Abstract 4481: Genetically encoded chimeric polypeptide nanoparticles for gemcitabine delivery to solid tumors

Abstract

Abstract Gemcitabine (2′,2′-difluorodeoxycytidine) (dFdC) is a chemotherapeutic drug indicated for the treatment of pancreatic, bladder, NSCLC, breast and ovarian cancers. The use of gemcitabine for the treatment of other cancers, including gallbladder cancer, cervical cancer, colorectal cancer, non-Hodgkin's lymphoma, and Kaposi's sarcoma, has been clinically investigated. The cytotoxic effect of gemcitabine is due to inhibition of DNA synthesis by two mechanisms of action: (i) dFdCTP directly competes with dCTP for incorporation into DNA, inhibiting further DNA synthesis via masked chain termination; (ii) dFdCDP inhibits ribonucleotide reductase (which catalyses reactions that produce deoxynucleoside triphosphates for DNA synthesis). However, the major fraction of the administered drug undergoes rapid metabolism into dFdU by deamination, primarily in blood and then in other major organs. Therefore, the plasma half-life of gemcitabine following intravenous administration is short, ranging from 8-17 min in human plasma and 9 min in murine plasma. Like other drugs, Gemcitabine also shows a lack of selectivity towards tumor cells, sub-optimal pharmacokinetics and bio-distribution, leading to limited efficacy and significant systemic toxicity. Finally, the rapid metabolism of gemcitabine generates the need for high doses of drug, which in turn exhibits dose-limiting systemic side effects, such as hematological (myelosuppression, neutropenia, anemia, thrombocytopenia) and other toxicities (edema, cutaneous toxicity, pulmonary toxicity, dyspnea). In an effort to overcome the limited efficacy and systemic toxicity of current Gemcitabine formulations, we have designed a novel polypeptide drug delivery system where Gemcitabine is covalently attached to a genetically engineered chimeric polypeptide (CP) through a pH sensitive linker such that covalent conjugation of multiple copies of Gemcitabine at one end of the CP triggers the formation of sub 100 nm size nanoparticles that are ideal for targeting solid tumors through the enhanced permeability and retention (EPR) effect. We found that upon conjugation, CP-Gemcitabine conjugate form nanoparticles with a diameter of ∼40 nm and narrow size distribution (<10%). In a human colon cancer cell (HCT-116), the CP-Gemcitabine conjugate showed substantial cytotoxicity that was similar 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 ongoing work that will be presented at the AACR meeitng, the efficacy of CP-Gemcitabine nanoparticles in a number of tumor models in mice will be reported. Citation Format: Jayanta Bhattacharyya, Ashutosh Chilkoti. Genetically encoded chimeric polypeptide nanoparticles for gemcitabine delivery to solid tumors. [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 4481. doi:10.1158/1538-7445.AM2014-4481