Bioreducible Block Copolymers Based on Poly(Ethylene Glycol) and Poly(γ-Benzyl l-Glutamate) for Intracellular Delivery of Camptothecin

Abstract

Poly(ethylene glycol)-b-poly(γ-benzyl L-glutamate)s bearing the disulfide bond (PEG-SS-PBLGs), which is specifically cleavable in intracellular compartments, were prepared via a facile synthetic route as a potential carrier of camptothecin (CPT). Diblock copolymers with different lengths of PBLG were synthesized by ring-opening polymerization of benzyl glutamate N-carboxy anhydride in the presence of a PEG macroinitiator (PEG-SS-NH(2)). Owing to their amphiphilic nature, the copolymers formed spherical micelles in an aqueous condition, and their particle sizes (20-125 nm in diameter) were dependent on the block length of PBLG. Critical micelle concentrations of the copolymers were in the range 0.005-0.065 mg/mL, which decreased as the block length of PBLG increased. CPT, chosen as a model anticancer drug, was effectively encapsulated up to 12 wt % into the hydrophobic core of the micelles by the solvent casting method. It was demonstrated by the in vitro optical imaging technique that the fluorescence signal of doxorubicin, quenched in the PEG-SS-PBLG micelles, was highly recovered in the presence of glutathione (GSH), a tripeptide reducing disulfide bonds in the cytoplasm. The micelles released CPT completely within 20 h under 10 mM GSH, whereas only 40% of CPT was released from the micelles in the absence of GSH. From the in vitro cytotoxicity test, it was found that CPT-loaded PEG-SS-PBLG micelles showed higher toxicity to SCC7 cancer cells than CPT-loaded PEG-b-PBLG micelles without the disulfide bond. Microscopic observation demonstrated that the disulfide-containing micelle could effectively deliver the drug into nuclei of SCC7 cells. These results suggest that PEG-SS-PBLG diblock copolymer is a promising carrier for intracellular delivery of CPT.

Synthesis and pharmacokinetic characterization of a pH-sensitive polyethylene glycol ginsenoside CK (PEG-CK) conjugate

“…Specifically, the intracellular pH of tumor cells (pH 5.0-6.5) is usually much lower than physiological pH (pH 7.4), and has encouraged researchers to develop pH-responsive pro-drug formulations to improve the therapeutic efficacy of drugs. [11][12][13][14][15] Here, we report a simple method of enhancing the solubility of CK. CK was chemically modified with hydrophilic PEG through esterification (PEG-CK).…”

Reduction-Responsive Polymeric Micelles and Vesicles for Triggered Intracellular Drug Release

“…Similarly, DOX-loaded PEG-SS-poly(leucine) (PEG-SS-PLeu) micelles exhibited accelerated DOX release in response to 10 mM DTT and enhanced antitumor efficacy in GSH-pretreated HepG2 cells (56). Thambi et al discerned that shell-sheddable PEG-SS-poly (c-benzyl l-glutamate) (PEG-SS-PBLG) micelles with high loading efficiency for camptothecin (CPT) and DOX revealed GSH-triggered drug release behavior and provoked higher cytotoxicity to SCC7 cancer cells than reductioninsensitive PEG-b-PBLG controls (69,70). Reductionsensitive shell-sheddable CPT-SS-PEG-SS-CPT prodrug micelles formed large aggregates with mean diameters over 1000 nm in response to 10 mM DTT and effectively inhibited cell growth under the tumor-relevant GSH concentration (39).…”

Stimuli-Responsive Polymeric Nanocarriers as Promising Drug and Gene Delivery Systems

“…Among these three types, shell-sheddable micelles have been widely investigated as a carrier for hydrophobic anticancer drugs. Since many amphiphilic block copolymer micelles with PEG shell and biodegradable hydrophobic cores such as polyesters [such as polycaprolactone (PCL), PLLA and poly(lactic-co-glycolic) acid (PLGA)] and polypeptides (such as PBLG) have been widely established as promising drug carriers, several researchers have developed sheddable micelles by incorporating disulfide between the PEG and the hydrophobic block (Sun et al 2009;Song et al 2011;Saeed et al 2011;Thambi et al 2011). These redox-responsive micelles demonstrated triggered drug release compared to the traditional micelles without disulfide bonds, which exhibits gradual degradation kinetics and sustained release of drugs over a period of days to week through diffusion-controlled mechanism that resulted in a reduced drug efficacy.…”