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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）：在美国，死于肺癌的人数（每年160，340人）超过前列腺癌、乳腺癌和结肠癌的总和。非小细胞肺癌（non-small cell lung cancer，NSCLC）是最常见的肺癌类型，占所有肺癌的75%。令人遗憾的是，85%的诊断为NSCLC的患者最终死于疾病的5年内，由于微转移和复发。目前，超过1200万癌症幸存者居住在美国，其中只有3.3%（约40万人）是肺癌幸存者。有效的癌症治疗方法的改进是迫切需要的，不仅可以大大有利于肺癌幸存者，而且也有利于其他癌症类型。该项目将开发一种“平台技术”，对于亲脂性和亲水性药物的外泌体制剂，使用源自牛乳的外泌体。具体来说，我们将制备标准化疗药物紫杉醇（PAC）和具有化学预防和治疗潜力的天然化合物醉茄素A（WFA）的外泌体制剂，并检查它们预防和治疗癌症的能力。我们将把重点放在肺癌上，并将寻求提高这些药物的口服生物利用度，减少其所需剂量。天然化合物通常遭受口服生物利用度问题，尽管高剂量。另一方面，静脉内给予的化疗药物伴随着血液水平的不期望的大峰值。由于固有的局限性，几十年来对脂质体和聚合物纳米颗粒制剂的研究仅提供了少数用于临床的有效药物。在本申请中，我们将优化外泌体分离和具有有效治疗活性的外泌体制剂，并确定其治疗功效和潜在毒性。牛乳来源的外泌体的生产将是可规模化的、经济上可行的和高度成本效益的。外泌体药物递送方法具有通过挑战涉及高剂量毒性化疗药物的现有范例来改变当前癌症治疗实践的潜力。我们假设口服施用的PAC和WFA的外泌体制剂将比各自的游离药物（没有外泌体制剂）更有效，并且制剂将减少所需的有效剂量，从而最小化或消除毒性。具体目的是（1）优化来自牛乳的外泌体分离/纯化，最大化PAC和WFA的载药量，并确定外泌体制剂的稳定性;和（2）确定PAC和WFA的外泌体制剂在细胞培养物和裸鼠异种移植模型中针对人肺癌细胞的功效，并确定小鼠模型中的潜在毒性。未来的努力将优化和确定PAC和WFA以及其他化合物（包括siRNA）的纳米喷雾干燥外泌体制剂的功效，确定它们的长期稳定性，使用原位肿瘤异种移植裸鼠模型测试PAC和WFA单独和组合的制剂对抗药物敏感性、耐药性和转移性肺癌细胞。