Abstract 4522: Nanoparticle chemosensitization.

Abstract

Abstract Systemic drug toxicity and multi-drug resistance are the two major obstacles in the treatment of cancer. While multi-drug resistance can be easily overcome by the use of chemosensitizers, the process of chemosensitization itself has been shown to be highly toxic to the normal cells. This is because chemosensitizers not only sensitize the tumor tissue but also the normal tissue to the effect of the drug leading to a substantial increase in the systemic toxicity of the drug. On the other hand, nanoparticles (NPs) can decrease systemic toxicity by virtue of their property of preferential accumulation at the site of tumor, making them an ideal candidate for the delivery of the chemosensitizers. We developed a novel method to overcome both of the major obstacles in cancer treatment by synthesizing NP formulations of two potent chemosensitizers, wortmannin (Wtmn) and olaparib. Wtmn is a highly effective PI3 kinase and DNA-PK inhibitor while olaparib is highly potent Poly ADP ribose polymerase (PARP) inhibitor. NP Wtmn and NP olaparib were synthesized using a biodegradable core-shell NP platform. We studied the chemosensitization effects of NP Wtmn and NP olaparib in vitro using the lung cancer cell lines H23 and H460, and a multi-drug resistant lung cancer cell line H69AR followed by the drug treatment. We used different chemotherapeutic drugs such as etoposide, gemcitabine and docetaxel to demonstrate the effect of NP chemosensitizers. The biodistribution of the NPs was determined using the mouse xenograft model of H460. Normal tissue toxicity was evaluated by using NP chemosensitizers and compared with their small molecule counterparts. Finally, we evaluated NP Wtmn and NP olaparib as a chemosensitizers in vivo using murine xenograft models of H69AR and H460 and compared them to that of free chemosensitizers. NP chemosensitizers, similar to their small molecule counterparts, are highly potent in vitro in all three cell lines. The biodistribution study showed that NP formulation leads to a higher tumor accumulation when compared to the free molecules. Toxicity study showed significantly less hepatic and hematologic toxicity with NP formulation than the free molecules. In vivo efficacy study demonstrated that NP Wtmn and NP olaparib are potent chemosensitizers and are more effective than their small molecule counterparts. Further, we demonstrated that NP Wtmn can overcome drug resistance in H69AR cell line. Our work demonstrates the proof of principle in utilizing nanomedicine for the improving chemosensitization. Citation Format: Manish Sethi, Sonya R. Kowalczyk, Chintan H. Kapadia, Michael E. Werner, Rohit Sukumar, Edina Wang, Andrew Z. Wang. Nanoparticle chemosensitization. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4522. doi:10.1158/1538-7445.AM2013-4522