Abstract 4530: Nanoparticle formulation of KU55933 as a potent radiosensitizer.

KU55933 is a potent and specific inhibitor of the Ataxia Telangiectasia Mutated (ATM) protein. Given ATM's critical role in DNA damage repair, specifically double-strand break repair, KU55933 holds high potential as a radiosensitizer. Indeed, previous preclinical studies have demonstrated the radiosentization effect of KU55933. However, clinical translation of KU55933 as a radiosensitizer has been prevented due to concerns of its potential toxicity. Systemic administration of KU55933 would sensitize normal cells as well as cancer cells to the effects of radiotherapy. Such sensitization would not improve the therapeutic index of radiotherapy. Therefore, the key challenge in the translation of KU55933 is to identify methods that can selectively deliver KU55933 to tumors while minimizing normal tissue dose. While traditional drug delivery methods cannot overcome this challenge, the development of nanoparticle (NP) drug delivery vehicles offers a unique opportunity. NPs are known to preferentially accumulate in tumors while provide low drug dose to nearby normal tissues. We hypothesize that NP delivery of KU55933 can not only improve the therapeutic efficacy of KU55933, but also lower its toxicity. In this study, we engineered a NP formulation of KU55933 using a biodegradable lipid-polymer NP. We then compared the radiosensitization effect of NP KU55933 to that of KU55933 in vitro using the non-small cell lung cancer (NSCLC) cell lines H23, A549 and H460. Clonogenic survival assays showed that NP KU55933 is a more potent radiosensitizer than KU55933. The differential radiosensitization effect of both KU55933 formulations was also evaluated in a xenograft mouse model of NSCLC. We validated our in vitro results by demonstrating that NP KU55933 is more effective than KU55933 as radiosensitizer in flank xenograft models of NSCLC. To compare the toxicity of NP KU55933 and KU55933, we determined the skin toxicity after radiotherapy with the two drug formulations. We found lower skin toxicity in mice treated with the NP KU55933 than that for KU55933. In conclusion, our studies demonstrate that NP formulation of KU55933 can enhance the radiosensitization effect and decreases the toxicity in vitro and in vivo. Our results suggest that NP KU55933 holds potential for clinical translation.Citation Format: Haydee Lara, Michael B. Foote, Edina C. Wang, Manish Sethi, Patricia Casbas-Hernandez, Andrew Z. Wang. Nanoparticle formulation of KU55933 as a potent radiosensitizer. [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 4530. doi:10.1158/1538-7445.AM2013-4530

Duke Scholars

Author Edina Wang Radiation Oncology