Interfacially-stabilized polymeric nanosystems for drug delivery

用于药物输送的界面稳定聚合物纳米系统

• 批准号: 9510684
• 负责人: Marc A Ilies
• 金额: $ 7.93万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-15 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9510684
• 关键词: Advanced Development; Adverse effects; Affect; American; Anemia; Animal Model; Area; Biodistribution; Blood; Blood Circulation; Breast; Breast Cancer Model; Breast Cancer Treatment; Chemicals; Clinic; Clinical; Cytotoxic agent; Data; Drug Controls; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug Stability; Drug toxicity; Drug usage; Endothelial Cells; Engineering; Enzymes; Esters; Exanthema; Exposure to; Formulation; Generations; Goals; Hour; Human; Hydrolysis; Hydrophobicity; In Vitro; Knowledge; Korea; Lead; Length; Life; Location; Malignant Neoplasms; Maximum Tolerated Dose; Metastatic breast cancer; Micelles; Mission; Myalgia; Nature; Neuropathy; Non-Small-Cell Lung Carcinoma; Oxides; Paclitaxel; Patients; Pharmaceutical Preparations; Plasma; Polyethylene Glycols; Polymers; Property; Public Health; Research; Shapes; Site; Solvents; Structure; Surface; System; Testing; Therapeutic; Therapeutic Index; Time; Toxic effect; United States National Institutes of Health; Water; Work; amphiphilicity; base; biodegradable polymer; biomaterial compatibility; chemotherapy; copolymer; cost effectiveness; cremophor EL; di-block copolymer; disability; docetaxel; drug development; drug efficacy; esterase; human subject; hydrophilicity; improved; in vivo; innovation; interfacial; malignant breast neoplasm; nano; nanoparticle; nanosystems; novel; poly(lactic acid); polycaprolactone; premature; resilience; scale up; self assembly; tumor

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.

聚合物药物递送系统（DDS）可以改变化疗药物的药代动力学， 将它们的作用集中在肿瘤部位。对于由嵌段共聚物制成的DDS，这些特征直接 受嵌段共聚物中存在的两个界面的结构的影响：亲水-疏水界面， 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 在传统的PEG基两亲性二嵌段共聚物中，界面重合，这使得它们易于 两亲性酯酶的水解和过早降解，导致其 体内循环时间。我们的长期目标是提高货架稳定性、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DDS的载药量和药物释放曲线， 基于PEG的两亲性共聚物的界面工程。本建议的总体目标是 测试一组具有调谐界面的PEG-PBO-PCL嵌段共聚物的上述性质， 在PEG和PCL嵌段之间插入水解稳定的疏水PBO接头。我们的中央 假设是PBO块将两个界面分开，限制了水解酶进入界面。 DDS的可生物降解的疏水核，增强了载体的药物负载和释放特性， 提供了对血液/肿瘤中酯酶的选择性稳定性。基本原理是， 两个界面的分离影响这些DDS的主要特征， DDS具有预编程的稳定性、加载和释放参数。该项目的具体目标是： 具体目标1：通过水解稳定的疏水PBO评价界面工程的影响 不同长度的连接剂对聚合物的物理化学性质、保存期限和水解稳定性的影响 针对存在于血液和肿瘤中的酯酶的纳米颗粒（选择性稳定性） 各种尺寸的PEG-PBO-PCL三嵌段共聚物与作为对照的PEG-PCL二嵌段共聚物的比较 标准具体目标2：评估不可水解PBO的性质和长度的影响 疏水性连接体对化疗药物多西他赛负载和释放曲线、毒性和循环时间的影响 各种尺寸的工程化PEG-PBO-PCL三嵌段共聚物与PEG-PCL二嵌段相比， 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 因为分离两个界面将增加聚合物材料的弹性和其自身的弹性， 在全身递送后血液中的组装物，将改善DDS的循环时间和储存稳定性，并且将 有效地调节其药物负载和释放性质。这一贡献将是重大的，因为它可能 导致具有增强的循环时间和选择性体内稳定性的DDS的开发， 靶向，具有增强的储存稳定性和改善的药物装载/释放和毒性特征。