Oligo(lactic acid)n-Prodrug Nanomedicines for Combination Therapy

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Project Summary/Abstract Taxol is commonly used to treat TNBC and increasingly in combination with oral signal transduction inhibitors (STIs), such as mTOR inhibitor (Afinitor) and MEK inhibitor (Koselugo), aiming for targeted therapies for this genetically heterogeneous disease. However, while these drug combinations are active in TNBC, they are associated with adverse effects, limiting clinical effectiveness. Our objective is to investigate oligo(lactic acid) (o(LA)n-) prodrugs, part drug and part biomaterial, and poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-b- PLA) nanotechnology for the treatment of TNBC, focusing on concurrent delivery of drug combinations, including delivery at synergistic drug ratios, termed ratiometric drug dosing. We will achieve this goal by developing a scale-up approach for the controlled assembly of o(LA)n-prodrugs and PEG-b-PLA micelles that produces novel nano-formulations for injection, characterized by high loading for a wide repertoire of chemotherapy and STIs, fixed o(LA)n-prodrug ratios and slower release in comparison to drugs themselves. Next, ratiometric dosing of o(LA)n-prodrug-loaded PEG-b-PLA micelles based on PTX, rapamycin (RAP) and selumetinib (SEL) will be characterized in immunocompetent mouse models of TNBC, hypothesizing lower toxicity and higher antitumor activity than Taxol, oral EVE and oral SEL. Mechanistically, we hypothesize that o(LA)n-prodrugs will prolong, elevate and overlap tumor exposure for synergistic drug ratios in comparison to Taxol, oral EVE and oral SEL. Further, o(LA)n-prodrug combinations may be potent immuno-modulators, which may be exploited for TNBC. Given that PEG-b-PLA micelles satisfy strict requirements in safety, solubility and scale-up for injection and PEG- b-PLA is readily available GMP-grade at varied molecular weights for adjustment of micelle stability in vivo, o(LA)n-prodrugs have strong potential to improve the effectiveness of drug combinations based on PTX and STIs, aimed at advancing TNBC therapies.