The lack of selectivity and low solubility of many chemotherapeutics has prompted the development of different biocompatible nanosized drug carriers. Amphiphilic block copolymers, composed of a hydrophilic and hydrophobic domain, show great potential because of their small size, large solubilizing power and loading capacity. We report on a novel class of degradable block copolymers based on the modification of hydrophilic (meth)-acrylamide monomers with a hydrolytically sensitive carbonate ester. In a first step, N-(2-hydroxypropyl)methacrylamide (HPMA) was modified with an ethyl group via a carbonate ester and polymerized by free radical polymerization using a PEG-based macroinitiatior. This resulted in a temperature-responsive polymer with a cloud point (cp) of 17 °C, above which the block copolymer self-assembles in micelles with a diameter of 40 nm. The block copolymer nanoparticles were capable of delivering a hydrophobic payload (i.e. fluorescent dyes and the anti-cancer drug paclitaxel) into cancer cells in both 2D and 3D in vitro cultures. In a next step, the use of RAFT polymerization as a controlled radical polymerization technique was investigated. Because of the more efficient polymerization of acrylamides in comparison to methacrylamides, N-(2-hydroxyethyl)acrylamide was subsequently modified with an ethyl- and benzyl carbonate ester group. A benzyl carbonate ester side chain was introduced to increase micellar stability and drug loading capacity, due to p-p stacking of the aromatic groups. By using both HEAM and PEG as hydrophilic block and by choosing different block lengths, influence on CMC and drug loading were examined. The versatility of the RAFT approach was further explored by (1) the use co-monomers that can stabilize nanoparticle against disassembly in serum through covalent crosslinking and (2) the use of a chain transfer agent bearing a small molecule targeting ligand for prostate cancer cells to engineer nanoparticles with active targeting capacity.

Transiently responsive block copolymer micelles based on (meth)acrylamides engineered with hydrolyzable carbonate side chains

253rd National Meeting (2017)

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