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）比死于前列腺癌、乳腺癌和结肠癌的人数总和还多。最常见的肺癌类型是非小细胞肺癌 (NSCLC)，占所有肺癌的 75%。遗憾的是，85%的非小细胞肺癌患者最终因微转移和复发而在5年内死亡。目前，美国有超过 1200 万癌症幸存者，其中只有 3.3%（约 40 万）是肺癌幸存者。迫切需要改进有效的癌症治疗方法，这不仅可以使肺癌幸存者受益，也可以使其他癌症类型的幸存者受益。该项目将开发“平台技术” 对于亲脂性和亲水性药物的外泌体制剂，使用牛乳来源的外泌体。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。我们将重点关注肺癌，并寻求提高这些药物的口服生物利用度并减少其所需剂量。尽管剂量较高，天然化合物仍经常遭受口服生物利用度问题。另一方面，静脉内给予的化疗药物会伴随着不良的血液浓度大幅升高。由于固有的局限性，几十年来脂质体和聚合物纳米颗粒制剂的研究只提供了少数有效的药物用于临床。在本申请中，我们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。牛奶来源的外泌体的生产将是可扩展的、经济上可行的并且具有高度的成本效益。外泌体药物递送方法有可能通过挑战涉及高剂量有毒化疗药物的现有范例来改变当前的癌症治疗实践。我们假设口服 PAC 和 WFA 的外泌体制剂将比各自的游离药物（无外泌体制剂）更有效，并且该制剂将减少所需的有效剂量，从而最大限度地减少或消除毒性。具体目标是（1）优化牛乳中外泌体的分离/纯化，最大化 PAC 和 WFA 的载药量，并确定外泌体配方的稳定性； (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对抗人肺癌细胞的功效，并确定小鼠模型中的潜在毒性。未来的工作将优化和确定 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，确定其长期稳定性，单独和组合测试 PAC 和 WFA 制剂对药物敏感的情况、耐药和转移性肺癌细胞，采用原位肿瘤异种移植裸鼠模型。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（3）

Milk-derived exosomes for oral delivery of paclitaxel.

用于口服输送紫杉醇的乳源性外泌体。

DOI：
10.1016/j.nano.2017.03.001
发表时间：
2017-07-01
期刊：
Nanomedicine : nanotechnology, biology, and medicine
影响因子：
0
作者：
A. Agrawal;F. Aqil;J. Jeyabalan;Wendy Spencer;J. Beck;Beth W. Gachuki;Sara S Alhakeem;Karine Z. Oben
通讯作者：
Karine Z. Oben

Exosomes as an Emerging Plasmid Delivery Vehicle for Gene Therapy.

外泌体作为一种新兴的基因治疗质粒递送载体。