Chitosan-plasmid DNA nanoplexes and adenoviruses as prostate cancer vaccines

描述（由申请人提供）：前列腺癌影响超过15%的男性。前列腺癌一旦转移，最终是无法治愈的。因此，包括免疫疗法在内的替代策略正在得到越来越多的研究。前列腺特异性抗原（PSA）是一种理想的免疫治疗靶抗原，因为它在组织中分布狭窄，几乎在所有前列腺癌中都有表达。基因传递技术有可能激发有效的抗肿瘤免疫。到目前为止，研究要么集中在非病毒传递系统，如质粒dna -多阳离子复合物协同作用，要么集中在病毒方法，如使用腺病毒编码前列腺特异性抗原。非病毒质粒DNA序列含有CpG基序。CpG基序增强了Ad5-PSA疫苗的肿瘤保护作用。CpG ODN以颗粒形式递送明显比以溶液形式递送更有效。壳聚糖是一种安全的天然聚合物，它与质粒DNA（含CpG基序）复合物形成非病毒基因递送纳米颗粒。本应用的目的是验证壳聚糖- pcdna - psa纳米复合物与AdPSA共同递送将增强前列腺癌小鼠模型的肿瘤保护作用的假设。该应用将验证编码前列腺特异性抗原（AdPSA）的腺病毒与壳聚糖- pcdna - psa纳米复合物共同递送将增强前列腺癌小鼠模型的肿瘤保护作用的假设。这将通过1)优化壳聚糖-pcDNA-PSA纳米复合物/腺病毒的基因递送配方，2)表征壳聚糖-pcDNA-PSA纳米复合物/腺病毒配方刺激的抗原特异性免疫反应，以及3)评估壳聚糖-pcDNA-PSA纳米复合物/腺病毒组合在小鼠前列腺癌模型中的免疫治疗保护作用来实现。

DESCRIPTION (provided by applicant): Prostate cancer affects over 15% of all men. Prostate cancer, when metastatic, is ultimately incurable. As a result, alternative strategies including immunotherapy are being increasingly investigated. Prostate specific antigen (PSA) is an ideal target antigen for immunotherapy because it has a narrow distribution in tissues and is expressed in virtually all prostate cancers. Gene delivery techniques have the potential to stimulate potent anti-tumor immunity. To date, studies have either focused on non-viral delivery systems such as plasmid DNA-polycation complex co-acervates or viral approaches such as the use of adenoviruses encoding prostate specific antigen. Non-viral plasmid DNA sequences contain CpG motifs. CpG motifs enhance the efficacy of Ad5-PSA vaccines tumor protection. CpG ODN delivered in particulate form is significantly more potent than delivery in solution. Chitosan is a safe natural polymer that complexes with plasmid DNA (with CpG motifs) to form non-viral gene delivery nanoparticles. The objective of this application is to test the hypothesis that co-delivery of chitosan-pcDNA-PSA nanoplexes with AdPSA will enhance tumor protection in a murine model of prostate cancer. This application will test the hypothesis that co-delivery of adenoviruses encoding the prostate specific antigen (AdPSA) with chitosan-pcDNA-PSA nanoplexes will enhance tumor protection in a murine model of prostate cancer. This will be achieved by 1) optimizing chitosan-pcDNA-PSA nanoplexes/adenovirus formulations for gene delivery, 2) characterizing the antigen-specific immune response stimulated from chitosan-pcDNA-PSA nanoplexes/adenovirus formulations and 3) evaluating the combined chitosan- pcDNA-PSA nanoplex/adenovirus formulations for immunotherapeutic protection in a murine prostate cancer model.