Intravesical Chitosan IL-12 Therapy in an Orthotopic Mouse Bladder Cancer Model

描述（由申请人提供）：这个SBIR项目汇集了Scion心血管公司（Scion C-V）、洛马琳达大学和北卡罗莱纳州立大学实验室的技能和资源，以推进一种新的信号分子治疗浅表性膀胱癌。该疗法使用Scion C-V的黏附、去热原壳聚糖（Ch）水凝胶（Ch+IL-12）作为载体，将细胞因子白细胞介素12 （IL-12）递送到膀胱壁。去热原化Ch+IL-12水凝胶的治疗效果将在相关的小鼠膀胱癌模型中进行研究，复制美国国家癌症研究所（NCI）的临床前研究。NCI研究显示，囊内灌注Ch+IL- 12治疗小鼠膀胱癌的疗效显著。NCI正准备在一项对照临床试验中测试Ch+IL-12对浅表性膀胱癌的治疗效果，但由于市售的“医疗级”壳聚糖中存在广泛的热原污染，该研究被取消。热原污染是一个公认的问题，它限制了壳聚糖作为植入式生物医学应用辅料的适用性。目前迫切需要确定一种通用的替代方法来降低壳聚糖和IL-12的全身毒性，以改善膀胱癌的免疫治疗。我们发现用非热常压氮气等离子体（NtANP）处理壳聚糖既可以减少壳聚糖内毒素，又可以增强壳聚糖的黏附。作为第一阶段的研究，我们将测试假设我们的NtANP技术将使FDA批准的安全和经济的Ch+IL-12运载工具成为可能。

DESCRIPTION (provided by applicant): This SBIR project brings together the skills and resources of laboratories at Scion Cardio-Vascular Inc. (Scion C-V), Loma Linda University, and North Carolina State University to advance a new signaling molecule treatment for superficial bladder cancer. This treatment delivers the cytokine Interleukin 12 (IL-12) to the bladder wall using Scion C-V's mucoadherent, depyrogenated chitosan (Ch) hydrogel (Ch+IL-12) as the vehicle. Therapeutic effectiveness of the depyrogenated Ch+IL-12 hydrogel will be studied in a relevant mouse bladder cancer model, replicating the pre-clinical studies performed at the National Cancer Institute (NCI). The NCI studies showed remarkable cures of bladder cancer in a mouse model treated with intravesicular Ch+IL- 12. The NCI was preparing to test treatment of superficial bladder cancer with Ch+IL-12 in a controlled clinical trial but cancelled the study because of widespread pyrogen contamination in commercially available "medical grade" chitosans. Pyrogen contamination is a well recognized problem that limits the applicability of chitosan as an excipient for implantable biomedical applications. There is an urgent need to define versatile alternative, methods that reduce the systemic toxicity of chitosan and IL-12 to improve bladder cancer immunotherapy. We have found that treating chitosan with non-thermal atmospheric nitrogen gas plasma (NtANP) both reduces chitosan endotoxins and may enhance mucoadhesion. As a Phase I study, we will test the hypothesis that our NtANP technology will enable an FDA approved safe and economical Ch+IL-12 delivery vehicle.