(21g) Engineering Polymer Drug Conjugates to Synergistically Schedule Chemotherapeutics

Combination chemotherapy is commonly used to treat metastatic breast cancer; however, the success is limited due to systemic toxicity. To improve therapeutic efficacy, polymer drug conjugates carrying synergistic ratios of chemotherapy drugs can be used to selectively target cancer cells. While the importance of drug ratio on synergy has been previously investigated, the effect of temporal scheduling is not well understood. Here, we systematically evaluated the effect of temporal scheduling of doxorubicin (DOX) and gemcitabine (GEM) to determine both synergistic drug ratios and drug schedules. To engineer the temporal scheduling of DOX and GEM, hyaluronic acid drug conjugates with distinct linkers conjugating both DOX and GEM were optimized to control: (i) their individual release kinetics so as to match the optimized schedule and (ii) their molar ratios so as to optimize the synergistic dose. We show that polymer conjugates that deliver DOX and GEM in synergistic schedules and ratios are more effective at killing breast cancer cells compared to healthy epithelial cells. These results emphasize the importance in understanding the effect release rates have on the efficacy of synergistic drugs and provide the groundwork for the design of novel delivery systems capable of delivering exact molar ratios of synergistic drugs with temporal control.