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

描述（由申请人提供）：该SBIR项目汇集了Scion血管公司实验室的技能和资源。（Scion C-V）、洛马琳达大学和北卡罗来纳州州立大学合作，推进一种新的信号分子治疗浅表性膀胱癌。该治疗使用Scion C-V的粘膜粘附的去热原壳聚糖（Ch）水凝胶（Ch+IL-12）作为载体将细胞因子白细胞介素12（IL-12）递送至膀胱壁。将在相关小鼠膀胱癌模型中研究去热原Ch+IL-12水凝胶的治疗有效性，复制在国家癌症研究所（NCI）进行的临床前研究。NCI研究显示，在用囊内Ch+IL- 12治疗的小鼠模型中膀胱癌的显著治愈。NCI准备在对照临床试验中测试Ch+IL-12治疗浅表性膀胱癌，但由于市售“医用级”壳聚糖中广泛存在热原污染而取消了该研究。热原污染是一个公认的问题，限制了壳聚糖作为可植入生物医学应用的赋形剂的适用性。迫切需要确定降低壳聚糖和IL-12的全身毒性以改善膀胱癌免疫治疗的通用替代方法。我们已经发现，用非热大气压氮气等离子体（NtANP）处理壳聚糖既减少了壳聚糖内毒素，又可以增强粘膜粘附。作为I期研究，我们将测试我们的NtANP技术将实现FDA批准的安全和经济的Ch+IL-12递送载体的假设。

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.