MODULAR SMART MOLECULES FOR TARGETED DRUG DELIVERY

Emily A. Savoy

doi:10.7273/000007085

Cancer is a dynamic and heterogeneous disease, necessitating a diverse arsenal of targeted chemotherapeutic agents for treatment. One of the major dilemmas facing the field of cancer-targeted therapeutics is the selectivity of treatments to cancer cells, efficacy of drug payloads, and delivery of sufficient dosages to tumor cells. To address this issue, we developed a targeted drug-delivery platform that incorporates our novel pH-responsive phosphoramidate-based linker scaffold designed to only be receptive to acidic pH and selectively release cargo in the endosomal/lysosomal compartments in target cells. The tunability of the phosphoramidate linker enables broad applicability through its pH-sensitive release platform. Not only can this universal linker system be used for a variety of payloads, but it also enhances clinical use of common lipophilic cytotoxic payloads by increasing aqueous solubility, thus allowing such payloads to be attached to any targeting moiety through use of a click ready module. The cell-surface enzyme, prostate-specific membrane antigen (PSMA) is the hallmark biomarker target for prostate cancer as it is up-regulated and strongly expressed on prostate cancer cells associated with both primary and metastatic tumors. Our lab has previously reported on our tight-binding, highly specific, irreversible binding, small-molecule PSMA inhibitors. We have also developed of a proof-of-concept PSMA-targeted small molecule drug conjugate (SMDC), based on both our small molecule PSMA-inhibitor and our acid-labile linker for responsive drug release of both amine and alcohol containing payloads. Additionally, we’ve developed a first-generation SMDC which was loaded with MMAE and demonstrated selective efficacy in vivo. Herein, this thesis will highlight successful applications of these acid-responsive phosphoramidate scaffolds for the controlled release of relevant alcohol-based payloads from our PSMA-targeted SMART molecule platform. Our PSMA-targeting SMDC carrying the chemotherapeutic agent, SN38 confirmed selective payload release and chemotherapeutic efficacy for PSMA(+) prostate cancer cells over PSMA(-) cells. It was found that this platform is stable with minimal payload release at physiological pH with most rapid payload release observed at pH values representing the endosome complex. In addition, we developed three phosphoramidate-based linker scaffolds carrying one of the taxane chemotherapeutic agents, paclitaxel, docetaxel and cabazitaxel. All three taxane-linker modules exhibited stability at physiological pH, as well as significantly increased water solubility of all taxanes. Cabazitaxel was successfully incorporated into a PSMA-targeted SMART molecule whilst maintaining nanomolar binding affinity to PSMA. These findings illustrate that chemotherapeutic agents with limited solubility can be conjugated to a water-soluble, click-ready platform enabling selective delivery to a broad spectrum of molecular targets.

MODULAR SMART MOLECULES FOR TARGETED DRUG DELIVERY

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