Current medical therapies have failed to treat pancreatic cancer effectively. There is an urgent need to investigate alternative treatments as the average survival rate remains less than 4%. The overall objective of this project is to develop a novel nanoscale vaccine delivery system that will lead to strong anti-tumor responses against pancreatic cancer. The tumor-associated antigen Mucin-1 is over expressed and differentially glycosylated by pancreatic adenocarcinomas. We will design vaccine formulations that encapsulate Mucin-1 into nanospheres of a novel amphiphilic polyanhydride copolymer system with immunomodulatory capabilities.
The specific aims are: (SA1) In vitro studies to determine cytotoxicity and activation of dendritic cells (DCs) by biodegradable amphiphilic polyanhydride nanospheres composed of 1,6-bis-(p-carboxyphenoxy)hexane (CPH) and 1,8-bis-(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG); and (SA2) In vivo studies of Mucin-1 loaded nanospheres using murine models to determine their immunogenicity and immunomodulatory capabilities. Our approach combines the elucidation of the uptake efficiency of antigen presenting cells (APCs), the activation and migration of these cells, and the induction of appropriate cell-mediated immunity (i.e. antigen-specific T cell responses). Since particle size plays a major role for efficient phagocytosis, SA1 will involve the fabrication of micro/nanospheres by different techniques: solid/oil/oil double emulsion, cryogenic aromization, and nanoprecipitation. Culture of the micro/nanospheres with murine bone marrow derived dendritic cells will investigate the cytotoxicity and efficient activation of DCs in the context of MHC I and MHC II molecules. After determination of which CPTEG:CPH formulation induce Th1 cytokines, these will be evaluated on murine models to identify formulations that will facilitate the induction of anti-tumor immunity. The immune response pathway and the immunomodulatory capabilities of the nanosphere adjuvants (i.e., Th1 vs. Th2) will be evaluated by means of the cytokine profiles and antibodies produced. Based on the results obtained, an anti-tumor response will be evaluated in wild type (C57BL/6) mice. The expected outcome of this project is the determination of CPTEG:CPH micro/nanosphere formulations for further testing in transgenic murine models to evaluate anti-tumor immunity in the context of tolerance and auto-immunity, which will lead to vaccine-based immunotherapies. Relevance. Development and application of this technology will facilitate the rational design of anti-tumor vaccines with the ability to appropriately modulate the immune response to develop protective immunity and lead to technologies that will revolutionize anti-tumor immunotherapies. ? ? ?
| Torres, Maria P; Wilson-Welder, Jennifer H; Lopac, Senja K et al. (2011) Polyanhydride microparticles enhance dendritic cell antigen presentation and activation. Acta Biomater 7:2857-64 |
| Lopac, Senja K; Torres, Maria P; Wilson-Welder, Jennifer H et al. (2009) Effect of polymer chemistry and fabrication method on protein release and stability from polyanhydride microspheres. J Biomed Mater Res B Appl Biomater 91:938-47 |
