Abstract 4655: Local drug activation: Making cytotoxics safer for local tumors
Authors: Sangeetha Srinivasan, Filemon Dela Cruz, Andrew Kung, Ervin Gaviria, Ethan Miller, Nathan Yee, Maksim Royzen, Jose Mejia-Oneto
Journal: Cancer Research (2018)

Abstract Only 1-2% of systemic chemotherapies actually reach a localized tumor while the rest cause myelosuppression and sometimes even cardiotoxicity. There is a critical need to deliver cytotoxic agents to the site of the tumor and reduce overall systemic toxicity. Shasqi's Therapy (Shasqi Tx) is a two-pronged approach based on bioorthogonal chemistry consisting of i) a drug-activating gel and ii) a systemic prodrug. The biocompatible gel, modified with tetrazine (Tz), is injected at tumor site. Then, a trans-cyclooctene (TCO)-modified prodrug of a cytotoxic agent such as doxorubicin (Dox), with attenuated activity, is given systemically. The prodrug concentrates at the tumor site through a covalent cycloaddition reaction between TCO and the Tz located at the gel. The active drug is spontaneously released over multiple days, providing sustained local delivery directly to the tumor compartment. Remaining inactive prodrug is rapidly cleared by systemic clearance routes, thereby minimizing off-target effects. The attenuation of drug activity allows us to maximize the total drug dose while reducing systemic side effects, as the active drug predominantly localizes to the gel site. To this effect, NSG-H mice were injected with Tz-modified alginate gel (TAG) and systemic TCO-doxorubicin (TCO-Dox; prodrug of Dox). The maximum tolerable dose (MTD) of TCO-Dox was &amp;gt;12x the single MTD of Dox (control). When given as 5 daily doses, TCO-Dox dosage could be increased to &amp;gt;38x of Dox MTD, without any adverse effects. Preliminary serum and tissue bioanalysis provides a basis for the improved safety of Shasqi Tx over traditional chemotherapy. TAG-injected BALB/c mice received TCO-Dox intravenously. In serum 5 minutes after injection more than &amp;gt;90% of the circulating anthracycline remained as intact prodrug while ~7% had been converted to Dox. Finally, we tested Shasqi Tx's safety profile in a pilot canine study with a local spontaneous adenocarcinoma. Standard Dox therapy led to disease progression (tumor growth) as well as a drastic drop in body weight. Then, multiple cycles of Shasqi Tx given at higher doses reduced tumor size and led to stable disease for more than 9 months, gain in body weight and without major side effects. Serial evaluations by echocardiogram did not reveal any signs of cardiotoxicity. Collectively, our preliminary toxicity studies suggest that Shasqi Tx enhances delivery of toxic drugs to a target site while limiting exposure in off-target tissues in small and large animals. In addition, the increase in therapeutic index allows greater doses of toxic drugs to be delivered safely. Citation Format: Sangeetha Srinivasan, Filemon Dela Cruz, Andrew Kung, Ervin Gaviria, Ethan Miller, Nathan Yee, Maksim Royzen, Jose Mejia-Oneto. Local drug activation: Making cytotoxics safer for local tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4655.