Reduction and pH dual-bioresponsive crosslinked polymersomes for efficient intracellular delivery of proteins and potent induction of cancer cell apoptosis.
The clinical applications of protein drugs are restricted because of the absence of viable protein delivery vehicles. Here, we report on reduction- and pH--sensitive crosslinked polymersomes based on the poly(ethylene glycol)-poly(acrylic acid)-poly(2-(diethyl amino)ethyl methacrylate) (PEG-PAA-PDEA) triblock copolymer for efficient intracellular delivery of proteins and the potent induction of cancer cell apoptosis. PEG-PAA-PDEA (1.9-0.8-8.2kgmol(-1)) was synthesized by controlled reversible addition-fragmentation chain transfer polymerization and further modified with cysteamine to yield the thiol-containing PEG-PAA(SH)-PDEA copolymer. PEG-PAA(SH)-PDEA was water-soluble at acidic and physiological pH but formed robust and monodisperse polymersomes with an average size of ∼35nm upon increasing the pH to 7.8 or above followed by oxidative crosslinking. These disulfide-crosslinked polymersomes, while exhibiting excellent colloidal stability, were rapidly dissociated in response to 10mM glutathione at neutral or mildly acidic conditions. Notably, these polymersomes could efficiently load proteins like bovine serum albumin and cytochrome C (CC). The in vitro release studies revealed that protein release was fast and nearly quantitative under the intracellular-mimicking reducing environment. Confocal microscopy observations showed that these dual-sensitive polymersomes efficiently released fluorescein isothiocyanate-CC into MCF-7 cells in 6h. Most remarkably, MTT assays showed that CC-loaded dual-sensitive polymersomes induced potent cancer cell apoptosis, in which markedly decreased cell viabilities of 11.3%, 8.1% and 52.7% were observed for MCF-7, HeLa and 293T cells, respectively, at a CC dosage of 160μgml(-1). In contrast, free CC caused no cell death under otherwise the same conditions. These dual-bioresponsive polymersomes have appeared as a multifunctional platform for active intracellular protein release.
Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, People's Republic of China.
Huanli
H
Sun
Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, People's Republic of China. Electronic address: fhmeng@suda.edu.cn.
Fenghua
F
Meng
Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, People's Republic of China.
Ru
R
Cheng
Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, People's Republic of China.
Chao
C
Deng
Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, People's Republic of China. Electronic address: zyzhong@suda.edu.cn.
Zhiyuan
Z
Zhong
D000180:Acrylic Resins / Q000138:chemical synthesis / Q000737:chemistry; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002417:Cattle; D003102:Colloids / Q000737:chemistry; D003432:Cross-Linking Reagents / Q000737:chemistry*; D045304:Cytochromes c / Q000494:pharmacology*; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D006367:HeLa Cells; D006736:Horses; D006801:Humans; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D061986:MCF-7 Cells; D009682:Magnetic Resonance Spectroscopy; D008689:Methacrylates / Q000138:chemical synthesis / Q000737:chemistry; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D009369:Neoplasms / Q000473:pathology*; D010084:Oxidation-Reduction / Q000187:drug effects; D010316:Particle Size; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry*; D012710:Serum Albumin, Bovine / Q000378:metabolism; D012995:Solubility; D014867:Water / Q000737:chemistry
D000180:Acrylic Resins; D003102:Colloids; D003432:Cross-Linking Reagents; D008689:Methacrylates; D011108:Polymers; D014867:Water; D012710:Serum Albumin, Bovine; D011092:Polyethylene Glycols; C006903:carbopol 940; D045304:Cytochromes c; D016650:Fluorescein-5-isothiocyanate; C519537:diethylaminoethyl methacrylate
Cancer therapy; Crosslinking; Dual-sensitive; Polymersomes; Protein delivery