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

描述(申请人提供)：聚(1-羟基酸)(PHAs)是一类生物可降解和生物相容的聚合物，已广泛用于药物输送。众所周知的PHA包括聚丙交酯、聚乙交酯和聚丙交酯-b-乙交酯。通过丙交酯、乙交酯以及丙交酯和乙交酯混合物的开环聚合，它们很容易从廉价的可再生资源中获得。然而，这些传统的PHA的一个缺点是它们缺乏侧链功能，这使得使能配体与PHA的偶联或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变得困难。一些广泛使用的PHA的合成，如聚丙交酯-乙交酯，通常需要升温，这导致PHA的相对分子质量(MWs)控制较差，且分子量分布(MWD)较宽。在这项应用中，我们的目标是开发一种方法，使其能够方便地制备具有可控分子量和功能的PHA，从而产生用于药物输送和组织工程的有用的生物材料。然后，我们的目标是通过药物引发聚合开发紫杉醇偶联PHAs，以制备PHA-紫杉醇纳米偶联药物载体。与纳米微囊相比，纳米结合物具有更高的载药量和载药效率，并且具有控释特性，显著降低了药物的突释。通过将PHA整合到NCS的配方中，PHA-紫杉醇纳米结合物有望显著改善药物释放动力学的可调性，并具有对其在抗癌药物输送中应用至关重要的官能团。 公共卫生相关性：聚(1-羟基酸)(1-PHAs)是一类生物可降解和生物相容的聚合物，已广泛用于药物输送。1-PHA的一个缺点是它们缺乏侧链官能团。为了解决这个问题，我们的目标是开发一种方法学，允许简单、可控地合成基本上具有任何蛋白水解性侧链的1-PHAs，用于药物输送应用。

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.