Circumvent PEGylation dilemma by implementing matrix metalloproteinase-responsive chemistry for promoted tumor gene therapy |
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| Affiliation: | 1. State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China;2. School of Bioengineering, Dalian University of Technology, Dalian 116024, China;3. Department of Neurosurgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China;1. State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China;2. Key Laboratory of Clinical and Medical Engineering, Department of Biomedical Engineering, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, China;3. Department of Clinical Laboratory, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China;4. Hunan Key Laboratory of Biomedical Nanomaterials and Devices, Hunan University of Technology, Zhuzhou 412007, China;1. College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, China;2. School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China;1. MOE Key Laboratory of Pollution Processes and Environmental Criteria / Tianjin Key Laboratory of Environmental Remediation and Pollution Control, College of Environmental Science and Engineering, Nankai University, Tianjin 300350, China;2. School of Energy and Environmental Engineering, Hebei University of Technology, Tianjin 300401, China;3. Department of Chemistry, Tianjin University, Tianjin 300072, China;1. Polymer Science Unit, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India;2. Centre for Advanced Materials, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India |
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| Abstract: | Surface modification by poly(ethylene glycol) (PEGylation) has been acknowledged as a powerful strategy in minimizing non-specific reactions for biomedical devices. Once applied into manufacture of drug/gene delivery systems, PEGylation has demonstrated to significantly improve their biocompatibility and stealthiness in physiological environment. Nonetheless, reluctant cell membrane affinities thus cellular uptake efficiencies owing to PEGylation brought up further issues that are imperative to be resolved. Pertain to this PEGylation dilemma, we attempted to introduce peptide (GPLGVRG) linkage between block copolymer of PEG-poly{N'-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} PAsp(DET), wherein the cationic PAsp(DET) could self-assemble with pDNA into nanoscaled complex core. Noteworthy was the peptide linkage whose amino acids sequence could be specifically recognized and degraded by matrix metalloproteinases (MMPs) (overexpressed in extracellular milieu of tumors). Therefore, our subsequent studies validated facile detachment of PEGylation from the aforementioned polyplex micelles upon treatment of MMPs, which elicited improved cytomembrane affinities and cellular uptake efficiencies. In addition, promoted escape from endosome entrapment was also confirmed through direct endosome membrane destabilization by PAsp(DET), which was further elucidated to be attributable to dePEGylation as well as elevated charged density of PAsp(DET) in acidic endosomes. These benefits from dePEGylation eventually contributed to promoted gene expression at the affected cells and potent tumor growth suppression based on anti-angiogenic approach. Therefore, our developed strategy has provided a facile approach in overcoming the dilemma of PEGylation, which could be informative in design of drug/gene delivery systems. |
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| Keywords: | PEGylation Tumor Polyplex micelle Gene delivery system Matrix metalloproteinase |
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