Abstract LB-196: Preventing breast cancer metastases with an anti-angiogenic and anticancer RGD-bearing nanomedicine

Abstract

Abstract Overcoming drug resistance, emerging either on recurring cancer or metastasis, is a major challenge of cancer treatments. The combination of anti-angiogenic agents with chemotherapeutic ones offers a promising therapeutic approach. Such combination can be achieved exploiting the multivalency of polymer therapeutics. We have recently showed that polymer conjugation of paclitaxel (PTX), a potent cytotoxic and anti-angiogenic drug, improved its pharmacokinetic profile. We hypothesized that actively targeting PTX to αvβ3-integrin, presents an attractive therapeutic strategy for breast cancer. Interestingly, overexpression of αvβ3-integrin, occurring on tumor endothelial and some epithelial cells during tumor growth, invasion, and metastasis, was found to correlate with PTX-resistance of breast cancer cells. We designed and synthesized a novel polyglutamic acid (PGA)-PTX-E-[c(RGDfK)2] nano-sized conjugate. Polymer conjugation converted PTX to a water-soluble macromolecule, which passively targeted the tumor tissue exploiting the enhanced permeability and retention (EPR) effect. The E-[c(RGDfK)2] was utilized as an additional active targeting moiety to αvβ3 integrin. PGA is enzymatically-degradable by cathepsin B, leading to PTX release. PGA-PTX-E-[c(RGDfK)2] displayed a potent anti-angiogenic activity, determined by several well-established in vitro assays. Preferential tumor accumulation of the RGD-bearing conjugate in orthotopic mammary tumors inoculated in mice, lead to enhanced antitumor efficacy and a marked decrease in toxicity compared with free PTX. We found that metastasis establishment was dependent on αvβ3-integrin expression as determined in vitro and ex vivo. PGA-PTX-E-[c(RGDfK)2] conjugate inhibited metastatic growth in an experimental breast cancer metastases model in mice. Taken together, inclusion of an active targeting moiety to integrin expressing-cells has the potential to decrease breast cancer metastases establishment by displaying an anti-angiogenic and anticancer activity. Citation Format: Anat Eldar-Boock, Dikla Ben-Shushan, Joaquin Sanchis, Ruth Lupu, Maria J. Vicent, Ronit Satchi-Fainaro. Preventing breast cancer metastases with an anti-angiogenic and anticancer RGD-bearing nanomedicine. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-196. doi:10.1158/1538-7445.AM2014-LB-196