Abstract 3629: Theranostic imaging of metastatic prostate cancer

Abstract

Abstract There is a compelling need to find effective treatments for metastatic prostate cancer. The ideal treatment would only target metastatic lesion while sparing normal tissue. Down-regulation of specific pathways using small interfering RNA (siRNA) provides unique opportunities to target cancer cells selectively while sparing normal tissue. Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein that has abundant expression on the surface of prostate carcinomas, particularly in androgen-independent, advanced and metastatic disease [1-2]. We are developing prostate specific membrane antigen (PSMA) targeted nanoplexes carrying multimodality imaging reporters together with small interfering RNA (siRNA) and a prodrug enzyme, bacterial cytosine deaminase (bCD), for theranostic imaging of metastatic prostate cancer. We have incorporated a low molecular weight PSMA binding agent in the nanoplex to target the nanoplex to prostate cancer cells [3]. Since choline kinase (Chk) is significantly upregulated in aggressive cancer cells we have used siRNA against Chk in the nanoplex. Our prototype nanoplexes are synthesized by conjugating: (i) a low molecular weight urea-based PSMA targeting moiety (2-(3-[1-carboxy-5-[7-(2,5-dioxo-pyrrolidin-1-yloxycarbonyl)-heptanoylamino]-pentyl]-ureido)-pentanedioic acid, (ii) the prodrug-activating enzyme bCD that converts nontoxic 5-fluorocytosine (5-FC) to cytotoxic 5-fluorouracil (5-FU), (iii) the multimodal imaging reporter carrier poly-L-lysine (PLL) that carries [111In]DOTA for SPECT or [Gd3+]DOTA for MR, and a near-infrared fluorescent probe Cy5.5 for optical imaging, and (iv) the siRNA delivery vector: PEI (polyethyleneimine)-PEG (polythethyeneglycol) co-grafted-polymer. Imaging studies with PSMA targeted nanoplexes were performed with PC-3 human prostate cancer xenografts genetically engineered to overexpress PSMA (PC-3 PIP) in SCID mice. Non PSMA expressing PC-3 xenografts (PC-3 FLU) were used as controls. The addition of a low molecular weight PSMA targeting moiety allowed specific targeting of the nanoplex to PSMA expressing prostate cancer cells in vivo, which was further established with blocking studies. Initial studies established the ability of the nanoplex to effectively downregulate Chk and total choline and convert the nontoxic prodrug 5-FC to 5-FU. The strategies developed here can be extended, in the future, to down-regulate multi-drug resistance pathways, or repair enzymes to increase the efficiency of chemo- or radiation therapy. 1. Schulke, N., et al., Proc Natl Acad Sci U S A, 2003; 2. Huang, X., et al., Prostate, 2004; 3. Mease, R., et al., Clin. Cancer Res., 2008. 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 3629. doi:10.1158/1538-7445.AM2011-3629