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.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Tucker, Jessica
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
Biomedical Engineering
Schools of Engineering
United States
Zip Code
Kern, Hanna B; Srinivasan, Selvi; Convertine, Anthony J et al. (2017) Enzyme-Cleavable Polymeric Micelles for the Intracellular Delivery of Proapoptotic Peptides. Mol Pharm 14:1450-1459
Fang, Chen; Wang, Kui; Stephen, Zachary R et al. (2015) Temozolomide nanoparticles for targeted glioblastoma therapy. ACS Appl Mater Interfaces 7:6674-82
Lane, D D; Su, F Y; Chiu, D Y et al. (2015) Dynamic intracellular delivery of antibiotics via pH-responsive polymersomes. Polym Chem 6:1255-1266
Wilson, John T; Postma, Almar; Keller, Salka et al. (2015) Enhancement of MHC-I antigen presentation via architectural control of pH-responsive, endosomolytic polymer nanoparticles. AAPS J 17:358-69
Berguig, Geoffrey Y; Convertine, Anthony J; Frayo, Shani et al. (2015) Intracellular delivery system for antibody-Peptide drug conjugates. Mol Ther 23:907-917
Roy, Debashish; Berguig, Geoffrey Y; Ghosn, Bilal et al. (2014) Synthesis and characterization of transferrin-targeted chemotherapeutic delivery systems prepared via RAFT copolymerization of high molecular weight PEG macromonomers. Polym Chem 5:1791-1799
Procko, Erik; Berguig, Geoffrey Y; Shen, Betty W et al. (2014) A computationally designed inhibitor of an Epstein-Barr viral Bcl-2 protein induces apoptosis in infected cells. Cell 157:1644-1656
Keller, Salka; Wilson, John T; Patilea, Gabriela I et al. (2014) Neutral polymer micelle carriers with pH-responsive, endosome-releasing activity modulate antigen trafficking to enhance CD8(+) T cell responses. J Control Release 191:24-33
Lundy, Brittany B; Convertine, Anthony; Miteva, Martina et al. (2013) Neutral polymeric micelles for RNA delivery. Bioconjug Chem 24:398-407
Berguig, Geoffrey Y; Convertine, Anthony J; Shi, Julie et al. (2012) Intracellular delivery and trafficking dynamics of a lymphoma-targeting antibody-polymer conjugate. Mol Pharm 9:3506-14

Showing the most recent 10 out of 13 publications