Bottlebrush polymer prodrugs for targeted delivery of combination therapies and in vivo imaging of pharmacological response

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ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with few effective treatments. The poor efficacy of current therapies including immune checkpoint inhibitors (ICIs) is partly attributed to the characteristic fibroinflammatory desmoplastic tumor microenvironment. Thus, strategies that overcome these stromal barriers have the potential to profoundly improve therapeutic outcomes in PDA. Towards this end, epigenetic therapies that broadly rewire cellular gene expression programs represent a promising approach for targeting PDA stromal barriers. Preliminary studies with inhibitors of Bromodomain and Extra-Terminal domain (BET) proteins, whose recognition of enhancer and super-enhancers drive cell-specific function, reveal a potent loss of immunosuppressive programs within multiple stromal cell populations as well as tumor cells. In addition, the clinical BET inhibitor OTX-015 (OTX) synergized with otherwise ineffective αPD-L1 immune checkpoint inhibition to promote intra-tumoral cytotoxic T cell activation and decrease PDA tumor burden. However, OTX negatively impacts T cell priming in secondary lymphoid tissue and long-term treatment is limited by systemic toxicities. To overcome these limitations, this proposal will develop bottlebrush polymer prodrug (BPDs) to selectively deliver drug cargoes to PDA tumors. BPDs are small, cylindrical macromolecules with multiple conjugated drugs within their cores. This unique architecture enables improved tissue penetration and predictable properties independent of drug composition, while molecular linkers facilitate highly selective drug release in target tissues. In Aim 1, the ability of OTX-BPD conjugates incorporating cleavable linkers to selectively deliver drugs to tumors will be evaluated in clinically relevant PDA mouse models. Subsequently, the ability of lead OTX-BPDs to synergize with αPD-L1 will be determined in both short-term intervention and long-term survival studies. The therapeutic utility of conjugating multiple drugs to BPDs will be determined in Aim 2. Specifically, chemotherapeutics found to synergize with OTX as free drugs will be conjugated to OTX-BPDs, and the abilities of these multidrug laden BPDs to reduce tumor growth and enhance anti-tumor immunity in combination with αPD-L1 will be determined in PDA mouse models. In parallel, the therapeutic benefits of actively targeting these multidrug-laden BPDs by conjugating to antibodies that recognize PDA cancer cell proteins will be assessed. In addition, the optimal ratio of drugs conjugated to individual BPDs to achieve maximal efficacy will be established, which will be distinct from free drugs. In combination, the development of targeted multidrug-laden BPDs will promote rational combination therapies that leverage both epigenetic- and chemo-therapies to potentiate immune checkpoint inhibitors. In the third aim, BPD reporters for drug-induced apoptosis and cytotoxic T cell activity will be developed by incorporating metal-free MRI organic radical contrast agents. These reporter BPDs will be used to validate the method-of-action of combination therapies developed in Aim 1 and Aim 2. Importantly, the ability of such BPDs to rapidly report on treatment efficacies has the potential to inform subsequent treatment decisions.