Abstract 5407: Tumor penetrating microparticles enhance siRNA delivery and expression in pancreatic cancer

Abstract

Abstract A major challenge for using siRNA as cancer therapeutics is the delivery to solid tumors, due to their unfavorable physicochemical properties (negative charges, large molecular size, and instability). Our laboratory has developed paclitaxel-loaded tumor-penetrating microparticles (TPM) for intraperitoneal therapy of peritoneal tumors (JPET, 327: 673-682, 2008). Embedded in the design of TPM is the tumor priming technology to promote nanomedicine delivery in solid tumors (JPET, 322:80-88, 2007). The goal of this study was to evaluate whether TPM can improve siRNA delivery and expression for treating solid tumors located in the peritoneal cavity. Nanoparticles containing survivin siRNA (siRNA-NP) were developed. Survivin, a major resistance factor, is selectively expressed in tumors and upregulated by various chemotherapeutic agents. The activity of paclitaxel (agent loaded in TPM) and siRNA was investigated in cultured cells using the clonogenic assay and the survivin level determined using western blotting. In vivo activity was evaluated in peritoneal pancreatic HS766T xenograft tumors; the pharmacodynamic endpoints were reduction of proliferation index (measured by Ki67 labeling), induction of apoptosis (measured by caspase 3 expression), prolongation of survival time, and survivin protein level (measured by immunohistochemical staining and quantitative image analysis using NIH ImageJ). The two negative controls were blank nanoparticles (without siRNA) and non-targeting siRNA. In cultured cells, siRNA-NP produced protein knockdown, decreased cell clonogenicity, and enhanced paclitaxel activity. However, siRNA-NP did not produce protein knockdown or antitumor activity in tumors grown in animals, indicating insufficient delivery in vivo. In contrast, when given in combination with TPM, siRNA-NP produced survivin knockdown and enhanced the antitumor activity of TPM. The results indicate that TPM treatment improves the delivery and transfection of siRNA in intraperitoneal tumors in vivo and suggest potential therapeutic utility of coadministered TPM and siRNA-NP combination. Supported in part by research grants R44CA103133 and R43CA134047 from NCI, DHHS. 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 5407. doi:10.1158/1538-7445.AM2011-5407