Biopolymer-based strategies for local delivery of cytokine therapeutics

描述(申请人提供)：基于细胞因子的免疫疗法有可能治疗包括癌症在内的多种疾病。不幸的是，具有强大抗肿瘤活性的促炎细胞因子在全身暴露时往往是有毒的。缺乏有效的局部给药策略来控制细胞因子的分布，使细胞因子治疗无法影响癌症免疫治疗。该项目提出了一种新的递送技术，其中有效的重组细胞因子IL-12(IL-12)在肿瘤内(I.T.)之前被化学连接到一种名为壳聚糖的可生物降解的多糖上。注射。这一新的策略有望在肿瘤微环境中提供持续的、高浓度的IL-12，同时将潜在的有害全身传播降至最低。提出的项目包括三个目标，重点是在临床前肿瘤模型中开发和评估IL-12-壳聚糖生物偶联物。在第一个目标中，我们将合成新型的IL-12-壳聚糖生物偶联物，并在体外进行生物活性评价。溶剂可及氨基酸的突变将允许IL-12与壳聚糖的位置特异性结合。目标2将评估安全性 通过记录IL-12-壳聚糖生物偶联物的时空分布以及与IL-12-壳聚糖给药相关的任何潜在毒性。目的3评价IL-12-壳聚糖生物偶联物的抗肿瘤效果，以及在相关临床前模型中肿瘤特异性免疫的阐述。该项目的总体目标是确定与壳聚糖的偶联是否可以在缓解毒性问题的同时保持IL-12的强大抗肿瘤活性。这一细胞因子-壳聚糖传递平台的长期验证可能为癌症免疫治疗中的其他细胞因子疗法铺平道路。

DESCRIPTION (provided by applicant): Cytokine-based immunotherapies have the potential to treat a wide range of diseases including cancer. Unfortunately, pro-inflammatory cytokines with potent antitumor activity are frequently toxic upon systemic exposure. The lack of effective local delivery strategies capable of controlling the distribution cytokines has prevented cytokine therapeutics from impacting cancer immunotherapy. This project proposes a novel delivery technology in which a potent recombinant cytokine, interleukin-12 (IL-12), is chemically-linked to a biodegradable polysaccharide called chitosan prior to intratumoral (i.t.) injection. This novel strategy is expected to provide sustained, high concentrations of IL-12 in the tumor microenvironment, while minimizing potentially harmful systemic dissemination. The proposed project is comprised of three aims focusing on the development and evaluation of IL-12-chitosan bioconjugates in preclinical tumor models. In the first aim, novel IL-12-chitosan bioconjugates will be synthesized and evaluated in vitro for bioactivity. The mutation of solvent accessible amino acids will allow for site-specific conjugation of IL-12 to chitosan. Aim 2 will assess safety by documenting the spatiotemporal distribution of IL-12-chitosan bioconjugates and any potential toxicities associated with IL-12-chitosan administration. Aim 3 will evaluate antitumor efficacy of IL-12-chitosan bioconjugates as well as the elaboration of tumor-specific immunity in relevant preclinical models. The overall goal of this project is to determine if conjugation to chitosan can maintain the potent antitumor activity of IL-12 while alleviating toxicity concerns. I the long-term, validation of this cytokine-chitosan delivery platform may pave the way for additional cytokine therapeutics in cancer immunotherapy.