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

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，已广泛用于药物输送。众所周知的pha包括聚（丙交酯），聚（乙醇酸）和聚（丙交酯-b-乙醇酸）。它们很容易从廉价的可再生资源中获得，分别通过丙交酯、乙二醇酯和丙交酯和乙二醇酯的混合物的开环聚合。然而，这些传统pha的一个缺点是它们缺乏侧链功能，这使得使配体与pha偶联或通过侧链修饰对pha衍生的递送载体的物理和药理学性质进行微调变得困难。一些广泛使用的相芳烃的合成，如聚丙交酯-b-羟基乙酸酯，通常需要升高温度，这导致相芳烃的分子量（MWs）控制不佳，分子量分布（MWDs）较宽。在这个应用中，我们的目标是开发一种方法，可以轻松制备具有控制分子量和功能的pha，从而为药物输送和组织工程提供有用的生物材料。然后，我们的目标是通过药物引发聚合制备pha -紫杉醇纳米缀合药物递送载体来制备紫杉醇偶联pha。与广泛应用于癌症药物递送的传统聚合物纳米胶囊相比，纳米缀合物具有更高的载药量和载药效率，并且具有明显减少药物爆发释放的控释特性。通过将PHA整合到nc的配方中，PHA-紫杉醇纳米偶联物有望大大改善药物释放动力学的可调性，并具有对其在癌症药物递送中的应用至关重要的官能团。

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.