Impact of Drug Conjugation Site and Corona Chemistry on the Therapeutic Activity of Polymer Nanorod – Drug Conjugates

Abstract

AbstractBiocompatible rod‐shaped nanoparticles of controlled length can be produced through the heat‐induced “living” seeded crystallization‐driven self‐assembly (CDSA) of poly(2‐isopropyl‐2‐oxazoline)‐containing block copolymers. With a hydrophilic poly(2‐methyl‐2‐oxazine) or poly(2‐methyl‐2‐oxazoline) corona, these nanorods have proven non‐cytotoxic, non‐hemolytic, and ideal for use as a polymer‐based drug delivery system. This study demonstrates a facile, one‐pot method for the synthesis of mycophenolic acid (MPA)‐conjugated block copolymer “unimers” for use in seeded CDSA. Through altering block order during sequential monomer addition cationic ring‐opening polymerization (CROP), MPA is conjugated to either the chain end of the core‐forming or corona‐forming block. This allows bioactive polymer nanorods to be prepared with MPA positioned at either the periphery of the corona, or at the core‐corona interface of the nanorod formed during seeded CDSA. In vitro, these nanorods arrest growth in human T and B lymphocytes, with reduced effect in “off‐target” monocytes when compared with unconjugated MPA. Furthermore, the conjugation of MPA to the core‐corona interface of the nanorods leads to a slower release and reduced cytostatic effect. This study offers a robust investigation into the effect of steric hindrance and corona chemistry on the therapeutic potential of drug‐conjugated CDSA nanorods and demonstrates the potential of poly(2‐oxazoline)/poly(2‐oxazine)‐based CDSA nanomaterials as effective drug delivery platforms.