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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）比死于前列腺癌、乳腺癌和结肠癌的人数加起来还要多。最常见的肺癌类型是非小细胞肺癌（NSCLC），占所有肺癌的75%。令人遗憾的是，85%被诊断为NSCLC的患者最终在5年内因微转移和复发而死亡。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，不仅可以极大地造福肺癌幸存者，还可以造福其他类型的癌症患者。该项目将开发一种“平台技术”