Abstract 5411: Development of SCLC specific nanoparticle-mediated therapeutic gene delivery

Abstract

Abstract Lung cancer is the most common cause of cancer-related deaths worldwide. Small cell lung cancer (SCLC) is a particularly aggressive form of lung cancer characterized by early metastatic behavior. Even with currently recommended therapy, the average survival of SCLC patients is less than 1 year. There is an urgent need for novel treatments. The majority (70-90%) of SCLC cases possess alterations in p53 and Rb. This relative genetic homogeneity makes SCLC an attractive context in which to develop and test novel gene therapy approaches. We have initiated studies using non-viral, poly-β amino acid ester (PBAE) nanoparticle delivery of gene therapy in SCLC. PBAE polymers possess numerous advantages over viral delivery systems such as structural diversity, cost effectiveness, low immunogenicity and higher stability. PBAEs encapsulate DNA to form biodegradable cationic nanoparticles and have been studied in a variety of cancer cell types and in primary endothelial cells. This is the first study of PBAEs in SCLC. A PBAE polymer library was screened in two SCLC lines using a luciferase-based high-throughput screen (HTS). Thirty-two of 112 polymers were further characterized in the H446 SCLC cell line using a CMV-GFP reporter construct and analyzed by qualitative (microscopy) and quantitative (flow cytometry) methods. This secondary screen revealed that the polymers had variable transfection efficiencies ranging from 8-55%. Four polymers, 446LG, 447LG, 456LG and 457 exhibited high transfection efficiencies (42-55%) in two SCLC cell lines, including one suspension line. Using PBAEs complexed with Cy5-labeled DNA, we were able to demonstrate that >90% cells bind and internalize the nanoparticles. We have initiated studies to better elucidate bottlenecks between nanoparticle uptake and gene expression. Additionally, preliminary studies in tumor-bearing athymic nude mice demonstrated gene uptake and expression via intratumoral injection of 457 and 446LG polymer/DNA complexes. Ongoing studies include further optimization of PBAEs for in vitro gene expression and systemic in vivo delivery. In parallel, we are performing genetic characterization of patient-derived primary SCLC xenografts to verify relevant gene targets. Taken together, our data supports further development of a non-viral PBAE-based gene delivery approach in SCLC. 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 5411. doi:10.1158/1538-7445.AM2011-5411