOX-loaded GO nanomaterials against cancer cells may be achieved by surface modification of polymers such as polyethylene glycol, hyaluronic acid, and chitosan. Doxorubicin-loaded GO nanoparticles have demonstrated theranostic potential for simultaneous diagnosis and therapy. Hybridization of GO with other nanocarriers such as silica and gold nanoparticles further broadens their potential anti-cancer therapy applications.
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Affiliation(s)
- Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, 34956 Istanbul, Turkey
| | - Hamidreza Saebfar
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Hossein Gholami
- DVM. Graduated, Faculty of Veterinary Medicine, Kazerun Branch, Islamic Azad University, Kazerun, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Amirhossein Zabolian
- Department of Orthopedics, School of Medicine, 5th Azar Hospital, Golestan University of Medical Sciences, Golestan, Iran
| | - Pooria Bikarannejad
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Esmaeel Sharifi
- Department of Tissue Engineering and Biomaterials, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, 6517838736 Hamadan, Iran
| | - Alan Prem Kumar
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.,Cancer Science Institute of Singapore and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan
| | | | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Navid Rabiee
- Department of Chemistry, Sharif University of Technology, Tehran, Iran.,School of Engineering, Macquarie University, Sydney, New South Wales, 2109, Australia
| | - Vijay Thakur Kumar
- Biorefining and Advanced Materials Research Center, Scotland's Rural College (SRUC), Kings Buildings, West Mains Road, Edinburgh EH9 3JG, U.K.,School of Engineering, University of Petroleum & Energy Studies (UPES), Dehradun 248007, Uttarakhand, India
| | - Pooyan Makvandi
- Istituto Italiano di Tecnologia, Centre for Materials Interface, viale Rinaldo Piaggio 34, 56025 Pontedera, Pisa, Italy
| | - Yogendra Kumar Mishra
- Mads Clausen Institute, NanoSYD, University of Southern Denmark, 6400 Sønderborg, Denmark
| | - Franklin R Tay
- The Graduate School, Augusta University, Augusta, GA, USA
| | - Yuzhuo Wang
- Department of Urological Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Sariyer 34396, Istanbul, Turkey
| | - Gorka Orive
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain.,Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN). Vitoria-Gasteiz, Spain.,University Institute for Regenerative Medicine and Oral Implantology - UIRMI (UPV/EHUFundación Eduardo Anitua). Vitoria-Gasteiz, Spain.,Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain.,Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower, Singapore
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA.,Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
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24
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Etrych T, Braunova A, Zogala D, Lambert L, Renesova N, Klener P. Targeted Drug Delivery and Theranostic Strategies in Malignant Lymphomas. Cancers (Basel) 2022; 14:626. [PMID: 35158894 PMCID: PMC8833783 DOI: 10.3390/cancers14030626] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/17/2022] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
Malignant lymphomas represent the most common type of hematologic malignancies. The first clinically approved TDD modalities in lymphoma patients were anti-CD20 radioimmunoconjugates (RIT) 131I-tositumomab and 90Y-ibritumomab-tiuxetan. The later clinical success of the first approved antibody-drug conjugate (ADC) for the treatment of lymphomas, anti-CD30 brentuximab vedotin, paved the path for the preclinical development and clinical testing of several other ADCs, including polatuzumab vedotin and loncastuximab tesirine. Other modalities of TDD are based on new formulations of "old" cytostatic agents and their passive trapping in the lymphoma tissue by means of the enhanced permeability and retention (EPR) effect. Currently, the diagnostic and restaging procedures in aggressive lymphomas are based on nuclear imaging, namely PET. A theranostic approach that combines diagnostic or restaging lymphoma imaging with targeted treatment represents an appealing innovative strategy in personalized medicine. The future of theranostics will require not only the capability to provide suitable disease-specific molecular probes but also expertise on big data processing and evaluation. Here, we review the concept of targeted drug delivery in malignant lymphomas from RIT and ADC to a wide array of passively and actively targeted nano-sized investigational agents. We also discuss the future of molecular imaging with special focus on monoclonal antibody-based and monoclonal antibody-derived theranostic strategies.
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Affiliation(s)
- Tomas Etrych
- Institute of Macromolecular Chemistry, Czech Academy of Sciences, 162 06 Prague, Czech Republic; (T.E.); (A.B.)
| | - Alena Braunova
- Institute of Macromolecular Chemistry, Czech Academy of Sciences, 162 06 Prague, Czech Republic; (T.E.); (A.B.)
| | - David Zogala
- Institute of Nuclear Medicine, General University Hospital and First Faculty of Medicine, Charles University in Prague, 128 08 Prague, Czech Republic;
| | - Lukas Lambert
- Department of Radiology, General University Hospital and First Faculty of Medicine, Charles University in Prague, 128 08 Prague, Czech Republic;
| | - Nicol Renesova
- First Faculty of Medicine, Institute of Pathological Physiology, Charles University, 121 08 Prague, Czech Republic;
| | - Pavel Klener
- First Faculty of Medicine, Institute of Pathological Physiology, Charles University, 121 08 Prague, Czech Republic;
- First Department of Internal Medicine-Hematology, General University Hospital and First Faculty of Medicine, Charles University in Prague, 128 08 Prague, Czech Republic
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25
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Sindhu R, Manonmani HK. L-asparaginase mediated therapy in L-asparagine auxotrophic cancers: A review. Anticancer Agents Med Chem 2022; 22:2393-2410. [PMID: 34994334 DOI: 10.2174/1871520622666220106103336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 09/28/2021] [Accepted: 11/15/2021] [Indexed: 11/22/2022]
Abstract
Microbial L-asparaginase is the most effective first-line therapeutic used in the treatment protocols of paediatric and adult leukemia. Leukemic cell's auxotrophy for L-asparagine is exploited as a therapeutic strategy to mediate cell death through metabolic blockade of L-asparagine using L-asparaginase. Escherichia coli and Erwinia chrysanthemi serve as the major enzyme deriving sources accepted in clinical practise and the enzyme has bestowed improvements in patient outcomes over the last 40 years. However, an array of side effects generated by the native enzymes due to glutamine co-catalysis and short serum stays augmenting frequent dosages, intended a therapeutic switch towards the development of biobetter alternatives for the enzyme including the formulations resulting in sustained local depletion of L-asparagine. In addition, the treatment with L-asparaginase in few cancer types has proven to elicit drug-induced cytoprotective autophagy mechanisms and therefore warrants concern. Although the off-target glutamine hydrolysis has been viewed in contributing the drug-induced secondary responses in cells deficient with asparagine synthetase machinery, the beneficial role of glutaminase-asparaginase in proliferative regulation of asparagine prototrophic cells has been looked forward. The current review provides an overview on the enzyme's clinical applications in leukemia and possible therapeutic implications in other solid tumours, recent advancements in drug formulations, and discusses the aspects of two-sided roles of glutaminase-asparaginases and drug-induced cytoprotective autophagy mechanisms.
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Affiliation(s)
- Sindhu R
- Department of Microbiology, Faculty of Life Sciences, JSS-AHER, Mysuru-570015, Karnataka, India
| | - H K Manonmani
- Food Protectants and Infestation Control Department, CSIR-Central Food Technological Research Institute, Mysuru-570020, Karnataka, India
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26
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Halama K, Schaffer A, Rieger B. Allyl group-containing polyvinylphosphonates as a flexible platform for the selective introduction of functional groups via polymer-analogous transformations. RSC Adv 2021; 11:38555-38564. [PMID: 35493229 PMCID: PMC9044137 DOI: 10.1039/d1ra06452e] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 11/23/2021] [Indexed: 11/21/2022] Open
Abstract
Polyvinylphosphonates are highly promising candidates for (bio)medical applications as they exhibit a tunable lower critical solution temperature, high biocompatibility of homo- and copolymers, and a broad foundation for post-synthetic modifications. In this work we explored polymer-analogous transformations with statistical polyvinylphosphonates comprising diethyl vinylphosphonate (DEVP) and diallyl vinylphosphonate (DAlVP). The C[double bond, length as m-dash]C double bonds were used as a starting point for a cascade of organic transformations. Initially, the reactive moieties were successfully introduced via bromination, epoxidations with OXONE and mCPBA, or thiol-ene click chemistry with methyl thioglycolate (6). The obtained substrates were then employed in a variety of consecutive reactions depending on the introduced functional motif: (1) the brominated substrates were converted with sodium azide to enable the copper-mediated alkyne-azide coupling with phenylacetylene (1). (2) The epoxides were reacted with sodium azide for an alkyne-azide click coupling with 1 as well as small nucleophilic compounds (phenol (2), benzylamine (3), and 4-amino-2,1,3-benzothiadiazol (4)). Afterwards the non-converted allyl groups were reacted with thiochloesterol (5) to form complex polymer conjugates. (3) An acid-labile hydrazone-linked conjugate was formed in a two-step approach. The polymeric substrates were characterized by NMR, FTIR, and UV/Vis spectroscopy as well as elemental analysis and gel permeation chromatography to monitor the structural changes of the polymeric substrates and to prove the success of these modification approaches.
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Affiliation(s)
- Kerstin Halama
- WACKER-Chair of Macromolecular Chemistry, Catalysis Research Center, Technical University of Munich Lichtenbergstraße 4 85748 Garching near Munich Germany
| | - Andreas Schaffer
- WACKER-Chair of Macromolecular Chemistry, Catalysis Research Center, Technical University of Munich Lichtenbergstraße 4 85748 Garching near Munich Germany
| | - Bernhard Rieger
- WACKER-Chair of Macromolecular Chemistry, Catalysis Research Center, Technical University of Munich Lichtenbergstraße 4 85748 Garching near Munich Germany
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27
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César Moreira Brito J, Gustavo Lima W, Magalhães Resende J, Cristina Sampaio de Assis D, Boff D, Nascimento Cardoso V, Almeida Amaral F, Maria Souza-Fagundes E, Odília Antunes Fernandes S, Elena de Lima M. Pegylated LyeTx I-b peptide is effective against carbapenem-resistant Acinetobacter baumannii in an in vivo model of pneumonia and shows reduced toxicity. Int J Pharm 2021; 609:121156. [PMID: 34624440 DOI: 10.1016/j.ijpharm.2021.121156] [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: 06/17/2021] [Revised: 09/27/2021] [Accepted: 10/03/2021] [Indexed: 10/20/2022]
Abstract
The World Health Organization (WHO) has been warning about the importance of developing new drugs against superbugs. Antimicrobial peptides are an alternative in this context, most of them being involved in innate immunity, acting in various ways, and some even showing synergism with commercial antimicrobial agents. LyeTx I-b is a synthetic peptide derived from native LyeTx I, originally isolated from Lycosa erythrognatha spider venom. Although LyeTx I-b is active against several multidrug-resistant bacteria, it shows some hemolytic and cytotoxic effects. To overcome this hindrance, in the present study we PEGylated LyeTx I-b and evaluated its toxicity and in vitro and in vivo activities on pneumonia caused by multi-resistant Acinetobacter baumannii. PEGylated LyeTx I-b (LyeTx I-bPEG) maintained the same MIC value as the non- PEGylated peptide, showed anti-biofilm activity, synergistic effect with commercial antimicrobial agents, and did not induce resistance. Moreover, in vivo experiments showed its activity against pneumonia. Additionally, LyeTx I-bPEG reduced hemolysis up to 10 times, was approximately 2 times less cytotoxic to HEK-293 cells and 4 times less toxic to mice in acute toxicity models, compared to LyeTx I-b. Our results show LyeTx I-bPEG as a promising antimicrobial candidate, significantly active against pneumonia caused by multidrug-resistant A. baumannii.
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Affiliation(s)
- Júlio César Moreira Brito
- Programa de Inovação Tecnológica e Biofarmacêutica, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil; Fundação Ezequiel Dias, Belo Horizonte, Minas Gerais, Brazil.
| | - William Gustavo Lima
- Laboratório de Radioisótopos, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Campus Pampulha, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Jarbas Magalhães Resende
- Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Débora Cristina Sampaio de Assis
- Escola de Veterinária, Departamento de Inspeção Sanitária, Campus Pampulha, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brasil
| | - Daiane Boff
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Valbert Nascimento Cardoso
- Laboratório de Radioisótopos, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Campus Pampulha, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Flávio Almeida Amaral
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Elaine Maria Souza-Fagundes
- Programa de Inovação Tecnológica e Biofarmacêutica, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
| | - Simone Odília Antunes Fernandes
- Laboratório de Radioisótopos, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Campus Pampulha, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Maria Elena de Lima
- Programa de Inovação Tecnológica e Biofarmacêutica, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil; Faculdade Santa Casa de Belo Horizonte: Programa de Pós-Graduação em Medicina-Biomedicina, Belo Horizonte, Minas Gerais, Brazil.
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Patra S, Singh M, Wasnik K, Pareek D, Gupta PS, Mukherjee S, Paik P. Polymeric Nanoparticle Based Diagnosis and Nanomedicine for Treatment and Development of Vaccines for Cerebral Malaria: A Review on Recent Advancement. ACS APPLIED BIO MATERIALS 2021; 4:7342-7365. [PMID: 35006689 DOI: 10.1021/acsabm.1c00635] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cerebral malaria occurs due to Plasmodium falciparum infection, which causes 228 million infections and 450,000 deaths worldwide every year. African people are mostly affected with nearly 91% cases, of which 86% are pregnant women and infants. India and Brazil are the other two countries severely suffering from malaria endemicity. Commonly used drugs have severe side effects, and unfortunately no suitable vaccine is available in the market today. In this line, this review is focused on polymeric nanomaterials and nanocapsules that can be used for the development of effective diagnostic strategies, nanomedicines, and vaccines in the management of cerebral malaria. Further, this review will help scientists and medical professionals by updating the status on the development stages of polymeric nanoparticle based diagnostics, nanomedicines, and vaccines and strategies to eradicate cerebral malaria. In addition to this, the predominant focus of this review is antimalarial agents based on polymer nanomedicines that are currently in the preclinical and clinical trial stages, and potential developments are suggested as well. This review further will have an important social and commercial impact worldwide for the development of polymeric nanomedicines and strategies for the treatment of cerebral malaria.
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Affiliation(s)
- Sukanya Patra
- School of Biomedical Engineering, Indian Institute of Technology-BHU, Varanasi 221005, India
| | - Monika Singh
- School of Biomedical Engineering, Indian Institute of Technology-BHU, Varanasi 221005, India
| | - Kirti Wasnik
- School of Biomedical Engineering, Indian Institute of Technology-BHU, Varanasi 221005, India
| | - Divya Pareek
- School of Biomedical Engineering, Indian Institute of Technology-BHU, Varanasi 221005, India
| | - Prem Shankar Gupta
- School of Biomedical Engineering, Indian Institute of Technology-BHU, Varanasi 221005, India
| | - Sudip Mukherjee
- Department of Bioengineering, Rice University, Houston, Texas 77030, United States
| | - Pradip Paik
- School of Biomedical Engineering, Indian Institute of Technology-BHU, Varanasi 221005, India
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Duan HX, Zhao Z, Jin YJ, Wang ZL, Deng JF, He J, Zhu B. PEG-modified subunit vaccine encoding dominant epitope to enhance immune response against spring viraemia of carp virus. JOURNAL OF FISH DISEASES 2021; 44:1587-1594. [PMID: 34165796 DOI: 10.1111/jfd.13481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/09/2021] [Accepted: 06/11/2021] [Indexed: 06/13/2023]
Abstract
Spring viraemia of carp (SVC) caused by spring viraemia of carp virus (SVCV) can infect almost all fish of cyprinids, which bring huge economic losses to aquaculture. Glycoprotein (G), as the most important antigenic determinant protein of SVCV, is widely considered as an effective method against SVCV. In our previous study, we found that G3 (131 aa) is the potential dominant antigen epitope that induces strong immune responses similar to G protein (510 aa). Here, in order to further improve the immune effect, we reported a subunit vaccine (PEG-G3) constructed by PEG-modified dominant epitope protein (G3). The results of serum antibody production, enzyme activities and immune-related genes expression showed that PEG-G3 induces significantly stronger immune protective responses against SVCV than G3. PEG modification significantly increased the serum antibody level of the vaccine, which increased significantly after immunization and reached the peak at 21 day post-vaccination. T-AOC and AKP activities in the lowest concentration group (5 μg) of PEG-G3 were significantly higher than those in the highest concentration group (20 μg) of G3. In PEG-G3 group, the expression of almost all genes increased at least 4 times compared with the control group. After 14-day challenge, the RPS (relative percentage survival) of the highest concentration of PEG-G3 group was 53.6%, while that of G3 group is 38.9%. Therefore, this work shows that PEG modification and dominant epitope screening may be effective methods to improve the immune protective effect of vaccines and to resist the infection of aquatic animal viral diseases.
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Affiliation(s)
- Hui-Xin Duan
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Zhao Zhao
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Ying-Jie Jin
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Zi-Long Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Jie-Fang Deng
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Jie He
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Bin Zhu
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
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Shariatinia Z, Pourzadi N. Designing novel anticancer drug release vehicles based on mesoporous functionalized MCM-41 nanoparticles. J Mol Struct 2021. [DOI: 10.1016/j.molstruc.2021.130754] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Indocyanine green loaded pH-responsive bortezomib supramolecular hydrogel for synergistic chemo-photothermal/photodynamic colorectal cancer therapy. Photodiagnosis Photodyn Ther 2021; 36:102521. [PMID: 34481977 DOI: 10.1016/j.pdpdt.2021.102521] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/04/2021] [Accepted: 08/30/2021] [Indexed: 12/20/2022]
Abstract
Colorectal cancer is with high incidence worlwide.. Because of the heterogeneity of the tumor, combination therapy is probably of great significance to improve the prognosis of colorectal cancer patients. Herein, the pH-responsive supramolecular hydrogels mPEG-luteolin-BTZ@ICG based on bortezomib (BTZ) and indocyanine green (ICG) were prepared, and the colorectal cancer was treated with mPEG-luteolin-BTZ@ICG through the combination of photothermal/photodynamic and chemotherapy. BTZ performed drug therapy, meanwhile ICG wrapped in supramolecular hydrogels possessed higher light stability than free ICG to perform photothermal/photodynamic therapy. In vitro and in vivo assays showed excellent inhibition of tumor cells due to the combined effect of BTZ and ICG. The mPEG-luteolin-BTZ@ICG combined with laser therapy possessed exceptional biological safety and provided new candidates for advanced colon cancer therapy and important references for other tumor therapies.
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Fan HY, Zhu ZL, Xian HC, Wang HF, Chen BJ, Tang YJ, Tang YL, Liang XH. Insight Into the Molecular Mechanism of Podophyllotoxin Derivatives as Anticancer Drugs. Front Cell Dev Biol 2021; 9:709075. [PMID: 34447752 PMCID: PMC8383743 DOI: 10.3389/fcell.2021.709075] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 07/22/2021] [Indexed: 02/05/2023] Open
Abstract
Podophyllotoxin (PTOX) is a biologically active compound derived from the podophyllum plant, and both it and its derivatives possess excellent antitumor activity. The PTOX derivatives etoposide (VP-16) and teniposide (VM-26) have been approved by the U.S. Food and Drug Administration (FDA) for cancer treatment, but are far from perfect. Hence, numerous PTOX derivatives have been developed to address the major limitations of PTOX, such as systemic toxicity, drug resistance, and low bioavailability. Regarding their anticancer mechanism, extensive studies have revealed that PTOX derivatives can induce cell cycle G2/M arrest and DNA/RNA breaks by targeting tubulin and topoisomerase II, respectively. However, few studies are dedicated to exploring the interactions between PTOX derivatives and downstream cancer-related signaling pathways, which is reasonably important for gaining insight into the role of PTOX. This review provides a comprehensive analysis of the role of PTOX derivatives in the biological behavior of tumors and potential molecular signaling pathways, aiming to help researchers design and develop better PTOX derivatives.
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Affiliation(s)
- Hua-yang Fan
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
| | - Zhuo-li Zhu
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
| | - Hong-chun Xian
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
| | - Hao-fan Wang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
| | - Bing-jun Chen
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
| | - Ya-Jie Tang
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China
| | - Ya-ling Tang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
| | - Xin-hua Liang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
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Ando H, Murakami Y, Eshima K, Ishida T. A novel polyethylene glycol (PEG)-drug conjugate of Venetoclax, a Bcl-2 inhibitor, for treatment of acute myeloid leukemia (AML). Cancer Rep (Hoboken) 2021; 5:e1485. [PMID: 34173723 PMCID: PMC8955075 DOI: 10.1002/cnr2.1485] [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: 03/27/2021] [Revised: 05/16/2021] [Accepted: 06/01/2021] [Indexed: 11/09/2022] Open
Abstract
Background Venetoclax (VTX) is an anticancer drug. It is a selective Bcl‐2 inhibitor that is clinically used for the treatment of patients with lymphomas and leukemias. Treatment with VTX, however, is accompanied by severe adverse events such as tumor lysis syndrome and neutropenia, because VTX readily binds to serum proteins, which results in poor pharmacokinetics and poor tumor tissue concentration. To avoid such adverse events, VTX is administered using a daily or weekly ramp‐up schedule that is cumbersome in clinical situations. Aims To overcome these shortcomings, we prepared a novel polyethylene glycol (PEG)‐drug conjugate of VTX (PEG‐VTX) and evaluated its cytotoxic effects on acute myeloid leukemia (AML) both in vitro and in vivo. Methods and results VTX and 4‐armed PEG derivatives were covalently attached through an amide bond linker. In a series of in vitro studies, PEG‐VTX selectively induced potent growth inhibition of MV4‐11 human AML cells via the inducement of Bcl‐2‐mediated apoptosis. PEG‐VTX had the effect of free VTX, presumably due to the protease‐mediated release of VTX from the conjugates. In in vivo studies with AML tumor‐xenograft mice models, intravenous PEG‐VTX promoted sufficient tumor growth suppression. Compared with a regimen of oral free VTX, the intravenous regimen in those studies used a VTX dosage that was 15–30 times smaller for an OCI‐AML‐2 xenograft model and a dosing regimen that was less frequent for an MV4‐11 xenograft model. The most important development, however, was the absence of weight loss related to severe side effects throughout the treatments. An increase in water solubility and the resultant hydrodynamic size of VTX via PEGylation improved the pharmacokinetics of VTX by avoiding protein interactions and lessening the extravasation from blood. The result was an increase in tumor accumulation and a decrease in the nonspecific distribution of VTX. Conclusion The results of this study suggest that PEG‐VTX could be an alternative therapeutic option for the safe and effective treatment of patients with AML.
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Affiliation(s)
- Hidenori Ando
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Yuta Murakami
- Biotechnology & Medical Division, Planning Department, Sanyo Chemical Industries, Ltd, Kyoto, Japan
| | | | - Tatsuhiro Ishida
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
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Bhandari PJ, Reddy MM, Rao KJ, Sandanaraj BS. Rapid Chemical Synthesis of Self-Assembling Semi-Synthetic Proteins. J Org Chem 2021; 86:8576-8589. [PMID: 34133144 DOI: 10.1021/acs.joc.1c00195] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The design of well-defined monodispersed self-assembling semi-synthetic proteins is emerging as a promising research avenue. These proteins hold great potential to be used as scaffolds for various protein nanotechnology applications. Currently, there are very few chemical methods reported; however, they suffer from elaborate multistep organic synthesis. Herein, we report a new chemical methodology for the rapid synthesis of a diverse set of semi-synthetic protein families, which include protein amphiphiles, facially amphiphilic protein-dendron conjugates, and pH-sensitive protein-dendron conjugates. This chemical method holds great potential to access a wide variety of semi-synthetic proteins in a short time.
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Affiliation(s)
| | - Mullapudi Mohan Reddy
- Department of Chemistry, Indian Institute of Science Education and Research, Pune 411008, India
| | | | - Britto S Sandanaraj
- Department of Chemistry, Indian Institute of Science Education and Research, Pune 411008, India
- Department of Biology, Indian Institute of Science Education and Research, Pune 411008, India
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Xu L, Kuan SL, Weil T. Contemporary Approaches for Site-Selective Dual Functionalization of Proteins. Angew Chem Int Ed Engl 2021; 60:13757-13777. [PMID: 33258535 PMCID: PMC8248073 DOI: 10.1002/anie.202012034] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Indexed: 12/16/2022]
Abstract
Site-selective protein functionalization serves as an invaluable tool for investigating protein structures and functions in complicated cellular environments and accomplishing semi-synthetic protein conjugates such as traceable therapeutics with improved features. Dual functionalization of proteins allows the incorporation of two different types of functionalities at distinct location(s), which greatly expands the features of native proteins. The attachment and crosstalk of a fluorescence donor and an acceptor dye provides fundamental insights into the folding and structural changes of proteins upon ligand binding in their native cellular environments. Moreover, the combination of drug molecules with different modes of action, imaging agents or stabilizing polymers provides new avenues to design precision protein therapeutics in a reproducible and well-characterizable fashion. This review aims to give a timely overview of the recent advancements and a future perspective of this relatively new research area. First, the chemical toolbox for dual functionalization of proteins is discussed and compared. The strengths and limitations of each strategy are summarized in order to enable readers to select the most appropriate method for their envisaged applications. Thereafter, representative applications of these dual-modified protein bioconjugates benefiting from the synergistic/additive properties of the two synthetic moieties are highlighted.
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Affiliation(s)
- Lujuan Xu
- Max Planck Institute for Polymer ResearchAckermannweg 1055128MainzGermany
- Institute of Inorganic Chemistry IUlm UniversityAlbert-Einstein-Allee 1189081UlmGermany
| | - Seah Ling Kuan
- Max Planck Institute for Polymer ResearchAckermannweg 1055128MainzGermany
- Institute of Inorganic Chemistry IUlm UniversityAlbert-Einstein-Allee 1189081UlmGermany
| | - Tanja Weil
- Max Planck Institute for Polymer ResearchAckermannweg 1055128MainzGermany
- Institute of Inorganic Chemistry IUlm UniversityAlbert-Einstein-Allee 1189081UlmGermany
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36
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Trachsel L, Zenobi-Wong M, Benetti EM. The role of poly(2-alkyl-2-oxazoline)s in hydrogels and biofabrication. Biomater Sci 2021; 9:2874-2886. [PMID: 33729230 DOI: 10.1039/d0bm02217a] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Poly(2-alkyl-2-oxazoline)s (PAOXAs) have been rapidly emerging as starting materials in the design of tissue engineering supports and for the generation of platforms for cell cultures, especially in the form of hydrogels. Thanks to their biocompatibility, chemical versatility and robustness, PAOXAs now represent a valid alternative to poly(ethylene glycol)s (PEGs) and their derivatives in these applications, and in the formulation of bioinks for three-dimensional (3D) bioprinting. In this review, we summarize the recent literature where PAOXAs have been used as main components for hydrogels and biofabrication mixtures, especially highlighting how their easily tunable composition could be exploited to fabricate multifunctional biomaterials with an extremely broad spectrum of properties.
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Affiliation(s)
- Lucca Trachsel
- Tissue Engineering + Biofabrication Laboratory, Department of Health Sciences and Technology, ETH Zürich, 8093 Zürich, Switzerland
| | - Marcy Zenobi-Wong
- Tissue Engineering + Biofabrication Laboratory, Department of Health Sciences and Technology, ETH Zürich, 8093 Zürich, Switzerland
| | - Edmondo M Benetti
- Laboratory for Surface Science and Technology, Department of Materials, ETH Zürich, Vladimir-Prelog-Weg 5, 8093 Zürich, Switzerland. and Biointerfaces, Swiss Federal Laboratories for Materials Science and Technology (Empa), Lerchenfeldstrasse 5, CH-9014, St. Gallen, Switzerland
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37
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Mohammad MA, Didelija IC, Stoll B, Nguyen TC, Marini JC. Pegylated arginine deiminase depletes plasma arginine but maintains tissue arginine availability in young pigs. Am J Physiol Endocrinol Metab 2021; 320:E641-E652. [PMID: 33427052 PMCID: PMC7988784 DOI: 10.1152/ajpendo.00472.2020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Pegylated arginine deiminase (ADI-PEG20) results in the depletion of arginine with the production of isomolar amounts of citrulline. This citrulline has the potential to be utilized by the citrulline recycling pathway regenerating arginine and sustaining tissue arginine availability. The goal of this research was to test the hypothesis that ADI-PEG20 depletes circulating arginine in pigs but maintains tissue arginine concentration and function, and to characterize the kinetics of citrulline and arginine. Two multitracer approaches (bolus dose and primed-continuous infusion) were used to investigate the metabolism of arginine and citrulline in Control (n = 7) and ADI-PEG20 treated (n = 8) pigs during the postprandial period. In addition, blood pressure was monitored by telemetry, and multiple tissues were collected to determine arginine concentration. Plasma arginine was depleted immediately after ADI-PEG20 administration, with an increase in plasma citrulline concentration (P < 0.01). The depletion of arginine did not affect (P > 0.10) blood pressure, whole body protein synthesis, or urea production. Despite the lack of circulating arginine in ADI-PEG20-treated pigs, most tissues were able to maintain concentrations similar (P > 0.10) to those in Control animals. The kinetics of citrulline and arginine indicated the high citrulline turnover and regeneration of arginine through the citrulline recycling pathway. ADI-PEG20 administration resulted in an absolute and almost instantaneous depletion of circulating arginine, thus reducing global availability without affecting cardiovascular parameters and protein metabolism. The citrulline produced from the deimination of arginine was in turn utilized by the citrulline recycling pathway restoring local tissue arginine availability.NEW & NOTEWORTHY Pegylated arginine deiminase depletes circulating arginine, but the citrulline generated is utilized by multiple tissues to regenerate arginine and sustain local arginine availability. Preempting the arginine depletion that occurs as result of sepsis and trauma with arginine deiminase offers the possibility of maintaining tissue arginine availability despite negligible plasma arginine concentrations.
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Affiliation(s)
- Mahmoud A Mohammad
- USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas
- Food Science and Nutrition Department, National Research Centre, Giza, Egypt
| | - Inka C Didelija
- USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas
| | - Barbara Stoll
- USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas
| | - Trung C Nguyen
- Pediatric Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Juan C Marini
- USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas
- Pediatric Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
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38
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Xu L, Kuan SL, Weil T. Contemporary Approaches for Site‐Selective Dual Functionalization of Proteins. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202012034] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Lujuan Xu
- Max Planck Institute for Polymer Research Ackermannweg 10 55128 Mainz Germany
- Institute of Inorganic Chemistry I Ulm University Albert-Einstein-Allee 11 89081 Ulm Germany
| | - Seah Ling Kuan
- Max Planck Institute for Polymer Research Ackermannweg 10 55128 Mainz Germany
- Institute of Inorganic Chemistry I Ulm University Albert-Einstein-Allee 11 89081 Ulm Germany
| | - Tanja Weil
- Max Planck Institute for Polymer Research Ackermannweg 10 55128 Mainz Germany
- Institute of Inorganic Chemistry I Ulm University Albert-Einstein-Allee 11 89081 Ulm Germany
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Dual Redox/pH-Sensitive Micelles Self-Assembled From Star-Like Amphiphilic Copolymers Based On Sucrose For Controlled Doxorubicin Delivery. J Pharm Sci 2020; 110:2196-2209. [PMID: 33373606 DOI: 10.1016/j.xphs.2020.12.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 10/20/2020] [Accepted: 12/22/2020] [Indexed: 11/23/2022]
Abstract
Novel dual redox/pH-sensitive star-like amphiphilic sucrose-oligo(butyl fumarate) (thioglycolic acid conjugate)-SS-poly(ethylene glycol) (Suc-OBF(TGA)-SS-PEG) copolymers and their self-assembled micelles were prepared and utilized for intracellular doxorubicin delivery. Importance of changing the hydrophobic chain length on micelles properties was investigated. Results showed that the micelles with longer hydrophobic chain exhibited smaller size and were more stable in aqueous solution. The redox and pH sensitivity of the micelles was confirmed by the change of micelle diameter/diameter distribution measured by dynamic light scattering and the change of micellar morphology observed by scanning electron microscope. The micelles display a decent doxorubicin loading capacity. In vitro release studies showed that only 14.3% doxorubicin was released from doxorubicin-loaded micelles under physiological conditions in 30 h. The release of doxorubicin was accelerated at pH 5.5 or in the presence of 10 mM glutathione at pH 7.4 (46.9% and 76.9% of doxorubicin was released, respectively, in 30 h). The doxorubicin release was further expedited under pH 5.5 and 10 mM GSH conditions (91.4%). Suc-OBF(TGA)-SS-PEG micelles displayed no cytotoxicity toward HDF cells. MTT assays indicated that doxorubicin-loaded micelles had good cytotoxicity against MCF-7 cells. This work suggested that star-like amphiphilic Suc-OBF(TGA)-SS-PEG copolymer micelles may provide a promising platform for delivering doxorubicin and other hydrophobic anticancer drugs.
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Göppert NE, Kleinsteuber M, Weber C, Schubert US. Degradable Poly(2-oxazoline) Analogues from Partially Oxidized Poly(ethylene imine). Macromolecules 2020. [DOI: 10.1021/acs.macromol.0c02143] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Affiliation(s)
- Natalie E. Göppert
- Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstr. 10, 07743 Jena, Germany
- Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany
| | - Maximilian Kleinsteuber
- Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstr. 10, 07743 Jena, Germany
- Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany
| | - Christine Weber
- Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstr. 10, 07743 Jena, Germany
- Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany
| | - Ulrich S. Schubert
- Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstr. 10, 07743 Jena, Germany
- Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany
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Pan Q, Deng X, Gao W, Chang J, Pu Y, He B. Small molecules-PEG amphiphilic conjugates as carriers for drug delivery: 1. the effect of molecular structures on drug encapsulation. J Drug Deliv Sci Technol 2020. [DOI: 10.1016/j.jddst.2020.101997] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Zhao S, Huang W, Wang C, Wang Y, Zhang Y, Ye Z, Zhang J, Deng L, Dong A. Screening and Matching Amphiphilic Cationic Polymers for Efficient Antibiosis. Biomacromolecules 2020; 21:5269-5281. [PMID: 33226784 DOI: 10.1021/acs.biomac.0c01330] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The amphiphilic cationic polymers that mimic antimicrobial peptides have received increasing attention due to their excellent antibacterial activity. However, the relationship between the structure of cationic polymers and its antibacterial effect remains unclear. In our current work, a series of PEG blocked amphiphilic cationic polymers composed of hydrophobic alkyl-modified and quaternary ammonium salt (QAS) moieties have been prepared. The structure-antibacterial activity relationship of these cationic polymers was investigated against E. coli and S. aureus, including PEGylation, random structure, molecular weights, and the content and lengths of the hydrophobic alkyl side chains. The results indicated that PEGylated random amphiphilic cationic copolymer (mPB35/T57) showed stronger antibacterial activity and better biocompatibility than the random copolymer without PEG (PB33/T56). Furthermore, mPB35/T57 with appropriate mole fraction of alkyl side chains (falkyl = 0.38), degree of polymerization (DP = 92), and four-carbon hydrophobic alkyl moieties was found to have the optimal structure that revealed the best antibacterial activities against both E. coli (MIC = 8 μg/mL, selectivity > 250) and S. aureus (MIC = 4 μg/mL, selectivity > 500). More importantly, mPB35/T57 could effectively eradicate E. coli biofilms by killing the bacteria embedded in the biofilms. Therefore, the structure of mPB35/T57 provided valuable information for improving the antibacterial activity of cationic polymers.
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Affiliation(s)
- Shuyue Zhao
- Department of Polymer Science and Technology, Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.,Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
| | - Wenjun Huang
- Department of Polymer Science and Technology, Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.,Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
| | - Changrong Wang
- Department of Polymer Science and Technology, Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.,Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
| | - Yaping Wang
- Department of Polymer Science and Technology, Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
| | - YuFeng Zhang
- Department of Polymer Science and Technology, Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
| | - Zhanpeng Ye
- Department of Polymer Science and Technology, Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
| | - Jianhua Zhang
- Department of Polymer Science and Technology, Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
| | - Liandong Deng
- Department of Polymer Science and Technology, Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
| | - Anjie Dong
- Department of Polymer Science and Technology, Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.,Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
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Kumari M, Sahni G, Datta S. Development of Site-Specific PEGylated Granulocyte Colony Stimulating Factor With Prolonged Biological Activity. Front Bioeng Biotechnol 2020; 8:572077. [PMID: 33330413 PMCID: PMC7710547 DOI: 10.3389/fbioe.2020.572077] [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: 06/12/2020] [Accepted: 10/07/2020] [Indexed: 11/13/2022] Open
Abstract
Currently, amino-terminal PEGylated human granulocyte colony stimulating factor (huG-CSF) is used to prevent and treat neutropenia. Although huG-CSF has been used as a drug for more than 20 years, it has three significant drawbacks: (i) it relies on PEG aldehyde for PEGylation of the alpha-amino group of the first amino acid, and this leads to non-specific PEGylation of the epsilon amino group of lysine residues within the G-CSF; (ii) longer-acting G-CSF variants are desirable to reduce the risk of chemotherapy-associated neutropenia; and (iii) G-CSF cannot be administered on the day of chemotherapy. In an attempt to overcome the above drawbacks, we engineered cysteine variants of G-CSF to facilitate the maleimide PEG-based site-specific PEGylation that leads to a highly homogenous PEGylated product. Importantly, we have demonstrated that 20 kDa thiol-reactive PEG conjugated by maleimide chemistry to the Cys2 G-CSF variant exhibits leukocyte proliferative activity similar to that of the commercially available G-CSF conjugated with aldehyde PEG in a neutropenia mice model. Moreover, we have demonstrated that PEGylation of the cysteine variant of huG-CSF with higher molecular weight PEGs, such as 30 kDa PEG and 40 kDa PEG, leads to significantly prolonged leukocyte proliferation activity compared to the variant conjugated with 20 kDa PEG. Importantly, even a half-dose of the engineered variant conjugated with 40 kDa PEG exhibited significantly longer biological activity than the commercially available 20 kDa PEGylated huG-CSF. Finally, we have demonstrated that administration of the engineered variant conjugated with 40 kDa PEG on the day of administration of cyclophosphamide for inducing neutropenia in mice can alleviate neutropenia through leukocyte proliferation. In summary, this study provides the design of site-specific PEGylated huG-CSF variants with improved therapeutic potential. It opens the possibility of long-acting and same-day prophylactic administration of G-CSF after chemotherapy drug regimens. These results may pave the way for the development of potential G-CSF derivatives possessing longer half-lives and favorable clinical attributes.
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Affiliation(s)
- Monika Kumari
- Council of Scientific and Industrial Research, Institute of Microbial Technology, Chandigarh, India
| | - Girish Sahni
- Council of Scientific and Industrial Research, Institute of Microbial Technology, Chandigarh, India
| | - Sonal Datta
- Council of Scientific and Industrial Research, Institute of Microbial Technology, Chandigarh, India
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de la Cruz N, Sousa-Herves A, Rojo J. Glyconanogels as a versatile platform for the multivalent presentation of carbohydrates: From monosaccharides to dendritic glycostructures. Eur Polym J 2020. [DOI: 10.1016/j.eurpolymj.2020.110023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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45
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Thakor P, Bhavana V, Sharma R, Srivastava S, Singh SB, Mehra NK. Polymer–drug conjugates: recent advances and future perspectives. Drug Discov Today 2020; 25:1718-1726. [DOI: 10.1016/j.drudis.2020.06.028] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 05/27/2020] [Accepted: 06/29/2020] [Indexed: 10/23/2022]
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46
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Tiwari SK, Dicks LMT, Popov IV, Karaseva A, Ermakov AM, Suvorov A, Tagg JR, Weeks R, Chikindas ML. Probiotics at War Against Viruses: What Is Missing From the Picture? Front Microbiol 2020; 11:1877. [PMID: 32973697 PMCID: PMC7468459 DOI: 10.3389/fmicb.2020.01877] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 07/16/2020] [Indexed: 01/07/2023] Open
Abstract
Our world is now facing a multitude of novel infectious diseases. Bacterial infections are treated with antibiotics, albeit with increasing difficulty as many of the more common causes of infection have now developed broad spectrum antimicrobial resistance. However, there is now an even greater challenge from both old and new viruses capable of causing respiratory, enteric, and urogenital infections. Reports of viruses resistant to frontline therapeutic drugs are steadily increasing and there is an urgent need to develop novel antiviral agents. Although this all makes sense, it seems rather strange that relatively little attention has been given to the antiviral capabilities of probiotics. Over the years, beneficial strains of lactic acid bacteria (LAB) have been successfully used to treat gastrointestinal, oral, and vaginal infections, and some can also effect a reduction in serum cholesterol levels. Some probiotics prevent gastrointestinal dysbiosis and, by doing so, reduce the risk of developing secondary infections. Other probiotics exhibit anti-tumor and immunomodulating properties, and in some studies, antiviral activities have been reported for probiotic bacteria and/or their metabolites. Unfortunately, the mechanistic basis of the observed beneficial effects of probiotics in countering viral infections is sometimes unclear. Interestingly, in COVID-19 patients, a clear decrease has been observed in cell numbers of Lactobacillus and Bifidobacterium spp., both of which are common sources of intestinal probiotics. The present review, specifically motivated by the need to implement effective new counters to SARS-CoV-2, focusses attention on viruses capable of co-infecting humans and other animals and specifically explores the potential of probiotic bacteria and their metabolites to intervene with the process of virus infection. The goal is to help to provide a more informed background for the planning of future probiotic-based antiviral research.
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Affiliation(s)
- Santosh Kumar Tiwari
- Department of Genetics, Maharshi Dayanand University, Rohtak, India,*Correspondence: Santosh Kumar Tiwari,
| | - Leon M. T. Dicks
- Department of Microbiology, Stellenbosch University, Stellenbosch, South Africa
| | - Igor V. Popov
- Center for Agro-Biotechnology, Faculty of Bioengineering and Veterinary Medicine, Don State Technical University, Rostov-on-Don, Russia
| | - Alena Karaseva
- Institute of Experimental Medicine, Saint Petersburg, Russia
| | - Alexey M. Ermakov
- Center for Agro-Biotechnology, Faculty of Bioengineering and Veterinary Medicine, Don State Technical University, Rostov-on-Don, Russia
| | - Alexander Suvorov
- Institute of Experimental Medicine, Saint Petersburg, Russia,Saint Petersburg State University, Saint Petersburg, Russia
| | | | - Richard Weeks
- Health Promoting Naturals Laboratory, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, Brunswick, NJ, United States
| | - Michael L. Chikindas
- Center for Agro-Biotechnology, Faculty of Bioengineering and Veterinary Medicine, Don State Technical University, Rostov-on-Don, Russia,Health Promoting Naturals Laboratory, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, Brunswick, NJ, United States
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Verkoyen P, Frey H. Long‐Chain Alkyl Epoxides and Glycidyl Ethers: An Underrated Class of Monomers. Macromol Rapid Commun 2020; 41:e2000225. [DOI: 10.1002/marc.202000225] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 05/27/2020] [Indexed: 12/14/2022]
Affiliation(s)
- Patrick Verkoyen
- Department of ChemistryJohannes Gutenberg University Mainz Duesbergweg 10‐14 Mainz 55128 Germany
| | - Holger Frey
- Department of ChemistryJohannes Gutenberg University Mainz Duesbergweg 10‐14 Mainz 55128 Germany
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Huang Y, Jin C, Yu J, Wang L, Lu W. A novel multifunctional 2-nitroimidazole-based bioreductive linker and its application in hypoxia-activated prodrugs. Bioorg Chem 2020; 101:103975. [PMID: 32474180 DOI: 10.1016/j.bioorg.2020.103975] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 05/05/2020] [Accepted: 05/23/2020] [Indexed: 10/24/2022]
Abstract
Tumor hypoxia has been widely explored over the years as a diagnostic and therapeutic marker. Herein, we designed, optimized and synthesized a new multifunctional bioreductive linker (12) containing an alkynyl group (potential click chemistry fragment); the linker is based on 2-nitroimidazole which was expected to simultaneously overcome the drawbacks of hypoxia-activated prodrugs (poor selectivity and unsatisfactory water solubility). Furthermore, a hypoxia-activated, water-soluble SN-38 prodrug was obtained, and it was stable under physiological conditions and was rapidly released as an active drug under hypoxic conditions.
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Affiliation(s)
- Ying Huang
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China
| | - Chen Jin
- Xingliu (Shanghai) Pharmaceutical Technology Co., Ltd, Room A406, 1#Building, No. 1976 Middle Gaoke Road, Shanghai 201210, PR China
| | - Jiahui Yu
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China
| | - Lei Wang
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China.
| | - Wei Lu
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China.
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Fadiji AE, Babalola OO. Elucidating Mechanisms of Endophytes Used in Plant Protection and Other Bioactivities With Multifunctional Prospects. Front Bioeng Biotechnol 2020; 8:467. [PMID: 32500068 PMCID: PMC7242734 DOI: 10.3389/fbioe.2020.00467] [Citation(s) in RCA: 171] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 04/22/2020] [Indexed: 01/06/2023] Open
Abstract
Endophytes are abundant in plants and studies are continuously emanating on their ability to protect plants from pathogens that cause diseases especially in the field of agriculture. The advantage that endophytes have over other biocontrol agents is the ability to colonize plant's internal tissues. Despite this attributes, a deep understanding of the mechanism employed by endophytes in protecting the plant from diseases is still required for both effectiveness and commercialization. Also, there are increasing cases of antibiotics resistance among most causative agents of diseases in human beings, which calls for an alternative drug discovery using natural sources. Endophytes present themselves as a storehouse of many bioactive metabolites such as phenolic acids, alkaloids, quinones, steroids, saponins, tannins, and terpenoids which makes them a promising candidate for anticancer, antimalarial, antituberculosis, antiviral, antidiabetic, anti-inflammatory, antiarthritis, and immunosuppressive properties among many others, even though the primary function of bioactive compounds from endophytes is to make the host plants resistant to both abiotic and biotic stresses. Endophytes still present themselves as a peculiar source of possible drugs. This study elucidates the mechanisms employed by endophytes in protecting the plant from diseases and different bioactivities of importance to humans with a focus on endophytic bacteria and fungi.
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Affiliation(s)
| | - Olubukola Oluranti Babalola
- Food Security and Safety Niche, Faculty of Natural and Agricultural Sciences, North-West University, Mmabatho, South Africa
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50
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Avramović N, Mandić B, Savić-Radojević A, Simić T. Polymeric Nanocarriers of Drug Delivery Systems in Cancer Therapy. Pharmaceutics 2020; 12:E298. [PMID: 32218326 PMCID: PMC7238125 DOI: 10.3390/pharmaceutics12040298] [Citation(s) in RCA: 141] [Impact Index Per Article: 28.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 03/20/2020] [Accepted: 03/23/2020] [Indexed: 01/10/2023] Open
Abstract
Conventional chemotherapy is the most common therapeutic method for treating cancer by the application of small toxic molecules thatinteract with DNA and causecell death. Unfortunately, these chemotherapeutic agents are non-selective and can damage both cancer and healthy tissues,producing diverse side effects, andthey can have a short circulation half-life and limited targeting. Many synthetic polymers have found application as nanocarriers of intelligent drug delivery systems (DDSs). Their unique physicochemical properties allow them to carry drugs with high efficiency,specificallytarget cancer tissue and control drug release. In recent years, considerable efforts have been made to design smart nanoplatforms, including amphiphilic block copolymers, polymer-drug conjugates and in particular pH- and redox-stimuli-responsive nanoparticles (NPs). This review is focused on a new generation of polymer-based DDSs with specific chemical functionalities that improve their hydrophilicity, drug loading and cellular interactions.Recentlydesigned multifunctional DDSs used in cancer therapy are highlighted in this review.
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Affiliation(s)
- Nataša Avramović
- Institute of Medical Chemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Boris Mandić
- Faculty of Chemistry, University of Belgrade, Studentski trg 12–16, 11000 Belgrade, Serbia;
| | - Ana Savić-Radojević
- Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (A.S.-R.); (T.S.)
| | - Tatjana Simić
- Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (A.S.-R.); (T.S.)
- Serbian Academy of Sciences and Arts, 11000 Belgrade, Serbia
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