Delivery systems for DNA vaccine are critically needed, in order to achieve successful clinical translation of gene-based immunotherapy against a wide range of diseases, including cancer and bacterial and viral infections. Biodegradable polymers present a promising avenue for DNA vaccine delivery;however, in vivo efficacy of the current delivery polymers is limited. Rational design of polymers for DNA vaccine delivery is difficult, largely due to a lack of understanding of detailed interactions between polymer carriers and the extremely complex immune system within the in vivo physiologic context. Our long-term goal is to develop biodegradable polymeric DNA vaccine carriers based on mechanistic understanding of the immune processes in vivo. We focus on a novel class of biodegradable poly (ortho esters) (POEs) that has shown preliminary efficacy in generating tumor-suppressing immunity in animals, and we propose the following two specific aims: (1) We will synthesize new pH-sensitive, biodegradable cationic block copolymers with defined structure and properties, and establish their efficacy for promoting DNA uptake, antigen production and presentation, and phenotypic maturation of antigen presenting cells. (2) We will investigate systematically the in vivo mechanisms of the block polymers carrying model DNA vaccines, quantify and track the time course of critical molecular and cellular events during immune activation, using novel multi-color flow cytometry and immunostaining assays that enable us to track, simultaneously, multiple cellular markers in response to both CD8 and CD4 epitopes. Furthermore, we will examine the activation of endogenous na?ve T cells in unperturbed in vivo context that is clinically relevant. Public Health Relevance: Combining a versatile and tunable biodegradable polymer system with advanced immunological tools and focusing on in vivo investigation, we hope to address important questions regarding how the timing, location, magnitude, and cells of immune processes may be optimally manipulated through better engineering of polymer delivery vehicles that will eventually lead to improved in vivo efficacy of DNA-based immunotherapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Gene and Drug Delivery Systems Study Section (GDD)
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Welch, Anthony R
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University of Minnesota Twin Cities
Biomedical Engineering
Schools of Engineering
United States
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Luo, Shi; Tao, Yangyang; Tang, Rupei et al. (2014) Amphiphilic block copolymers bearing six-membered ortho ester ring in side chains as potential drug carriers: synthesis, characterization, and in vivo toxicity evaluation. J Biomater Sci Polym Ed 25:965-84
Xu, Zhangyan; Lai, Junping; Tang, Rupei et al. (2014) Synthesis and characterization of homopolymers bearing acid-cleavable cationic side-chains for pH-modulated release of DNA. Macromol Biosci 14:1015-24
Palumbo, R Noelle; Zhong, Xiao; Wang, Chun (2012) Polymer-mediated DNA vaccine delivery via bystander cells requires a proper balance between transfection efficiency and cytotoxicity. J Control Release 157:86-93
Palumbo, R Noelle; Zhong, Xiao; Panus, David et al. (2012) Transgene expression and local tissue distribution of naked and polymer-condensed plasmid DNA after intradermal administration in mice. J Control Release 159:232-9
Ji, Weihang; Panus, David; Palumbo, R Noelle et al. (2011) Poly(2-aminoethyl methacrylate) with well-defined chain length for DNA vaccine delivery to dendritic cells. Biomacromolecules 12:4373-85
Tang, Rupei; Ji, Weihang; Panus, David et al. (2011) Block copolymer micelles with acid-labile ortho ester side-chains: Synthesis, characterization, and enhanced drug delivery to human glioma cells. J Control Release 151:18-27
Tang, Rupei; Ji, Weihang; Wang, Chun (2011) Synthesis and characterization of new poly(ortho ester amidine) copolymers for nonviral gene delivery. Polymer (Guildf) 52:921-932
Palumbo, R Noelle; Nagarajan, Lakshmi; Wang, Chun (2011) Recombinant monomeric CD40 ligand for delivering polymer particles to dendritic cells. Biotechnol Prog 27:830-7
Tang, Rupei; Palumbo, R Noelle; Nagarajan, Lakshmi et al. (2010) Well-defined block copolymers for gene delivery to dendritic cells: probing the effect of polycation chain-length. J Control Release 142:229-37
Tang, Rupei; Ji, Weihang; Wang, Chun (2010) Amphiphilic block copolymers bearing ortho ester side-chains: pH-dependent hydrolysis and self-assembly in water. Macromol Biosci 10:192-201

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