Ultrasound-based diagnostic and monitoring of bladder cancer treatment with drug released from nanoparticles

项目摘要/摘要：膀胱移行细胞癌(TCC)是最常见的第五种类型 预计2019年新增病例将超过8万例。对于早期癌症，患者 接受卡介苗(BCG)膀胱内免疫治疗或经尿道膀胱电切术 肿瘤(TURBT)加膀胱内化疗。两者都与高复发率和 最终的进展。卡介苗使许多免疫功能低下或经历不良反应的患者失败 反应，而TURBT与化疗失败，因为化疗药物不够 滞留在膀胱内以穿透未切除的病变。因此，有必要改进药物。 早期(CIS、Ta、T1、T2)TCC的配方：1)穿透肿瘤的表浅 细胞层，以及2)增加化疗药物与癌细胞之间的停留/接触时间。 为此，NanoMedTrix(NMTx)开发了一种基于介孔二氧化硅纳米颗粒(MSN)的颗粒 它携带已知的化疗药物，旨在提高它们的特异性、停留时间和肿瘤 穿透力。我们的第一阶段SBIR项目超出了我们的目标，并证明了MSN的安全性和有效性 小鼠膀胱移行细胞癌模型体内携带和释放表柔比星的颗粒及体外培养 人TCC细胞。通过参与美国国立卫生研究院i-Corps计划，我们与主要舆论领袖进行了交谈 (泌尿外科肿瘤学家)在临床膀胱癌领域。因此，我们将使用以下工具完成第一阶段的工作 MSN在同一模型中提供临床相关剂量的吉西他滨、多西他赛和丝裂霉素-C。 在我们的第一阶段成功之后，我们的第二阶段SBIR旨在完成以下所需的数据采集 FDA批准NMTx MSN在人体临床试验中的IND批准。具体目标1描述了 必要的体外任务：优化粒子化学并使用培养细胞验证我们更大的犬类模型 和犬类TCC有机化合物。具体目标2描述了小鼠原位研究的完成和开始 自发性膀胱移行细胞癌犬的临床前试验。具体目标3列出了我们的实施计划 CGMP的合成、包装和分析。 除了为FDA IND批准和首个人体临床试验奠定基础外，第二阶段的完成将 加强我们在制药行业投资者/合作伙伴中的地位，我们将在SBIR中与他们合作 第二阶段、第三阶段及以后，以扩大临床试验并最终将该技术商业化。我们是 继续与我们在i-Corps建立的渴望参与临床试验的泌尿科联系人合作， 我们已经收到了制药公司(百时美施贵宝、Urovant等)的兴趣。我们的 专利技术将为持牌人提供现有化疗药物的改进性能 这些技术已经过了专利期，因此使我们的技术在临床和商业上都具有吸引力。 这项SBIR工作的最终商业成功将极大地造福人类健康，同时降低医疗成本。

Project Summary/Abstract: Transitional cell carcinoma (TCC) of the bladder is the fifth most common form of cancer in the U.S., with over 80,000 new cases expected in 2019. For early-stage carcinomas, patients receive intravesical bacillus Calmette-Guerin (BCG) immunotherapy, or transurethral resection of the bladder tumor (TURBT) with intravesical chemotherapy. Both are associated with a high rate of recurrence and eventual progression. BCG fails many patients who are immunocompromised or who experience adverse reactions, while TURBT with chemotherapy fails because the chemotherapeutic agent is not sufficiently retained in the bladder to penetrate lesions that aren’t resected. Thus, there is a need for an improved drug formulation for early-stage (CIS, Ta, T1, T2) TCC capable of 1) penetrating the tumor beyond the superficial cell layers, and 2) increasing the dwell/contact time between the chemotherapeutic agent and the cancer cells. To that end, NanoMedTrix (NMTx) has developed a particle based on mesoporous silica nanoparticles (MSN) that carries known chemotherapeutic agents and is designed to improve their specificity, dwell time, and tumor penetration. Our Phase I SBIR project exceeded our goals and demonstrated the safety and efficacy of the MSN particles in carrying and releasing epirubicin in vivo in a murine TCC orthotopic model and in vitro using cultured human TCC cells. Through our participation in the NIH I-CORPS program we spoke with key opinion leaders (urologic oncologists) in the clinical bladder cancer space. As a result, we are completing our Phase I work using the MSN to deliver clinically relevant doses of gemcitabine, docetaxel, and mitomycin-c in the same model. Following our Phase I success, our Phase II SBIR is designed to complete the acquisition of data required by the FDA for initiation of IND approval of NMTx MSN in human clinical trials. Specific Aim 1 describes the necessary in vitro tasks: optimizing particle chemistry and validating our larger canine model using cultured cells and canine TCC organoids. Specific Aim 2 describes completion of murine orthotopic studies and the start of pre-clinical trials in dogs with spontaneously occurring TCC. Specific Aim 3 lays out our plan for carrying out cGMP synthesis, packaging, and analysis of our IND. Beyond setting the stage for FDA IND approval and first-in-human clinical trials, Phase II completion will strengthen our position with investors/partners in the pharmaceutical industry, with whom we will partner in SBIR Phase IIB, Phase III and beyond to expand clinical trials and ultimately commercialize the technology. We are continuing to work with the urology contacts we made in I-CORPS who are eager to participate in clinical trials, and we have received interest from Pharma companies (Bristol-Myers Squibb, Urovant, and others). Our proprietary technology will provide licensees with improved performance from established chemotherapeutics that have already gone off-patent, thus making our technology attractive both clinically and commercially. Ultimate commercial success of this SBIR work will greatly benefit human health while reducing medical costs.