Abstract 382: Evaluation of folate-targeted ChemoRad nanoparticle as intraperitoneal chemoradiotherapy for ovarian cancer
Authors: Werner Michael E. , Karve Shrirang , Sukumar Rohit , Cummings Natalie D. , Wang Andrew Z. 
Published: June 2012

Abstract
Approximately 15,000 women die of ovarian cancer in the U.S. each year. One of the most common causes of mortality in these patients is peritoneal metastases. While intraperitoneal (IP) chemotherapy and IP radioisotope therapy have shown favorable clinical results, both lead to significant toxicities. Chemoradiotherapy has been shown to be superior to either therapy alone in many cancers, such as head and neck cancer, cervical cancer and rectal cancer. However it has not been evaluated in ovarian cancer due to concerns of toxicity. Advances in nanotechnology have enabled the development of biologically targeted nanoparticle (NP) therapeutic carriers. These NPs allow preferential delivery of therapeutics to tumors, which in turn increases efficacy and minimizes toxicity. Our laboratory was the first to develop a nanoparticle platform, the ChemoRad NP, which can deliver both chemotherapy and radiotherapy. We hypothesized that a ChemoRad NP targeted against ovarian cancer cells can be a novel and effective treatment for ovarian peritoneal metastases.
In this study, we engineered a folate-targeted ChemoRad NP encapsulating paclitaxel and Y90 for IP chemoradiotherapy of ovarian cancer. The NP was evaluated using the SKOV-3 ovarian carcinoma cell line and a murine model of ovarian peritoneal metastases. Folate was utilized as a targeting ligand as most ovarian cancers overexpress the folate receptor. Paclitaxel (Ptxl), a first-line chemotherapy for ovarian cancer, was used as the model drug. Y90 was employed as the therapeutic radioisotope based on its high-energy emission and low toxicity.
The folate-targeted ChemoRad NP was formulated by a nanoprecipitation method. The resulting NPs have a hydrophobic polymeric core where Ptxl is encapsulated. The NP surface is covered by a self-assembled monolayer of lipid and lipid-polymer. Metal chelators were incorporated into the sub-surface layer for the chelation of Y90. Characterization of the NPs showed particle size of 70+/−5 nm and 60% Ptxl encapsulation efficiency. Drug release study showed controlled release with more than 95% of Ptxl released at 24 hrs. We demonstrated folate mediated cellular uptake of targeted NP Ptxl Y90 by SKOV-3 cells. An in vitro efficacy study showed the folate-targeted NP Ptxl Y90 (T-NP Ptxl Y90) is more effective than that of non-targeted NP Ptxl Y90. We then validated our folate NP containing Ptxl and Y90 in vivo. Peritoneal xenograft metastases were induced by injecting SKOV-3 cells IP in nude mice. Therapeutics were given IP at 3 weeks post tumor implantation. We were able to demonstrate that T-NP Ptxl Y90 is more effective than T-NP Ptxl, T-NP Y90, and non-targeted NPs containing either or both therapeutic agents.
In conclusion, we have demonstrated that folate-targeted NP Ptxl Y90 is a biologically targeted chemoradiotherapy for ovarian cancer. It represents a potential novel treatment for ovarian peritoneal metastases.
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 382. doi:10.1158/1538-7445.AM2011-382