Development of Functional Poly(alpha-hydroxy acids) for Drug Delivery Application

用于药物输送应用的功能性聚（α-羟基酸）的开发

• 批准号: 7641437
• 负责人: Jianjun Cheng
• 金额: $ 21.78万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7641437
• 关键词: Acids; Address; Alanine; Amines; Amino Acids; Antineoplastic Agents; Bathing; Biocompatible Materials; Development; Dioxolanes; Drug Delivery Systems; Drug Formulations; Goals; Hydroxy Acids; Hydroxyl Radical; Ice; Illinois; Kinetics; Lead; Life; Ligands; Mediating; Metals; Methodology; Methods; Modification; Molecular Weight; Motivation; N-glycylalanine; Nanoconjugate; Organic solvent product; Paclitaxel; Pharmaceutical Preparations; Poly-5; Polymers; Preparation; Property; Research; Resources; Scheme; Side; Solubility; Temperature; Tissue Engineering; Universities; arginyllysine; biocompatible polymer; catalyst; controlled release; design; formal glycol; functional group; guanidinium; improved; interest; lysylglutamic acid; monomer; nanoparticle; nanoparticulate; phenylalanylleucine; poly(lactide); polymerization; public health relevance

DESCRIPTION (provided by applicant): Poly(1-hydroxy acids) (PHAs) are a class of biodegradable and biocompatible polymers that have been widely used in drug delivery. Well-known examples of PHAs include poly(lactide), poly(glycolide) and poly(lactide-b-glycolide). They are readily available from inexpensive, renewable resources through ring- opening polymerizations of lactide, glycolide and a mixture of lactide and glycolide, respectively. One drawback of these conventional PHAs, however, is their lack of side-chain functionality, which makes it difficult for conjugation of enabling ligands to the PHAs or for fine-tuning of the physical and pharmacological properties of PHA-derived delivery vehicles through side-chain modifications. Syntheses of some extensively used PHAs, such as poly(lactide-b-glycolide), typically involve elevated temperature, which leads to PHAs with poorly controlled molecular weights (MWs) and broad molecular weight distributions (MWDs). In this application, we aim to develop method that will allow facile preparation of PHAs with controlled molecular weight and functionality will lead to useful biomaterials for drug delivery and tissue engineering. We then aim to develop paclitaxel-conjugated PHAs via drug-initiated polymerization for preparing PHA-paclitaxel nanoconjugate drug delivery vehicles. Compared to nanoencapsulates, conventional polymeric nanoparticles that have been widely used in cancer drug delivery, nanoconjugates have much higher drug loading and drug loading efficiency, and show controlled release profiles with significantly reduced drug burst release. By integrating PHA to the formulation of NCs, the PHA-paclitaxel nanoconjugates are expected to have substantially improved tunability of drug release kinetics and have functional groups that are critical for their application in cancer drug delivery. PUBLIC HEALTH RELEVANCE: Poly(1-hydroxy acids) (1-PHAs) are a class of biodegradable and biocompatible polymers that have been widely used in drug delivery. One drawback of the 1-PHAs is their lack of side-chain functional groups. Addressing this issue, we aim to develop methodology that allows facile, controlled synthesis of 1-PHAs bearing essentially any proteolytic side chains for drug delivery applications.

描述（由申请人提供）：聚（1-羟基酸）（PHA）是一类生物可降解和生物相容性聚合物，已广泛用于药物递送。众所周知的PHA的实例包括聚（丙交酯）、聚（乙交酯）和聚（丙交酯-b-乙交酯）。它们分别通过丙交酯、乙交酯以及丙交酯和乙交酯的混合物的开环聚合容易地从廉价的可再生资源获得。然而，这些常规PHA的一个缺点是它们缺乏侧链官能度，这使得难以将使能配体缀合至PHA或难以通过侧链修饰来微调PHA衍生的递送载体的物理和药理学性质。一些广泛使用的PHA（如聚（丙交酯-乙交酯））的合成通常涉及升高的温度，这导致PHA具有较差控制的分子量（MW）和宽的分子量分布（MWD）。在本申请中，我们的目标是开发方法，该方法将允许容易地制备具有受控分子量和功能的PHA，这将导致用于药物递送和组织工程的有用的生物材料。然后，我们的目标是开发紫杉醇共轭PHA通过药物引发聚合制备PHA-紫杉醇纳米共轭药物载体。与已广泛用于癌症药物递送的纳米胶囊、常规聚合物纳米颗粒相比，纳米缀合物具有高得多的药物负载和药物负载效率，并且显示出具有显著降低的药物突释的受控释放曲线。通过将PHA整合到NC的制剂中，预期PHA-紫杉醇纳米缀合物具有显著改善的药物释放动力学的可调谐性，并且具有对其在癌症药物递送中的应用至关重要的官能团。 公共卫生相关性：聚1-羟基酸（1-PHAs）是一类生物可降解、生物相容性好的高分子材料，广泛应用于药物载体。1-PHA的一个缺点是它们缺乏侧链官能团。针对这一问题，我们的目标是开发方法，允许简单，控制合成1-PHA轴承基本上任何蛋白水解侧链的药物输送应用。