Abstract 4105: Localized and triggered release of oxaliplatin for the treatment of colorectal liver metastasis

Abstract

Abstract Though systemic chemotherapy is the standard of care for the treatment of unresectable metastatic colorectal cancer, new drug delivery platforms are needed to mitigate the associated toxicities. The aim of this study was to develop and evaluate a liposome formulation that delivers oxaliplatin under magnetic field stimulus in a rat model of colorectal liver metastases. The drug delivery platform was synthesized by encapsulating iron oxide nanocubes and oxaliplatin in sterically stabilized polyethylene glycol (PEG)-coated liposomes of ~140 nm size. Magnetic properties and efficacy of drug release were determined by exposing the liposomes to an alternating magnetic field (AMF). In vitro efficacy of the liposomes was tested by performing viability assay on rat colorectal liver metastasis cell line (CC-531 cell line). For in vivo studies, rats implanted with CC-531 cells were divided into various groups and the efficacy of systemically delivered oxaliplatin was compared to localized and triggered delivery. Localized delivery and triggered release of drug was imaged by quantitative magnetic resonance and optical imaging methods. The rats were euthanized after 3 weeks, tumors harvested and H&E and Prussian blue staining was performed. Kinetics of oxaliplatin bioavailability was performed by ICP-MS analysis for platinum at various time points and in different tissues. The analysis of feasibility and efficacy of multiple cycles of triggered release is currently in progress. Drug-loaded magnetic liposomes presented an oxaliplatin loading content of ~2 %. Magnetic liposomes separated from the solution within 30 min, when exposed to a permanent magnet. An increase in drug release (~18%) was observed by both HPLC and optical imaging methods when the samples were exposed to the AMF. Viability assay demonstrated that under high-dose oxaliplatin conditions (0.17-0.33 mg/mL), the cell viability after liposome treatment and exposure to AMF was significantly lower than those not exposed to AMF (p< 0.001). MR imaging revealed that all the rats developed tumors within 1 week. Optical imaging on rats showed that nanomaterial could be infused locally via mesenteric vein into liver and there is a consistent increase in the release of drug when exposed AMF. Although the tumors showed metastasis by the end of third week, triggered release of drug was well tolerated and shrinkage of primary tumor with necrotic regions was prominent in the MR imaging. Prussian blue staining and quantitative MR imaging showed delivery of liposomal cargo to the tumor site when exposed to AMF. H&E staining revealed marked necrotic regions in the tumor among the animals exposed to magnetic field. In conclusion, AMF triggered oxaliplatin release from liposome for increased cell death of CC-531 cell line. Triggering was well tolerated by rats and, further, can be employed to targeted killing of tumor by optimizing the dose of drug. Citation Format: Venkateswara R. Gogineni, Woo Ram Park, Jaidip Jagtap, Abdul Parchur, Gayatri Sharma, Amit Joshi, Dong-Hyun Kim, Andrew C. Larson, Sarah B. White. Localized and triggered release of oxaliplatin for the treatment of colorectal liver metastasis [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 4105.