Novel Drug Delivery Platform as Medical Countermeasure for treatment of Gastrointestinal Radiation Damage

项目总结/摘要 Tiny Cargo公司提供了一种独特的口服医疗对策， 预防癌症放射治疗（RT）的胃肠道（GI）副作用。我们的治疗方法是 由乳源性细胞外囊泡（mEV）组成， 辐射防护药物-我们称之为Milactatm的配方。RT并发症包括恶心，呕吐， 疼痛和消化不良、粘膜屏障破坏和营养吸收不良-长期影响， 也可能包括累积的和不可逆的肠道疤痕。目前，没有治疗方法， 预防或减轻RT的这些副作用。我们从弗吉尼亚理工大学获得的全球独家许可包括 我们的放射防护药物的组合物和将药物装载到mEV中的方法的未决专利， 以及用于工业规模化生产和分离药用级mEV的方法， 牛奶。mEV受FDA的最低限度监管，我们的辐射防护药物是一种新型， 模拟人间隙连接蛋白C末端的短9氨基酸肽（RPRPDDLEI） 连接蛋白43.我们的技术前提是，在mEV中封装RPRPRDDLEI将使口服 在消化道吸收之前，我们的脆弱肽治疗剂在消化液中的递送和保护 细胞我们的初步数据表明，优化的mEV-药物加载方法，摄取的证明， 口服给药后肠道细胞/组织对mEV的影响以及我们的RPRPDDLEI-mEV 制剂对大鼠胃肠道衍生原代细胞培养物提供有效水平的辐射防护 IEC-6线，与III期临床试验治疗性α CT 1相当。我们有两个目标：1）承担 体内测试我们的mEV-RPRPDDLEI制剂的预防功效（即，Milacta）在小鼠体内 全身照射模型，以及; 2）确定最佳给药方案（即预防性、后- 辐射、双重处理）以最大化辐射防护。Tiny Cargo的技术满足了 临床需求，可增加患者对高效放射性治疗的接受率和依从性 癌症缓解策略，以及提供可能具有高度战略意义的医疗技术 这对美国和我们的军队都有好处。此外，我们的基于mEV和药物加载的方法代表了一种 平台技术，在未来可以适用于其他“难以药物”的生物制剂，包括 microRNA和其他治疗肽，从而提供新的许可和商业 Tiny Cargo在制定缓解措施以外的业务计划和管道时， 放射治疗对癌症患者的影响。

Project Summary/Abstract The Tiny Cargo Company offers a unique, orally administered medical countermeasure for treatment and prevention of the gastrointestinal (GI) side effects of cancer radiation therapy (RT). Our therapeutic is comprised of milk-derived extracellular vesicles (mEVs) loaded with a safe and highly effective radioprotective drug – a formulation that we call Milactatm. RT complications include nausea, vomiting, pain and dyspepsia, mucosal barrier breakdown, and nutrient malabsorption - with long-term effects that can also include cumulative and irreversible scarring of the gut. Presently, there are no treatments to prevent or mitigate these side-effects of RT. Our world-wide exclusive license from Virginia Tech includes pending patents for the composition and method of drug loading into mEVs of our radioprotective drug, as well as methods for industrially scalable production and isolation of pharmaceutical-grade mEVs from bovine milk. mEVs are subject to minimal regulation by the FDA and our radioprotective drug is a novel, short 9 amino acid peptide (RPRPDDLEI) mimicking the C-Terminus of the human gap junction protein Connexin 43. Our technical premise is that encapsulation of RPRPRDDLEI in mEVs will enable oral delivery and protection of our fragile peptide therapeutic in digestive juices prior to uptake in GI-tract cells. Our preliminary data indicates an optimized mEV-drug loading approach, demonstration of uptake of mEVs by gut cells/tissues following oral administration and in vitro data that our RPRPDDLEI-mEV formulation provides potent levels of radioprotection to cultures of the rat GI-tract derived primary cell line IEC-6, comparable to Phase III Clinical Trial therapeutic αCT1. In two aims we will: 1) Undertake testing in vivo of the prophylactic efficacy of our mEV-RPRPDDLEI formulation (i.e., Milacta) in a mouse model of whole-body irradiation, and; 2) Determine the optimal dosing regimens (i.e. prophylactic, post- irradiation, dual-treatment) for maximized radioprotection. Tiny Cargo’s technology meets an urgent clinical need that could increase patient uptake and compliance with highly effective radiation-based cancer mitigation strategies, as well as providing a medical technology that is likely to be of high strategic interest to the US and our military. Moreover, our mEV-based and drug loading method represents a platform technology that in the future could be adapted for other “difficult-to-drug” biologics, including microRNAs and other therapeutic peptides, thereby providing new licensing and commercial collaborative opportunities for Tiny Cargo as it develops its business plan and pipeline beyond mitigation of the effects of radiation therapy in cancer patients.