In recent years, bottlebrush polymers (BPs) have found widespread applications in fields ranging from drug delivery and molecular imaging to photonics and lithography. Graft-through ring-opening metathesis polymerization (ROMP) offers distinct advantages for BP synthesis including exceptionally high functional group tolerance and efficiency even for sterically-hindered multivalent macromonomers (MMs). In our group, a branched MM platform consisting of a ROMP-compatible norbornene analogue along with two orthogonally functionalizable sites is employed for the synthesis of novel bottlebrush and star polymer architectures. These sites can be furnished with either a therapeutic/imaging agent and a diluent polymer (eg. PEG) for biomedical applications, or 2 dissimilar polymers for branched block copolymer self-assembly studies. We recently developed a revised synthetic protocol that dramatically simplifies the synthesis of branched MMs, enabling hundred-gram scale preparations in overall 87% yield (compared to 43% for our previous system) and minimal purification steps. Furthermore, by repeating these steps in a manner similar to peptide synthesis, we were able to introduce additional functionalizable sites which can be subsequently loaded with the aforementioned moieties. Given the previously reported excellent therapeutic efficacy of our brush-arm star polymer nanoparticles (BASP NPs) based on the ability to precisely control the drug loading onto a three-drug-conjugated NP with favourable in vivo circulation and biodistribution, we are currently utilizing this concept to tackle multiple myeloma via deploying clinically relevant combination therapy to our BASP platform. Moreover, we have developed nitroxide-based BASP MRI organic contrast agents capable of tumor imaging over long time periods using clinical high-field 1H MRI techniques. As a consequence of their unique nano-architectures, nitroxide-containing-BASPs feature per nitroxide transverse relaxivities up to ~44-fold greater than common nitroxides, exceptional stability in highly reducing environments, addressing long standing weaknesses that essentially rendered nitroxides incapable of being effective MRI contrast agents.

Brush-first ring-opening metathesis polymerization as a modular and scalable strategy for combination cancer therapy and molecular imaging

255th National Meeting (2018)

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