Incorporation of water-insoluble anticancer drug into polymeric micelles and control of their particle size

Abstract

A water-insoluble anticancer drug, KRN 5500 (KRN), was incorporated into polymeric micelles forming from poly(ethylene glycol–poly(amino acid) block copolymers by physical entrapment utilizing hydrophobic interactions between this drug and the poly(amino acid) chain block of the block copolymers. Three block copolymers were examined for this incorporation; poly(ethylene glycol)–poly(β-benzyl l-aspartate) (PEG–PBLA) and its two derivatives obtained by partial hydrolysis at the β-benzyl l-aspartate (BLA) units (PEG–P(Asp, BLA)) and by partial cetyl ester substitution at the BLA units (PEG–P(C 16, BLA)), respectively. Among these block copolymers, considerable effects of the cetyl esterification were seen on KRN yield and particle size. Considerable differences in the KRN incorporation yield and particle size were also observed between DMF and DMS used as solvent to dissolve KRN and the block copolymers. Sonication was turned out to be an effective method to obtain a polymer micelles fraction in high efficiency, and sonication was considered to work for separating intermicellar associates into dispersed micelles. A KRN incorporation procedure by dialysis using PEG–P(C 16, BLA) and DMSO (as solvent) followed by sonication brought about polymeric micelles of 71 nm in weight–average diameter. This shows successful incorporation of a water-insoluble drug into polymeric micelles by optimizing block copolymer structure and incorporation conditions.