Abstract 374: Nanoparticle formulation of wortmannin as a novel radiosensitizer
Authors: Karve Shrirang , Werner Michael , Sukumar Rohit , Cummings Natalie , Wang Andrew 
Published: June 2012

Abstract
Many small molecules drugs have shown great promise as cancer therapeutics preclinically but their clinical potentials have not been realized due to challenges in delivery. These challenges include poor solubility, instability in vivo, high toxicity and low bioavailability. One such molecule is wortmannin (Wtmn), an inhibitor of phosphoinositide 3-kinases (PI3Ks). It once held great promise as a cancer therapeutic as well as a radiosensitizer. However, its poor solubility, short half-life of10 minutes in serum, and toxicity prevented clinical translation. Today, its use is limited to scientific research. Advances in nanotechnology lead to the development of nanoparticle (NP) therapeutic carriers. Delivery through NP can modify fundamental properties of therapeutics such as solubility and biodistribution as well as to protect the drug from the in vivo environment. We hypothesized that NP delivery of Wtmn would improve its solubility, increase its stability, and lower its toxicity.
In this study, we have engineered a biodegradable and biocompatible NP formulation of Wtmn using a lipid-polymer hybrid NP platform. The NP is comprised of a PLGA core surrounded by a self-assembled lipid monolayer composed of lecithin and PEGylated lipids. It is capable of encapsulating 5 % wt/wt Wtmn. NP characterization shows a narrow size distribution with average size of 80 ± 4 nm and a negative zeta potential of – 40 ± 3mV. We evaluated its ability as a radiosensitizer using the head and neck cancer cell line KB, prostate cancer cell line PC3, and colorectal cancer cell line HT29. Wtmn-encapsulated NPs showed lower cytotoxicity but a higher radiosensitization effect in vitro as compared to that of a cremphor formulation of Wtmn. Western blot studies of KB cells treated with free Wtmn or Wtmn NPs confirmed the mechanism of radiosensitization is through the inhibition of PKB/Akt phosphorylation and DNA repair. We then validated the potential of NP Wtmn as a radiosensitizer in vivo. In vivo toxicity study of NP Wtmn was conducted in 3 strains of mice, including white CD1, black C57BL/6 and the NOD. The maximum tolerated dose for NP wortmannin is 3-4 times higher than that of the cremphor Wtmn formulation, confirming the lower toxicity of NP Wtmn in vivo. Using a murine xenograft model of head and neck cancer, we compared the radiosensitization efficacy of NP alone, NP Wtmn, and cremphor Wtmn. We showed that NP Wtmn is a potent radiosensitizer and is more effective than cremphor Wtmn. In summary, we have developed a NP formulation of Wtmn that has improved the stability and solubility of the drug while lowering its toxicity. We have demonstrated that it is a highly effective radiosensitizer with potential to improve the treatment of many cancers. Our work also demonstrates that other small molecules with delivery challenges can be re-evaluated for NP drug delivery.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 374. doi:10.1158/1538-7445.AM2011-374