Chemical tailoring of micelle-forming poly(ethylen oxide)-block-poly(ester) copolymers for drug delivery

本研究的主要目的是设计和开发一种新型的合成生物材料，使其能够充分溶解治疗药物，并以适当的速度和位置释放药物，同时又能安全用于人体。这些化合物有望模仿生物运输系统的功能：在体内被识别为自我，携带足够数量的药物到其作用部位，在其细胞和分子靶点附近释放其治疗货物，然后降解为生物相容的成分。在这种情况下，合成生物材料可能有利于其生物对应物，因为易于结构修饰，稳定性和安全性给药。在本项目的第一部分，我们开发了一种新型的自缔合嵌段共聚物，由聚（环氧乙烷）-聚（酯）组成，聚（酯）嵌段上有羧基或芳基。所开发的嵌段共聚物由于聚（环氧乙烷）具有生物相容性，由于聚（酯）具有生物可降解性，由于聚合物的两亲性可以自结合成纳米级胶束结构，并且由于聚（酯）上不同侧基的存在，可以与胶束核心内的疏水或亲水分子进行化学偶联和/或物理相互作用。这些生物材料在结构和功能上接近于血液中的天然药物载体，即脂蛋白，但具有化学柔韧性的优势。在该项目的第二部分，我们将继续开发用于递送基于核酸的治疗方法的人工病毒。高分子纳米载体的发展，可以结合DNA和RNA结构的静电或疏水相互作用，并将其传递到适当的细胞内目标将继续追求。所提出的结构将基于生物相容性和可生物降解的聚（环氧乙烷）-聚（酯）嵌段共聚物，聚（环氧乙烷）外壳上有靶向配体，聚（酯）核心上有疏水性和阳离子基团。

Design and development of novel synthetic biomaterials that adequately solubilize therapeutic agents, release them in an appropriate rate and location, and at the same time, are safe for application in humans is the main purpose of this research. Such compounds are expected to mimic the function of biological transport systems: be recognized as self within the body, carry adequate quantities of the drug to its site of action, release their therapeutic cargo in the vicinity of their cellular and molecular targets and degrade to biocompatible components afterwards. In this context, synthetic biomaterials may be advantageous to their biological counterparts due to the ease of structural modifications, stability and safety of administration. In the first part of this project, we have developed novel self associating block copolymers consisting of poly(ethylene oxide)-poly(ester)s bearing pendent carboxyl or aromatic groups on the poly(ester) block. The developed block copolymers are bio-compatible due to the poly(ethylene oxide), biodegradable due to poly(ester), can self associate to nanoscopic micellar structures due to the amphiphilic nature of the polymer, and allow chemical conjugation and/or physical interaction with hydrophobic or hydrophilic molecules within the micellar core due to the presence of different side groups on the poly(ester). These biomaterials structurally and functionally are close to natural drug carriers in blood, i.e., lipoprotein, but have the advantage of chemical flexibility. In the second part of the project, we will pursue development of artificial viruses for the delivery of nuclearic acid based therapeutics. Development of polymeric nano-carriers that can incorporate DNA and RNA structures by electrostatic or hydrophobic interactions and deliver them to appropriate intracellular targets will be pursued. The proposed structures will be based on biocompatible and biodegradable poly(ethylene oxide)-poly(ester) block copolymers bearing targeting ligands on the poly(ethylene oxide) shell and hydrophobic and cationic groups in the poly(ester) core.