Folate‐functionalized polymeric micelles for tumor targeted delivery of a potent multidrug‐resistance modulator FG020326

Abstract To overcome multidrug resistance (MDR) existing in tumor chemotherapy, polymeric micelles encoded with folic acid on the micelle surface were prepared with the encapsulation of a potent MDR modulator, FG020326. The micelles were fabricated from diblock copolymers of poly(ethylene glycol) (PEG) and biodegradable poly(ε‐caprolactone) (PCL) with folate attached to the distal ends of PEG chains. The folate‐conjugated copolymers, folate‐PEG‐PCL, were synthesized by multistep chemical reactions. First, allyl‐terminated copolymer (allyl‐PEG‐PCL) was synthesized through a ring‐opening polymerization of ε‐caprolactone in bulk employing monoallyl‐PEG as a macroinitiator. Second, the allyl terminal groups of copolymers were converted into primary amino groups by a radical addition reaction, followed by conjugation of the carboxylic group of folic acid. In vitro studies at 37°C demonstrated that FG020326 release from micelles at pH 5.0 was faster than that at pH 7.4. Cytotoxicity studies with MTT assays indicated that folate‐functionalized and FG020326‐loaded micelles resensitized the cells approximately five times more than their folate‐free counterparts ( p < 0.01) in human KB v200 cells treated with vincristine (VCR). The in vitro Rhodamine 123 efflux experiment using MDR KB v200 cells revealed that when cells were pretreated with folate‐attached and FG020326‐loaded micelles, the P‐glycoprotein (P‐gp) drug efflux function was significantly inhibited. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res 2008