title: Triggered-release polymeric conjugate micelles for on-demand intracellular drug delivery.
abstract: Nanoscale drug delivery platforms have been developed over the past four decades that have shown promising clinical results in several types of cancer and inflammatory disorders. These nanocarriers carrying therapeutic payloads are maximizing the therapeutic outcomes while minimizing adverse effects. Yet one of the major challenges facing drug developers is the dilemma of premature versus on-demand drug release, which influences the therapeutic regiment, efficacy and potential toxicity. Herein, we report on redox-sensitive polymer-drug conjugate micelles for on-demand intracellular delivery of a model active agent, curcumin. Biodegradable methoxy poly(ethylene glycol)-poly(lactic acid) copolymer (mPEG-PLA) was conjugated with curcumin via a disulfide bond or ester bond (control), respectively. The self-assembled redox-sensitive micelles exhibited a hydrodynamic size of 115.6 ± 5.9 (nm) with a zeta potential of -10.6 ± 0.7 (mV). The critical micelle concentration was determined at 6.7 ± 0.4 (μg mL(-1)). Under sink conditions with a mimicked redox environment (10 mM dithiothreitol), the extent of curcumin release at 48 h from disulfide bond-linked micelles was nearly three times higher compared to the control micelles. Such rapid release led to a lower half maximal inhibitory concentration (IC50) in HeLa cells at 18.5 ± 1.4 (μg mL(-1)), whereas the IC50 of control micelles was 41.0 ± 2.4 (μg mL(-1)). The cellular uptake study also revealed higher fluorescence intensity for redox-sensitive micelles. In conclusion, the redox-sensitive polymeric conjugate micelles could enhance curcumin delivery while avoiding premature release, and achieving on-demand release under the high glutathione concentration in the cell cytoplasm. This strategy opens new avenues for on-demand drug release of nanoscale intracellular delivery platforms that ultimately might be translated into pre-clinical and future clinical practice.
authors.affiliation: School of Pharmaceutical Science & Technology, Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency, and Collaborative Innovation Center of Chemical Science and Engineering, Tianjin University, Tianjin 300072, People's Republic of China.
authors.forename: Yanwu
authors.initials: Y
authors.lastname: Cao
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.forename: Aiping
authors.initials: A
authors.lastname: Fan
authors.forename: Ju
authors.initials: J
authors.lastname: Zhang
authors.forename: Deling
authors.initials: D
authors.lastname: Kong
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Dan
authors.initials: D
authors.lastname: Peer
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D001672:Biocompatible Materials / Q000737:chemistry; D020134:Catalytic Domain; D002470:Cell Survival; D003474:Curcumin / Q000737:chemistry; D003593:Cytoplasm / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry; D004337:Drug Carriers; D005978:Glutathione / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D057446:Hydrodynamics; D006863:Hydrogen-Ion Concentration; D007249:Inflammation; D020128:Inhibitory Concentration 50; D007773:Lactates / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D008970:Molecular Weight; D050997:Nanomedicine / Q000379:methods; D053758:Nanoparticles / Q000737:chemistry; D036103:Nanotechnology / Q000379:methods*; D010084:Oxidation-Reduction; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D013696:Temperature
chemical_list: D001672:Biocompatible Materials; D004220:Disulfides; D004337:Drug Carriers; D007773:Lactates; D008823:Micelles; D011108:Polymers; C088513:poly(lactic acid-ethylene glycol); D011092:Polyethylene Glycols; D005978:Glutathione; D003474:Curcumin