Graft Copolymer Nanoparticles with pH and Reduction Dual-Induced Disassemblable Property for Enhanced Intracellular Curcumin Release

Abstract

Nanoparticle (NP)-assisted drug delivery systems with disassemblable behaviors in response to intracellular microenvironment are urgently demanded in systemic cancer chemotherapy for enhanced intracellular drug release. Curcumin (CUR), an effective and safe anticancer agent, was limited by its water insolubility and poor bioavailability. Herein, pH and reduction dual-induced disassemblable NPs for high loading efficiency and improved intracellular release of CUR were developed based on an acid degradable cyclic benzylidene acetal groups (CBAs)-functionalized poly(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl)ethane methacrylate)-g-SS-poly(ethylene glycol) (PTTMA-g-SS-PEG) graft copolymer, which was readily prepared via RAFT copolymerization and coupling reaction. The NPs self-assembled from PTTMA-g-SS-PEG copolymers were stable at physiological pH, and quickly disassembled in mildly acidic and reductive environments because of the hydrolysis of CBAs in hydrophobic PTTMA core and the cleavage of disulfide-linked detachable PEG shell. PTTMA-g-SS-PEG NPs exhibited excellent CUR loading capacity with drug loading content up to 19.2% and entrapment efficiency of 96.0%. Within 20 h in vitro, less than 15.0% of CUR was released from the CUR-loaded NPs in normal physiological conditions, whereas 94.3% was released in the presence of reductive agent and mildly acidic conditions analogous to the microenvironment in endosome/lysosome and cytoplasm. Confocal fluorescence microscopies revealed that the CUR-loaded PTTMA-g-SS-PEG NPs exhibited more efficiently intracellular CUR release for EC-109 cells than that of CUR-loaded reduction-unresponsive PTTMA-g-PEG NPs and free CUR. In vitro cytotoxicity studies displayed blank PTTMA-g-SS-PEG NPs showed low toxicity at concentrations up to 1.0 mg/mL, whereas CUR-loaded PTTMA-g-SS-PEG NPs demonstrated more efficient growth inhibition toward EC-109 and HepG-2 cells than reduction-unresponsive controls and free CUR. Therefore, the above results indicated that pH and reduction dual-induced disassemblable PTTMA-g-SS-PEG NPs may have emerged as superior nanocarriers for active loading and promoted intracellular drug delivery in systemic cancer chemotherapy.

Tumor-triggered drug release from calcium carbonate-encapsulated gold nanostars for near-infrared photodynamic/photothermal combination antitumor therapy

“…Because of the natural acidic environment inside endosomes/lysosomes and cytoplasm 35, the entrapped ICG was gradually released from GNS@CaCO 3 /ICG, showing luminescence after endocytosis based on its pH-triggered fluorescence imaging. The NIR fluorescence imaging was performed in MGC803 cells incubated with free ICG (20 μg/mL) and GNS@CaCO 3 /ICG (Equivalent to 20 μg/mL ICG).…”

Development of silk fibroin-derived nanofibrous drug delivery system in supercritical CO2

“…Its multi biomedical potential [12][13][14] was limited due to low solubility and low bioavailability. A CM-releasing SF-derived nanofibrous drug delivery system was prepared by SEDS in this study.…”

Core cross-linked poly(ethylene glycol)-graft-Dextran nanoparticles for reduction and pH dual responsive intracellular drug delivery

“…[1][2][3][4] The preclinical and clinical studies have demonstrated that the polymeric nanocarriers are able to prolong circulation time in vivo, target specific tumor tissues via the enhanced permeability and retention (EPR) effect, and reduce side effects of drug, leading to improved therapeutic efficiency. [5][6][7] Due to the distinct tumor microenvironment as compared with normal tissues, the nanocarriers are usually designed to be stable in the blood circulation while releasing the cargos in response to biological stimuli at tumor sites or intracellular space. In these cases, various stimuli-responsiveness, such as pH, [8][9][10][11] glutathione (GSH), [12][13][14][15][16] temperature, 17, 18 light [19][20][21] and enzyme, [22][23][24] have been extensively investigated.…”