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

描述(由申请者提供)：这个SBIR项目汇集了Scion Cardio-Vasculate Inc.(SCION C-V)、Loma Linda大学和北卡罗来纳州立大学的实验室的技能和资源，以推进一种治疗浅表性膀胱癌的新的信号分子疗法。这项治疗使用Scion C-V的粘附性脱热壳聚糖(CH)水凝胶(CH+IL-12)作为载体，将细胞因子IL-12输送到膀胱壁。脱热的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，复制在国家癌症研究所(NCI)进行的临床前研究。NCI的研究表明，在一个小鼠模型中，CH+IL-12膀胱内注射能显著治愈膀胱癌。NCI正准备在一项对照临床试验中测试CH+IL-12治疗浅表性膀胱癌的效果，但由于商业上可获得的“医用”壳聚糖中普遍存在热原污染，该研究取消了这项研究。热原污染是一个公认的问题，限制了壳聚糖作为辅料在植入性生物医学应用中的应用。为了提高膀胱癌的免疫治疗水平，迫切需要找到一种通用的方法来降低壳聚糖和IL-12的全身毒性。我们发现，用常温常压氮气等离子体(NtANP)处理壳聚糖既能减少壳聚糖内毒素，又能增强粘附性。作为一项第一阶段的研究，我们将测试这样一个假设，即我们的NtANP技术将使FDA批准的安全、经济的CH+IL-12递送工具成为可能。

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.