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， 将他们的行动集中在肿瘤部位。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结构的影响：亲水-疏水 界面以及化学稳定和可生物降解的聚合物嵌段之间的界面。两人 传统的基于 PEG 的两亲性二嵌段共聚物中的界面重合，这使得它们容易受到影响 两亲性酯酶的水解和过早降解，导致其活性急剧下降 体内循环时间。我们的长期目标是增强货架稳定性、体内动态选择性稳定性 和循环时间、药物保护以及控制聚合物 DDS 的药物负载和药物释放曲线 基于 PEG 的两亲性共聚物的界面工程。该提案的总体目标是 通过调整界面测试一组 PEG-PBO-PCL 嵌段共聚物的上述性能 在 PEG 和 PCL 嵌段之间插入水解稳定的疏水性 PBO 连接体。我们的中央 假设是 PBO 块分隔了两个界面，限制了水解酶进入 DDS 的可生物降解疏水核心，增强载体的载药量和释放曲线 提供针对血液/肿瘤中酯酶的选择性稳定性。基本原理是关于如何 两个界面的分离影响了这些 DDS 的主要特征，将允许生成聚合物 具有预编程稳定性、加载和释放参数的 DDS。该项目的具体目标是： 具体目标 1：通过水解稳定的疏水性 PBO 评估界面工程的影响 不同长度的连接体对聚合物的理化性质、保质期和水解稳定性的影响 纳米颗粒针对血液和肿瘤中存在的酯酶（选择性稳定性），由工程化产生 不同尺寸的 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 疏水连接体对化疗药物多西紫杉醇负载和释放曲线、毒性和循环时间的影响 与 PEG-PCL 二嵌段相比，不同尺寸的工程 PEG-PBO-PCL 三嵌段共聚物的性能 使用乳腺癌动物模型进行体外和体内研究。我们认为所提出的研究具有创新性 因为分离两个界面会增加聚合物材料的弹性及其自粘性 全身输送后血液中的组装将改善 DDS 的循环时间和储存稳定性，并将 有效调节其药物负载和释放特性。这一贡献将是巨大的，因为它可能 导致 DDS 的发展，具有更长的循环时间和选择性的体内稳定性，适用于 靶向性，具有增强的货架稳定性和改善的药物负载/释放和毒性特征。