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.

• Authors: Thavasyappan Thambi, Hong Yeol Yoon, Kwangmeyung Kim, Ick Chan Kwon, Chang Kyoo Yoo, Jae Hyung Park
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 22 Issue 10 Pg. 1924-31 (Oct 19 2011) ISSN: 1520-4812 [Electronic] United States
• PMID: 21899345 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Drug Carriers
• Micelles
• Succinimides
• poly-gamma-benzyl-L-glutamate
• Polyglutamic Acid
• Polyethylene Glycols
• polyethylene glycol bis(succinimidyl succinate)
• Camptothecin

Topics

• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Camptothecin (administration & dosage, pharmacokinetics)
• Cell Line, Tumor
• Cell Membrane Permeability
• Drug Carriers (chemistry)
• Humans
• Micelles
• Polyethylene Glycols (chemistry)
• Polyglutamic Acid (analogs & derivatives, chemistry)
• Succinimides (chemistry)