Micellar drug delivery vehicles formed from amphiphilic block copolymers bearing photo-cross-linkable cyclopentenone side groups

Abstract

Amphiphilic block copolymers are of specific interest in the field of nanomedicine, and are used to encapsulate hydrophobic drugs for targeted drug delivery. To improve micellar stability in highly diluted conditions, cross-linkable functional groups can be incorporated in the polymer backbone to covalently link the block copolymers and create nanogels. In this work, we propose the use of a poly(oligo(ethylene glycol) methyl ether acrylate) macro-RAFT agent for the controlled polymerization of 4-oxocyclopentenyl acrylate (4CPA) and lauryl acrylate to obtain amphiphilic block copolymers. The cyclopentenone side groups belonging to the 4CPA monomer are able to dimerize under illumination with UV light, resulting in core cross-linked assemblies. A series of block copolymers containing different hydrophilic and hydrophobic block lengths were synthesized. The block copolymers were able to self-assemble after direct dissolution in water to form micellar structures. However, more defined, smaller, and spherical micelles of between 29 and 161 nm were obtained by producing them via a solvent exchange method. The micellar cores were cross-linked using UV irradiation and remained stable in organic solvent where the unmodified micelles dissociated and formed smaller assemblies. The drug loading capacity was firstly investigated using the model drug probes pyrene and Nile red. The most promising block copolymer was loaded with doxorubicin (DOX) with a loading content of 23.8%. In vitro release studies showed a delayed DOX release from the UV cross-linked micelles. Furthermore, the release was accelerated at lower pH. Cell viability essays of the DOX loaded micelles confirmed the relevance of the synthesized block copolymers as drug delivery vehicles by showing high cytotoxicity towards breast adenocarcinoma cells. The same non-loaded micelles showed low cytotoxicity at the targeted concentrations towards mouse fibroblast cells.