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

项目摘要/摘要 微小货运公司提供了一种独特的口服药物治疗和治疗方法 预防癌症放射治疗的胃肠道(GI)副作用。我们的治疗方法是 由牛奶衍生的细胞外小泡(MEV)组成，装载着安全高效的 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，营养吸收不良-具有长期影响， 也可以包括肠道累积的和不可逆转的疤痕。目前，还没有治疗方法 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 我们的辐射防护药物的组合物和将药物加载到MEV的方法正在申请专利， 以及工业可规模生产和分离药用级MEV的方法 牛奶。MEV受到FDA最低限度的监管，我们的辐射防护药物是一种新的药物， 模拟人缝隙连接蛋白C末端的短9位氨基酸(RPRPDDLEI) 连接蛋白43。我们的技术前提是将RPRPRDDLEI封装在MEVS中将使口腔 我们的脆性多肽治疗药物在胃肠道摄取前在消化液中的传递和保护 细胞。我们的初步数据表明，一种优化的MEV-药物加载方法，显示了摄取 口服给药后肠道细胞/组织对MEV的影响以及我们的RPRPDDLEI-MEV体外数据 配方对培养的大鼠胃肠道来源的原代细胞具有有效的辐射防护作用 品系IEC-6，与第三阶段临床试验治疗αCT1相当。我们将在两个目标中：1)承担 我们的MEV-RPRPDDLEI制剂(即Milacta)在小鼠体内预防效果的测试 全身照射模型，以及2)确定最佳剂量方案(即预防、后照射和预防)。 辐射、双重治疗)，以实现最大限度的辐射防护。Tiny Cargo的技术遇到了紧急情况 可提高患者对高效放射治疗的摄取率和依从性的临床需求 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 关系到美国和我们军队的利益。此外，我们基于MEV的药物加载方法代表了一种 平台技术，在未来可能被改编成其他“难以用药”的生物制剂，包括 MicroRNAs和其他治疗性多肽，从而提供新的许可和商业 为微型货物提供协作机会，因为它制定了业务计划和管道，超越了缓解 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.