While vaccines have been widely used for the prevention of infectious disease, the concept of therapeutic vaccination for the treatment of cancer has only recently been introduced. Although the results of animal studies suggest that this new form of immunotherapy can be highly effective, to date human cancer vaccines have shown only limited success, due mainly to inadequate potency. Two key events must occur for the induction of effective immunity to tumors: the antigens (Ags) must be delivered to dendritic cells (DCs), the most powerful antigen presenting cells known, and these cells must be activated in a manner that ensures their migration to lymphoid organs and their efficient presentation of Ag to T cells. In this proposal, we describe a new, versatile and robust chemical approach to prepare nanoparticle-based delivery vehicles for Ag-based vaccines. Our preliminary studies indicate that these nanoparticles are capable of delivering Ags to DCs in a manner that leads to potent systemic immunity. The particles include acid-labile components that have been designed such that, upon their cellular uptake and trafficking to the phagosome, they degrade readily. This induces an increase in osmotic pressure and disruption of the compartmental walls so that the encapsulated Ags are freed and delivered into the ARC cytoplasm. We propose to 1) incorporate into the nanoparticles immunostimulatory agents, in addition to Ags, that specifically activate the DCs; 2) develop new polymer scaffold and components for improved degradation kinetics and biocompatibility; 3) investigate the use of DC specific ligands and alternative routes of delivery to maximize targeting of the vaccine to DCs; and 4) evaluate the ability of our vaccine particles to induce tumor eradication in tumor bearing animals. Our ultimate goal is to create a new class of vaccines that integrates the latest developments in the fields of immunology and materials chemistry and that can be applied not only to cancer but also to a wide range of other diseases. The relevance of this research to public health lies in the development of novel therapeutic nanoparticles that can be used to create a broad range of vaccines that will activate the immune system to both protect against and combat disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB005824-04
Application #
7470042
Study Section
Special Emphasis Panel (ZRG1-BCMB-A (50))
Program Officer
Henderson, Lori
Project Start
2005-09-20
Project End
2009-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
4
Fiscal Year
2008
Total Cost
$481,915
Indirect Cost
Name
University of California Berkeley
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Floyd 3rd, William C; Datta, Gopal K; Imamura, Shinichi et al. (2011) Chemotherapeutic evaluation of a synthetic tubulysin analogue-dendrimer conjugate in c26 tumor bearing mice. ChemMedChem 6:49-53
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Beaudette, Tristan T; Bachelder, Eric M; Cohen, Joel A et al. (2009) In vivo studies on the effect of co-encapsulation of CpG DNA and antigen in acid-degradable microparticle vaccines. Mol Pharm 6:1160-9
Bachelder, Eric M; Beaudette, Tristan T; Broaders, Kyle E et al. (2008) Acid-degradable polyurethane particles for protein-based vaccines: biological evaluation and in vitro analysis of particle degradation products. Mol Pharm 5:876-84
Paramonov, Sergey E; Bachelder, Eric M; Beaudette, Tristan T et al. (2008) Fully acid-degradable biocompatible polyacetal microparticles for drug delivery. Bioconjug Chem 19:911-9

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