Abstract 4509: Genetically encoded chimeric polypeptide nanoparticles for paclitaxel delivery to triple negative breast cancer.

Abstract

Abstract Triple negative breast cancer (TNBC) represents an important clinical challenge, because TNBC, like other breast cancer subtypes is highly metastatic, but TNBC displays a shorter median time to relapse and death. Chemotherapy remains the mainstay of treatment of TNBC, as it gives a markedly higher response rate than endocrine therapy or other available targeted agents. Current treatment strategies for TNBC include treatment with anthracyclines, taxanes, and platinates. Like other drugs, paclitaxel shows a lack of selectivity towards tumor cells, sub-optimal pharmacokinetics and bio-distribution, leading to limited efficacy and significant systemic toxicity. Although AbraxaneTM (albumin bound paclitaxel) an improved formulation of paclitaxel compared to the original chremophor formulation has been used to treat TNBC, it also suffers from systemic toxicity such as sensory neuropathy, neutropenia, nausea, and anemia. In an effort to overcome the limited efficacy and systemic toxicity of current paclitaxel formulations, we have designed a novel polypeptide drug delivery system where paclitaxel is covalently attached to a genetically engineered chimeric polypeptide (CP) through a pH sensitive linker such that covalent conjugation of multiple copies of Paclitaxel at one end of the CP spontaneously triggers the self-assembly of the drug-CP conjugate into sub 100 nm size nanoparticles that are ideal for targeting solid tumors through the enhanced permeability and retention (EPR) effect.We found that in a human triple negative breast cancer cell (MDA-MB-231), the CP-paclitaxel conjugate showed substantial cytotoxicity that was similar to free drug. CP-Paclitaxel nanoparticle treated mice with orthotopic MDA-MB-231 tumors showed significantly greater tumor regression as well as enhanced overall survival compared to free drug. These results are promising because they demonstrate the potential of rationally engineered nanoparticle drug carriers to greatly improve the efficacy of currently approved cytotoxic agents for the treatment of solid tumors. In future work, we will evaluate the efficacy of CP-Paclitaxel nanoparticles combined with a tyrosine kinase inhibitor that mimics current combination chemotherapy. Citation Format: Jayanta Bhattacharyya, Jonathan McDaniel, Ashutosh Chilkoti. Genetically encoded chimeric polypeptide nanoparticles for paclitaxel delivery to triple negative breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4509. doi:10.1158/1538-7445.AM2013-4509