Collaborative Research: Polysaccharide Derivatives for Enhanced Drug Delivery

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：合作研究：用于增强药物递送的多糖衍生物智力优势：PIs提出合成，机制研究和筛选测试开发，用于设计新型纤维素生物材料，以确保水不溶性药物的有效和安全递送。这项研究有望创造对非晶态基质的基本理解，从而产生有效的新型非晶态基质系统，用于递送高活性、低生物利用度的药物。因此，它将解决生产性药物开发的一个关键障碍。该提案有以下具体目标：(1)通过机理研究阐明模型药物在固相和固相中非晶态聚合物稳定的关键要求。(2)建立快速评价新型纤维素衍生物的筛选方法。(3)合成两个新的纤维素衍生物家族，具有药物混溶性、缓释性和ph触发释放性以及安全性。(4)基于关键药物的溶解度和生物利用度问题的筛选结果和溶解度测试，设计第二代纤维素衍生物。弗吉尼亚理工大学的研究小组将合成新型的羧甲基纤维素长链酯衍生物和新型的己二酸酯纤维素，改变羧甲基和其他取代基的取代程度，以提供一系列的疏水性和释放速率。普渡大学的研究小组将对自旋涂层聚合物/模型药物薄膜进行偏振光光学显微镜观察，这将提供机理理解，并最终为新的聚合物输送系统提供一种筛选方法。他们将通过药物在聚合物溶液中的可见和紫外光谱来筛选溶液的稳定性，使用溶液的1H NMR光谱来提供机理理解。了解非晶态药物在固体状态下，特别是在溶液中，如何通过聚合物基质稳定的机制，以及创造新的稳定筛选方法，将为该领域提供有价值的新工具。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，以挽救失败的管道药物，提高已上市药物的功效，并使可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，包括一些抗癌和抗真菌药物，由于其晶体形式的水溶解度低，生物利用度差。解决这个问题的一个策略是生产非晶修饰的药物，鉴于非晶材料的溶解度普遍提高。本提案开发了一种使用纤维素衍生物来抑制药物结晶度和提高生物利用度的一般方法。它将开发一种系统的方法来理解这种增强背后的机制。这项工作可能产生非常重大的影响，因为许多药物的有效递送是有效实施这些药物的主要障碍。该项目为培养学生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，而且将与开发具有实用价值的药物配方有关。普渡大学将通过现有的药学多元文化项目鼓励少数族裔本科生参与研究，该项目为学生津贴提供50%的费用分摊。根据以往的经验，每年的夏季和学年都会有3-5名学生参与。

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.