Abstract 2672: Effect of conjugating gemcitabine with novel temperature responsive polymer in improving drug targeting, retention, and release in the KPC mouse model of pancreatic cancer

Introduction: Pancreatic cancer remains a devastating disease where most chemotherapies are modestly effective in part because of limited drug penetration into the stroma rich hypovascular tumors. Our goal was to develop a drug delivery mechanism that allows cancer specific release of cytotoxic agents and minimizes off-target effects. We have developed a gemcitabine-polyacetal drug conjugate that has a highly selective drug release profile via temperature response, pH-degradation, and ability for tuning reverse temperature transitions. The gemcitabine-polyacetal conjugates release drug selectively in acidic environments but remain inert in others. Objective: Here, we present in vitro and in vivo data on the efficacy of gemcitabine-polyacetal drug conjugates in pancreatic cancer cell lines and KPC (KrasG12D/+;Trp53R172H/+;Pdx1-Cre) derived allografts. Methods: The drug release of polyacetal-drug conjugates were previously characterized using Gel Permeation Chromatography and Nuclear Magnetic Resonance. In the current study, drug release is characterized using viability of KPC-derived cell lines and BxPC3 cells. We assessed the drug efficacy of solo-gemcitabine and gemcitabine-polyacetal drug conjugates at 24, 48, and 72-hour time points at two pHs: physiological pH using HEPES media, and PDAC tumor pH by phosphate buffer set at pH 6.8. Drug free polyacetal was used as a negative control. Results: In the two KPC and one BxPC3 cell lines tested, statistically significant differences in cell viability were observed. Gemcitabine-polyacetal conjugate at pH 6.8 showed 3-6% cell viability at drug concentrations less than 5μmol within 24 hours, while the conjugate in HEPES media (at pH ~8.0) showed more than 90% cell viability up to 72 hours. In contrast, solo-gemcitabine showed 5-8% cell viability in both pH’s. Percutaneous injection of 25μM dose of gemcitabine-polyacetal drug conjugate into allograft tumors showed a significant decrease in % of Ki67+ cells (p=0.0.009) compared to controls injected with PBS. Conclusions: The gemcitabine-polyacetal conjugate serves as a drug deactivator in its conjugated form. In acidic pH, the drug is activated and released with high selectivity. This site-specific drug release could significantly reduce off-target effects that are reported with gemcitabine. Here, we showed significant effect on direct tumor injection of the conjugated gemcitabine. As previously shown, polyacetal-drug conjugates can be synthesized using dozens of chemotherapeutic drugs without chemical modification, making polyacetal conjugation a versatile approach to minimize off-target effects and ultimately systemic cytotoxicity in a variety of chemotherapeutic treatments. These results support further development of this delivery strategy in treatment of pancreatic cancer. Citation Format: Jarwei Fang, Porakrit Leophairatana, Jeffrey Koberstein, Tamas Gonda, Chathuranga De Silva. Effect of conjugating gemcitabine with novel temperature responsive polymer in improving drug targeting, retention, and release in the KPC mouse model of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2672.