Intracellular delivery of proapoptotic peptide drugs for the treatment of cancer

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Many cancers are thought to be caused by survival and growth of abnormal cells with impaired apoptotic machinery that, under normal circumstances, would undergo programmed cell death. Short peptides containing pro-apoptotic subgroups that antagonize the anti-apoptotic members have been developed as a means of restoring normal apoptotic signaling. However, cell specific peptide-based drugs that trigger apoptosis in cancerous cells while avoiding toxicity to healthy tissues have not yet achieved clinical utility. Despite the enthusiasm for peptide-based therapeutics, formidable obstacles persist that hinder their clinical application in humans with advanced cancer. Maintaining peptide stability and bioactivity as well as achieving targeted, intracellular delivery remain as major hurdles that must be overcome before these and other therapeutic peptides can be applied to in vivo systems and thereby realize their full potential. This proposal will bring together the Stayton Lab's drug delivery systems with the Press' labs clinical cancer experience to develop preliminary animal validation of functional proapoptotic peptide delivery in an ovarian cancer model. The unifying hypothesis underlying this research proposal is that facilitating tumor targeting, circulation stability, and translocation of proapoptotic peptides across intracellular membranes will augment their anti- tumor potency and substantially enhance their effectiveness. In addition, the project will evaluate the potential of antibody targeting in a xenograft model to enhance tumor localization using a herceptin-targeted carrier system. This project will take advantage of a strong cross-institutional collaboration between the Stayton group at UW and the Press group at the FHCRC to build strong preliminary data to support a future multi-investigator proposal around new peptide-based therapies for ovarian cancer. PUBLIC HEALTH RELEVANCE: Cancer remains a leading cause of death in the United States. Radiation and chemotherapy lead to negative side effects caused by toxicity in healthy tissues and are prone to tumor persistence and recurrence due to emergence of resistant cells. In order to address this unmet need this proposal will design and synthesize targeted polymeric carrier that can be utilized to deliver pro-apoptotic peptides to enhance tumor cell death in vivo.