Exosomal drug formulations

外泌体药物制剂

基本信息

批准号：
8780989
负责人：
RAMESH C GUPTA
金额：
$ 22.5万
依托单位：
3P BIOTECHNOLOGIES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-05 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8780989
关键词：
Accounting Alzheimer&apos s Disease Animal Model Biodistribution Biological Availability Biotechnology Blood Cancer Survivor Cattle Cell Culture Techniques Chemopreventive Agent Chronic Clinic Colon Carcinoma Cosmetics Data Data Analyses Data Reporting Diagnosis Disease Dose Drug Delivery Systems Drug Formulations Drug resistance Drug usage Drug-sensitive Excision Exhibits Future Goals Human Immunologist Immunotherapy In Vitro Individual Inflammation Liposomes Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of prostate Marketing Methods Milk Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Nude Mice Oral Paclitaxel Pathologist Patients Pharmaceutical Preparations Phase Preparation Prevention Primary Cancer Prevention Problem Formulations Production Recurrence Relapse Research Project Grants Sampling Small Business Technology Transfer Research Source Staging Technology Testing Therapeutic Therapeutic Uses Tissues Toxic effect Treatment Efficacy Vision Work Xenograft Model anticancer activity cancer cell cancer therapy cancer type commercial application cost effective disorder later incidence prevention high risk improved innovation macromolecule malignant breast neoplasm mouse model nano nanoparticle prevent prophylactic public health relevance response stability testing stem tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): More people in the U.S. (160,340 per year) die of lung cancer than of prostate, breast, and colon cancer combined. The most common type of lung cancer, non-small-cell lung cancer (NSCLC), accounts for 75% of all lung cancers. Regrettably, 85% of all patients diagnosed with NSCLC eventually die of the disease within 5 years, due to micro-metastasis and relapse. Currently, over 12 million cancer survivors reside in the U.S., of which only 3.3% (about 400,000) are lung cancer survivors. Improved methods in effective cancer treatment are urgently needed and could greatly benefit not only lung cancer survivors, but also those of other cancer types. This project will develop a "platform technology" for exosome formulations, using bovine-milk-derived exosomes, of both lipophilic and hydrophilic drugs. Specifically, we will prepare exosome formulations of a standard chemotherapeutic (chemo) drug, paclitaxel (PAC), and a natural compound with chemopreventive and therapeutic potential, withaferin A (WFA), and examine their ability to prevent and treat cancer. We will focus on lung cancer and will seek to enhance the oral bioavailability of these drugs and reduce their required doses. Natural compounds often suffer from oral bioavailability issues, despite high doses. On the other hand, chemotherapeutic (chemo) drugs given intravenously are accompanied by undesirable large spikes in blood levels. Decades of work with liposomal and polymeric nanoparticle formulations have rendered only a handful of effective drugs for use in the clinics due to inherent limitations. In this application e will optimize exosome isolation and exosome formulations with potent therapeutic activity, and determine their therapeutic efficacy and potential toxicity. Production of the bovine milk-derived exosomes will be scalable, economically feasible, and highly cost effective. The exosomal drug delivery approach has the potential to change the current practice of cancer treatment by challenging the existing paradigm involving high doses of toxic chemo drugs. We hypothesize that exosome formulations of PAC and WFA administered orally will be more effective than respective free drugs (without exosome formulation), and that the formulation will reduce the required effective dose, thus minimizing or eliminating toxicity. The specific aims are to (1) optimize exosome isolation/purification from bovine milk, maximize drug loading of PAC and WFA, and determine stability of the exosome formulations; and (2) determine the efficacy of exosome formulations of PAC and WFA, in cell culture and in a nude mouse xenograft model, against human lung cancer cells, and also determine potential toxicities in a mouse model. Future efforts will optimize and determine the efficacy of nano spray-dried exosome formulations of PAC and WFA and other compounds, including siRNAs, determine their long-term stability, test formulations of PAC and WFA, both individually and in combination, against drug-sensitive, drug-resistant and metastatic lung cancer cells, using orthotopic tumor xenograft nude mouse models.

描述（由申请人提供）：美国死亡的人（每年160,340人）多于前列腺，乳腺癌和结肠癌的肺癌。最常见的肺癌类型，非小细胞肺癌（NSCLC），占所有肺癌的75％。遗憾的是，由于微米切氏症和复发，所有被诊断为NSCLC的患者中有85％最终在5年内死于该疾病。目前，超过1200万癌症幸存者居住在美国，其中只有3.3％（约40万）是肺癌幸存者。迫切需要改善有效癌症治疗的方法，不仅可以使肺癌幸存者，而且还可以使其他癌症类型的方法受益。该项目将开发一个“平台技术” 用于外泌体制剂，使用牛乳源性外泌体的亲脂性药物和亲水性药物。具体而言，我们将准备标准化学治疗（化学）药物，紫杉醇（PAC）的外泌体配方，以及具有化学预防和治疗潜力的天然化合物，伴有AFERIN A（WFA）（WFA），并检查其预防和治疗癌症的能力。我们将专注于肺癌，并寻求增强这些药物的口服生物利用度并减少其所需剂量。天然化合物尽管剂量高剂量，但通常会遇到口服生物利用度问题。另一方面，静脉注射的化学治疗（化学）药物在血液水平上伴随着不良的大峰值。由于固有的局限性，使用脂质体和聚合物纳米颗粒制剂的制剂仅渲染了少数有效的药物供诊所使用。在本应用中，E将优化具有有效治疗活性的外泌体分离和外泌体配方，并确定其治疗功效和潜在毒性。牛奶衍生的外泌体的生产将是可扩展的，在经济上可行的，并且具有高度的成本效益。外泌体药物输送方法有可能通过挑战涉及高剂量有毒化学药物的现有范式来改变当前的癌症治疗方法。我们假设口服PAC和WFA的外泌体配方比各自的自由药物（无外泌体配方）更有效，并且该配方将减少所需的有效剂量，从而最大程度地减少或消除毒性。具体目的是（1）优化从牛奶中优化外泌体分离/纯化，最大化PAC和WFA的药物载荷，并确定外泌体配方的稳定性；（2）确定PAC和WFA外泌体制剂在细胞培养和裸小鼠异种移植模型中对人肺癌细胞的疗效，并确定小鼠模型中的潜在毒性。未来的努力将优化和确定纳米喷涂的PAC和WFA的喷雾剂外泌体配方以及其他化合物（包括siRNAS）确定其长期稳定性，对PAC和WFA的测试配方，无论是单独且组合，都针对药物敏感，药物耐药性，耐药性和转移性肺癌细胞，使用Orthopopic tumorpopic tumor Xenover nude nude nude nude nude nude nude。