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

基于超声的诊断和监测纳米颗粒释放药物治疗膀胱癌

基本信息

批准号：
10356881
负责人：
Joe Assouline
金额：
$ 95.69万
依托单位：
NANOMEDTRIX, LLC
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-07 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10356881
关键词：
Address Adult Adverse event Adverse reactions Alpha Particles Animal Model Animal Testing Animals BCG Live Bacillus Calmette-Guerin Therapy Bladder Bladder Neoplasm Cancer Patient Canis familiaris Carcinoma Carcinoma in Situ Cells Chemistry Clinical Clinical Trials Contracts Cultured Cells Cyclic GMP Data Data Set Development Diagnostic Disease Dose Drug Formulations Drug Industry Drug Kinetics Ensure Epirubicin Evaluation Funding Future GMP lots Goals Gravid Health Health Care Costs Hour Human Immune system Immunocompromised Host In Situ In Vitro Innovation Corps Iowa Lead Lesion Licensing Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of urinary bladder Medical Medical Care Costs Mitomycin C Modeling Monitor Mus Oncologist Organoids Pain Papillary Patients Penetration Performance Pharmaceutical Preparations Pharmacologic Substance Pharmacy facility Phase Pilot Projects Positioning Attribute Private Sector Privatization Process Production Property Recurrence Research Resected Safety Ships Silicon Dioxide Small Business Innovation Research Grant Spasm Specificity Technology Teratogenic effects Testing Therapeutic Time Toxicology Transitional Cell Carcinoma Translating Transurethral Resection United States National Institutes of Health Universities Urination Urology Work base bladder transitional cell carcinoma cGMP production cancer cell cancer therapy canine model chemotherapeutic agent chemotherapy clinically relevant college commercialization contrast imaging cost data acquisition design detrusor muscle docetaxel first-in-human follow-up gemcitabine improved in vitro testing in vivo interest intravesical mouse model nanomaterials nanoparticle neoplastic cell novel novel strategies novel therapeutics off-patent particle preclinical study preclinical trial programs prototype response scale up screening side effect standard care standard of care success tumor tumor growth ultrasound urologic

项目摘要

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.

项目摘要/摘要：膀胱移行细胞癌 (TCC) 是第五种最常见的癌症形式美国的癌症发病率预计将在 2019 年增加 80,000 多例。对于早期癌症，患者接受膀胱内卡介苗（BCG）免疫治疗，或经尿道膀胱切除术膀胱内化疗（TURBT）两者都与高复发率相关。 BCG 对许多免疫功能低下或出现不良反应的患者失败。反应，而 TURBT 联合化疗失败，因为化疗药物不充分保留在膀胱中以穿透未切除的病变因此，需要一种改进的药物。适用于早期（CIS、Ta、T1、T2）TCC 的制剂，能够 1) 穿透肿瘤超出表面细胞层，2) 增加化疗剂和癌细胞之间的停留/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) 的颗粒携带已知的化疗药物，旨在提高其特异性、停留时间和肿瘤我们的第一阶段 SBIR 项目超出了我们的目标，并证明了 MSN 的安全性和有效性。颗粒在小鼠 TCC 原位模型中体内携带和释放表柔比星以及在体外使用培养的通过参与 NIH I-CORPS 项目，我们与关键意见领袖进行了交谈。（泌尿肿瘤学家）在临床膀胱癌领域因此，我们正在使用它完成我们的第一阶段工作。 MSN 在同一模型中提供临床相关剂量的吉西他滨、多西紫杉醇和丝裂霉素-c。继第一阶段的成功之后，我们的第二阶段 SBIR 旨在完成以下项目所需的数据采集： FDA 启动 NMTx MSN 人体临床试验 IND 批准的具体目标 1 描述了：必要的体外任务：优化颗粒化学并使用培养细胞验证我们的大型犬模型和犬 TCC 类器官具体目标 2 描述了小鼠原位研究的完成和开始。对患有自发性 TCC 的狗进行的临床前试验制定了我们的实施计划。我们的 IND 的 cGMP 合成、包装和分析。除了为 FDA IND 批准和首次人体临床试验奠定基础之外，第二阶段的完成还将加强我们在制药行业的投资者/合作伙伴中的地位，我们将与他们在 SBIR 中合作 IIB 期、III 期及以后扩大临床试验并最终将该技术商业化。继续与我们在 I-CORPS 中建立的泌尿科联系人合作，他们渴望参与临床试验，我们已经收到了制药公司（百时美施贵宝、Urovant 等）的兴趣。技术将为被许可人提供现有化疗药物的改进性能专利已经过期，从而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。