New routes to mucoadhesive block copolymer micelles for ocular drug delivery

Purpose: The topical delivery of drugs to the front of the eye is inefficient due to natural clearing mechanisms that prevents up to 95% of the drug from penetrating the cornea and sclera tissues. The Sheardown lab has previously developed a novel mucoadhesive block copolymer micelle for the delivery of a hydrophobic drug (Cyclosporine A) to the anterior surface of the eye to treat dry-eye disease.¹ The copolymer consists of a polylactide (PLA) block connected to a block containing a copolymer of methacrylic acid (MAA) and 3-(-acrylamido)phenylboronic acid (PBA). PBA can interact with the diol groups of mucins and polysaccharides of the ocular mucosa to form a boronate ester, enhancing the residence time of the micelle, and consequently the therapeutic agent, on the surface of the eye. The efficacy of this system was previously demonstrated in a dry-eye disease model with rats. However, the block copolymer was synthesized using Reversible Addition-Fragmentation chain Transfer (RAFT) polymerization, a controlled living radical polymerization technique that allows the second block of the copolymer to be directly polymerized from the first block through the use of a macro-RAFT initiator. In an effort to commercialize this technology, concerns have been raised over the scalability of the RAFT polymerization method in an industrial setting. Creating diblock copolymers through free-radical polymerization is not trivial. One approach is to end functionalize the polymers with complimentary reactive group that can be used to connect the polymer blocks together. The thiol-ene ‘click’ reaction is efficient and cost effective and requires the polymer blocks to be terminated with a ‘thiol’ and an alk‘ene’ group. The introduction of a functional group to one end of a polymer created using free-radical polymerization can be achieved by first creating a functional radical initiator. However, the initiator cannot interfere with the radical present during polymer growth, nor can it react with the monomers being polymerized. Since thiols can react with acrylic monomers, a thiol functional initiator must be protected during the polymerization process.