Tumoral acidic extracellular pH targeting of pH-responsive MPEG-poly(β-amino ester) block copolymer micelles for cancer therapy

• DOI: 10.1016/j.jconrel.2007.07.012
• Publication Date: 2007-08-09T11:38:50Z
• Authors: Jinyoung Ko; Kyeongsoon Park; Yoo-Shin Kim; Min Sang Kim; Jong Kwon Han; Kwangmeyung Kim; Rang-Woon Park; In-San Kim; Hyun Kyu Song; Doo Sung Lee; Ick Chan Kwon
• Keywords: Male; Drug Carriers; Antibiotics, Antineoplastic; Polymers; Chemistry, Pharmaceutical; Drug Compounding; Melanoma, Experimental; Esters; 02 engineering and technology; Hydrogen-Ion Concentration; Polyethylene Glycols; 3. Good health; Mice, Inbred C57BL; Kinetics; Mice; Doxorubicin; Cell Line, Tumor; Delayed-Action Preparations; Animals; Nanoparticles; Particle Size; 0210 nano-technology; Micelles

The main objective of this study was to develop and characterize a pH-responsive and biodegradable polymeric micelle as a tumor-targeting drug delivery system. The pH-responsive block copolymer was synthesized by a Michael-type step polymerization of hydrophilic methyl ether poly(ethylene glycol) (MPEG) and pH-responsive and biodegradable poly(beta-amino ester), resulting in an amphiphilic MPEG-poly(beta-amino ester) block copolymer. This copolymer, which formed nano-sized self-assembled micelles under aqueous conditions, could be efficiently (74.5%) loaded with doxorubicin (DOX) using a solvent evaporation method. In an in vitro drug release study, these DOX-loaded polymeric micelles showed noticeable pH-dependent micellization-demicellization behavior, with rapid release of DOX from the micelles in weakly acidic environments (pH 6.4) but very slow release under physiological conditions (pH 7.4). Moreover, due to demicellization, the tumor cell uptake of DOX released from polymeric micelles was much higher at pH 6.4 than at pH 7.4. When in vivo anti-tumor activity of pH-responsive polymeric micelles was evaluated by injecting the DOX-loaded polymeric micelles into B16F10 tumor-bearing mice, these micelles notably suppressed tumor growth and also prolonged survival of the tumor-bearing mice, compared with mice treated with free DOX.