METHODS FOR THE PREPARATION OF TARGETING AGENT FUNCTIONALIZED DIBLOCK COPOLYMERS FOR USE IN FABRICATION OF THERAPEUTIC NANOPARTICLES

摘要

This application provides methods of making nanoparticles using pre-functionalized poly(ethylene glycol) (also referred to as PEG) as a macroinitiator for the synthesis of diblock copolymers. These diblock copolymers comprise a poly(ethylene glycol) block bearing a targeting agent at its terminus and a second biocompatible and biodegradable hydrophobic polymer block (e.g. a poly(ester)). The poly(ethylene glycol) is hetero-bifunctional with a targeting moiety (agent) covalently bound to its α terminus and a polymerization initiating functional group (e.g., a hydroxyl group) present on its ω terminus. Ring opening polymerization yields the desired poly(ester)-poly(ethylene glycol)-targeting agent polymer that is used to impart targeting capability to therapeutic nanoparticles. This “polymerization from” approach typically employs precursors of the targeting agent wherein the reactivity of functional groups of the targeting agent is masked using protecting groups. Also described is a “coupling to” that utilized the poly(ethylene glycol)-targeting agent conjugate where the targeting agent remains in its native un-protected form. This method uses “orthogonal” chemistry that exhibit no cross reactivity towards functional groups typically found within targeting agents of interest. Nanoparticles produced according to the disclosed methods as well as their use in the treatment of various diseases are also provided.