Biopolymer-based strategies for local delivery of cytokine therapeutics

描述（由申请人提供）：基于细胞因子的免疫疗法具有治疗包括癌症在内的多种疾病的潜力。不幸的是，具有强效抗肿瘤活性的促炎细胞因子在全身暴露后通常是有毒的。缺乏能够控制细胞因子分布的有效局部递送策略已经阻止了细胞因子治疗剂对癌症免疫治疗的影响。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白细胞介素-12（IL-12）在肿瘤内（i.t.）注射这种新的策略有望在肿瘤微环境中提供持续的高浓度IL-12，同时最大限度地减少潜在的有害全身传播。 拟议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-壳聚糖生物缀合物。在第一个目标中，将合成新型IL-12-壳聚糖生物缀合物并在体外评价其生物活性。溶剂可及氨基酸的突变将允许IL-12与壳聚糖的位点特异性缀合。目标2将评估安全性 通过记录IL-12-壳聚糖生物缀合物的时空分布和与IL-12-壳聚糖施用相关的任何潜在毒性。目的3评价IL-12-壳聚糖生物缀合物的抗肿瘤功效以及在相关临床前模型中的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缀合是否可以保持IL-12的有效抗肿瘤活性，同时减轻毒性问题。从长远来看，这种精氨酸-壳聚糖递送平台的验证可能为癌症免疫治疗中的其他细胞因子治疗铺平道路。

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.