Interfacially-stabilized polymeric nanosystems for drug delivery

聚合物给药系统(DDSS)可以改变化疗药物的药代动力学， 将他们的行动集中在肿瘤部位。对于由嵌段共聚物制成的DDSS，这些特征直接 受嵌段共聚物中两种界面结构的影响：亲水-疏水 界面以及化学稳定的和可生物降解的聚合物嵌段之间的界面。两个人 在传统的聚乙二醇基两亲嵌段共聚物中，界面重合，这使得它们很容易受到影响 由于两亲性酯酶的水解和过早降解，导致它们的 体内循环时间。我们的长期目标是增强货架稳定性，体内动态选择稳定性 和循环时间、药物保护以及控制聚合物DDSS的载药量和药物释放曲线 聚乙二醇基两亲共聚物的界面工程。这项提议的总体目标是 通过实验测试了一组界面可调的聚乙二醇-聚对苯二甲酸丁二醇酯嵌段共聚物的上述性能 在PEG和PCL嵌段之间插入稳定的水解性疏水PBO连接物。我们的中央 假设PBO区块分隔两个界面，限制水解酶对 DDS的可生物降解的疏水核心，增强了载体的药物加载和释放特性，并 对血液/肿瘤中的酯酶提供选择性稳定性。其基本原理是关于如何 这两个界面的分离影响了这些DDSS的主要特征，将允许产生聚合物 具有预编程稳定性、加载和释放参数的DDSS。该项目的具体目标是： 具体目标1：评估通过稳定的水解性疏水PBO进行界面工程的影响 不同长度的连接剂对聚合物的物化性能、保质期和水解性的影响 抗酯酶纳米粒存在于血液和肿瘤中(选择性稳定性) 不同尺寸的PEG-PBO-PCL三嵌段共聚物与PEG二嵌段对照的比较 标准。具体目标2：评估非水解性PBO的性质和长度的影响 疏水连接物对化疗药物多西他赛载药量和释放量、毒性及循环时间的影响 不同尺寸的工程聚乙二醇-聚氧化铅-聚氯乙烯三嵌段共聚物与聚乙二醇-聚氯乙烯两嵌段的比较，在 在体外和体内，使用乳腺癌的动物模型。在我们看来，拟议的研究是创新的 因为分离两个界面会增加聚合物材料及其自身的弹性。 全身给药后血液中的集合体，将改善DDS的循环时间和货架稳定性，并将 有效调节其载药和释药特性。这一贡献将是重大的，因为它可能 导致DDSS的开发具有增强的循环时间和选择性的体内稳定性，适用于 靶向性，提高了货架稳定性，改善了药物装载/释放和毒性曲线。

Polymeric drug delivery systems (DDSs) can change the pharmacokinetics of chemotherapeutic drugs, focusing their action on the tumor site. For DDSs made out of block copolymers these features are directly influenced by the structure of the two interfaces present in the block copolymers: the hydrophilic-hydrophobic interface and the interface between the chemically stable and the biodegradable polymeric blocks. The two interfaces coincide in conventional PEG-based amphiphilic diblock copolymers, which make them susceptible to hydrolysis and premature degradation by amphiphilic esterases, resulting in a dramatic decrease of their circulation time in vivo. Our long-term goal is to enhance the shelf stability, in vivo dynamic selective stability and circulation time, drug protection and to control drug loading and drug release profile of polymeric DDSs via interfacial engineering of the PEG-based amphiphilic copolymers. The overall objective of this proposal is to test the above-mentioned properties of a set of PEG-PBO-PCL block copolymers with tuned interfaces via insertion of a hydrolytically stable hydrophobic PBO linker in between the PEG and PCL blocks. Our central hypothesis is that the PBO block separates the two interfaces, limits access of hydrolytic enzymes to the biodegradable hydrophobic core of the DDS, enhances drug loading and release profiles of the carrier and provides selective stability against esterases in blood/tumor. The rationale is that knowledge on how separation of the two interfaces affects the main features of these DDSs will allow generation of polymeric DDSs with pre-programmed stability, loading and release parameters. The specific aims of this project are: Specific Aim 1: To evaluate the impact of interfacial engineering via a hydrolytically stable hydrophobic PBO linker of various lengths on the physicochemical properties, shelf life and hydrolytic stability of polymeric nanoparticles against esterases present in blood and in tumors (selective stability) generated from engineered PEG-PBO-PCL triblock copolymers of various sizes in comparison with PEG-PCL diblocks as control standards. Specific Aim 2: To assess the impact of the nature and length of non-hydrolyzable PBO hydrophobic linker on chemotherapeutic drug docetaxel loading and release profile, toxicity and circulation time of engineered PEG-PBO-PCL triblock copolymers of various sizes in comparison with PEG-PCL diblocks, in vitro and in vivo, using animal models of breast cancer. In our opinion the proposed research is innovative because separating the two interfaces will increase the resilience of the polymeric material and its self- assemblies in blood following systemic delivery, will improve circulation time and shelf stability of DDS, and will efficiently modulate its drug loading and release properties. This contribution will be significant because it may lead to the development of DDSs with enhanced circulation time and selective in vivo stability, suitable for targeting, with enhanced shelf stability and improved drug loading/release and toxicity profiles.