Chitosan-plasmid DNA nanoplexes and adenoviruses as prostate cancer vaccines

描述(申请人提供)：前列腺癌影响超过15%的男性。前列腺癌在转移时，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，因为它在组织中的分布很窄，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强大的抗肿瘤免疫。到目前为止，研究的重点要么是非病毒递送系统，如质粒DNA-聚阳离子复合体共醋酸酯，要么是病毒途径，如使用编码前列腺特异性抗原的腺病毒。非病毒质粒DNA序列含有CpG基序。CpG基序增强Ad5-PSA疫苗的肿瘤保护作用。CpG ODN以颗粒形式递送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(带有CpG基序)络合形成非病毒基因递送纳米粒。这项应用的目的是验证壳聚糖-pcDNA-PSA纳米复合体与AdPSA共同传递将在前列腺癌小鼠模型中增强肿瘤保护的假设。这项应用将检验这样一种假设，即编码前列腺特异性抗原(AdPSA)的腺病毒与壳聚糖-pcDNA-PSA纳米复合体共同传递将增强对前列腺癌小鼠模型的肿瘤保护。这将通过以下方法实现：1)优化用于基因传递的壳聚糖-pcDNA-PSA纳米复合物/腺病毒配方，2)表征壳聚糖-pcDNA-PSA纳米复合材料/腺病毒制剂刺激的抗原特异性免疫反应，以及3)评估壳聚糖-pcDNA-PSA纳米复合材料/腺病毒制剂在小鼠前列腺癌模型中的免疫治疗保护作用。

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.