Collaborative Research: Polysaccharide Derivatives for Enhanced Drug Delivery

合作研究：用于增强药物输送的多糖衍生物

• 批准号: 0804501
• 负责人: Kevin Edgar
• 金额: $ 21万
• 依托单位: Virginia Polytechnic Institute and State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0804501&HistoricalAwards=false
• 关键词: Collaborative; Research; Polysaccharide; Derivatives; Enhanced

Lead ID: DMR/BMAT(7623) 0804609 Lead PI: Taylor, Lynne ORG: PurdueNon-Lead ID: DMR/BMAT(7623) 0804501 Non-Lead PI: Edgar, Kevin ORG: Virginia TechTitle: COLLABORATIVE RESEARCH: Polysaccharide Derivatives for Enhanced Drug DeliveryINTELLECTUAL MERIT: The PIs propose synthesis, mechanistic study, and screening test development for the design of novel cellulosic biomaterials to ensure effective and safe delivery of water-insoluble drugs. The research promises to create fundamental understanding of amorphous matrices, leading to effective new amorphous matrix systems for delivery of highly active, poorly bioavailable drugs. It will thus address a key impediment to productive drug development. The proposal has the following specific objectives: (1) Elucidate key requirements for polymeric stabilization of the amorphous form of model drugs in both the solid and solution phases by mechanistic studies. (2) Create screening methods to rapidly evaluate novel cellulose derivatives. (3) Synthesize two novel families of cellulose derivatives designed for drug miscibility, slow release, and pH-triggered release, as well as safety. (4) Design second generation cellulose derivatives based on screening results and solubility testing of key drugs with solubility and bioavailability issues. The team at Virginia Tech will synthesize novel long chain ester derivatives of carboxymethyl cellulose, and novel adipate esters of cellulose, varying the degree of substitution of carboxymethyl and other substituents to provide a range of hydrophobicity and release rates. The team at Purdue will carry out polarized light optical microscopy of spin coated polymer/model drug films that will provide mechanistic understanding and ultimately a screening method for new polymer delivery systems. They will screen solution stabilization by visible and UV spectroscopy of drug in polymer solution, using 1H NMR spectroscopy of the solutions to provide mechanistic understanding. Mechanistic understanding of how amorphous drugs are stabilized in the solid state, and especially in solution, by polymeric matrices, and creation of novel stabilization screening methods will provide valuable new tools of general use in the field. Furthermore, the research will generate biomaterials forming the basis of new drug delivery systems for rescue of failed pipeline drugs, enhancing efficacy of marketed drugs, and enabling conversions of injectable formulations to oral for enhanced compliance.BROADER IMPACTS: Many important drugs, including several anticancer and antifungal agents, suffer from poor bioavailability due to the low aqueous solubility of their crystalline forms. One strategy for addressing this problem is to produce the drug in an amorphous modification, given the generally improved solubility of the amorphous material. This proposal develops a general approach to using cellulose derivatives to suppress drug crystallinity and enhance bioavailabilty. It will develop a systematic approach to understanding the mechanisms underlying this enhancement. The work could have very substantial impact inasmuch as effective delivery of many drugs represents a major impediment to their efficient implementation. The project provides an attractive multidisciplinary platform for the training of students, who will be associated not only with synthesis and characterization of materials but with developing drug formulations with practical utility. Minority undergraduate research participation will be encouraged at Purdue through the existing Pharmacy Multicultural Program, which provides 50% cost sharing for the student stipend. Past experience suggests that 3-5 students will be involved each year during the summers as well as the academic year.

电极导线ID：DMR/BMAT（7623）0804609 主要研究者：Taylor、Lynne ORG：Purdue非电极导线ID：DMR/BMAT（7623）0804501 非主要研究者：埃德加、凯文·奥格：弗吉尼亚州技术标题：合作研究：多糖衍生物用于增强药物递送的智力优势：PI提出了新型纤维素生物材料设计的合成，机理研究和筛选测试开发，以确保水不溶性药物的有效和安全递送。该研究有望建立对无定形基质的基本理解，从而产生有效的新无定形基质系统，用于递送高活性、生物利用度差的药物。 因此，它将解决生产性药物开发的一个关键障碍。该提案具有以下具体目标：（1）通过机理研究阐明模型药物的无定形形式在固相和溶液相中的聚合物稳定化的关键要求。(2)创建筛选方法以快速评估新型纤维素衍生物。(3)合成两种新型纤维素衍生物，旨在实现药物的可溶解性、缓释性、pH触发释放性以及安全性。(4)根据筛选结果和溶解度测试，设计第二代纤维素衍生物，解决溶解度和生物利用度问题。弗吉尼亚理工大学的研究小组将合成羧甲基纤维素的新型长链酯衍生物和纤维素的新型己二酸酯，改变羧甲基和其他取代基的取代度，以提供一系列疏水性和释放速率。普渡大学的团队将对旋涂聚合物/模型药物薄膜进行偏振光光学显微镜检查，这将为新的聚合物递送系统提供机械理解和最终筛选方法。他们将通过聚合物溶液中药物的可见光和紫外光谱来筛选溶液稳定性，使用溶液的1H NMR光谱来提供机理理解。无定形药物如何在固态，特别是在溶液中，通过聚合物基质稳定的机制的理解，和创造新的稳定筛选方法将提供有价值的新工具，在该领域的一般用途。此外，该研究将产生生物材料，形成新的药物输送系统的基础，用于拯救失败的管道药物，提高上市药物的疗效，并使注射制剂转化为口服制剂，以提高依从性。更广泛的影响：许多重要的药物，包括几种抗癌和抗真菌药物，由于其晶体形式的水溶性低，生物利用度差。 解决该问题的一种策略是生产无定形修饰的药物，因为无定形材料的溶解度通常得到改善。 该建议开发了一种使用纤维素衍生物抑制药物结晶和提高生物利用度的通用方法。它将制定一个系统的方法来理解这种增强的机制。 这项工作可能会产生非常重大的影响，因为许多药物的有效供应是有效实施的主要障碍。 该项目为学生的培训提供了一个有吸引力的多学科平台，这些学生不仅将与材料的合成和表征有关，而且还将与开发具有实用性的药物制剂有关。 普渡大学将通过现有的药学多元文化项目鼓励少数民族本科生参与研究，该项目为学生提供50%的费用分摊。 过去的经验表明，3-5名学生将参与每年在夏季以及学年。