ID: MPS/DMR/BMAT(7623) 1207022 PI: Sofou, Stavroula ORG: Rutgers University ID: MPS/DMR/BMAT(7623) 1206943 PI: Hall, Carol ORG: NC State University
INTELLECTUAL MERIT: The most promising strategy at present to provide effective control of advanced solid cancer is a combination of therapies. A potential component of this combination is antivascular therapy. The goal of this work is to design iv-administered theranostic liposome nanocarriers that can be programmed to target tumor vasculature while sparing healthy sites and to release a chemotherapeutic agent, deliver a radioactive imaging agent or both. This will be accomplished through a combined experimental and theoretical approach to develop highly selective lipid vesicles composed of a new class of bi-lipid membranes that rapidly and extensively release doxorubicin intracellularly or deliver positron emitters. The high killing efficacy of the liposomes is based on a dual fusion mechanism that is activated only upon cellular internalization. The project's innovation lies in the choice of individual base components and the synergistic way that they work together to optimize delivery of the drug to the proper site. An additional innovation is the use of molecular level computer simulation to explore the consequences of various choices of liposome parameters "in silico" before trying them out in the lab, thus reducing the number of trial-and-error steps that would normally characterize this type of work . The base components are the following: PSMA (Prostate Specific Membrane Antigen), which is present on tumor vasculature but not in normal tissue, is the target. An anti-PSMA antibody is the ligand. The liposomes are comprised of two functionalized lipids: PEGylated lipids tethered to anti-PSMA antibodies and lipids functionalized with a fusion peptide that promotes fusion with the endosomal membrane. The mechanisms of delivery are the following. During circulation in the blood, the exposed anti-PSMA antibodies result in selective neovasculature targeting while uniformly distributed PEGylated lipids on the liposome surface mask the fusion peptides. Upon endocytosis of liposomes by tumor endothelial cells, pH-induced lipid phase-separation, and domain formation on liposome membranes activates two fusion mechanisms: (1) The fusion peptides become unmasked and bind to the endosome membrane, and (2) The liposomal domain boundaries serve as sites to nucleate fusion with the endosomal membrane. The net result is that the liposome releases its cargo directly into the cytoplasm of tumor endothelial cells, as opposed to the endosome, avoiding entrapment in the endosomal pathway and subsequent degradation by the lysosome. There are three aims: (1) Develop an experimentally informed general computational tool to facilitate the design of liposomes and to test hypotheses about the role of the different components in the proposed hierarchical assembly. (2) Engineer liposomes containing anti-PSMA ligands and small fusion peptides, and investigate the conditions in which the corresponding functionalities exhibit optimal behavior. (3) Demonstrate that dual-fusion liposomes loaded with doxorubicin and Y-86 exhibit: (a) selective targeting of tumor endothelium analogues, (b) effective release of chemotherapeutics and killing of targeted cells, and (c) delivery of sufficient amounts of Y-86 for diagnostic applications.
BROADER IMPACTS: Since advanced solid cancer has no cure, many patients could benefit from the proposed research that aims to develop diagnostic and treatment protocols that significantly extend the life expectancy and improve patients? quality of life. The research pursued here will be supplemented by a strong educational component that includes training of two female graduate students and several undergraduate students assigned to this project, integration of several topics of this research in a newly launched open-ended senior design project, general outreach and mentoring activities for high school students and their teachers, and mentoring activities for women graduate students and faculty across the nation. In particular, the 6-week outreach summer program, which will be conducted at Rutgers University, aims to encourage underrepresented and minority high school students to follow a career in sciences and engineering. The program includes hands-on research training, a series of lectures given by speakers from academia and industry on contemporary issues related to biomaterials, and visits to neighboring pharmaceutical industries. Educational materials will be developed that highlight this research including a power point presentation introducing the basics of nanotechnology and drug delivery via soft materials for dissemination over the web.
