Nanoparticulate drug delivery systems: synthesis and characterization of amphiphilic diblock copolymers

两亲分子，如二嵌段共聚物，是具有亲水性和疏水性嵌段的大分子。另一种大分子，称为树突状大分子，是高度分支的大分子，具有明确的大小，能够结合药物分子。这些聚合物都形成纳米级的球形颗粒：自缔合胶束（大分子聚集体）、囊泡（由共聚物分子和内部水核组成的外膜）、树状大分子（单分子胶束）和纳米球（固体核心颗粒）。这些所谓的纳米输送系统都可以装载疏水药物，如紫杉醇，有些还可以装载亲水药物，如顺铂。很少有研究探讨聚合物的性质、形成的纳米颗粒类型与纳米递送系统的性能特征之间的关系，如稳定性、药物释放、与血液成分的相互作用、与粘膜组织表面的相互作用和药代动力学。本研究的目的是比较载药聚合物纳米球、囊泡、胶束和树突状制剂在静脉给药和直接局部滴注膀胱治疗膀胱癌后的递送特性、血液/组织相互作用和肿瘤靶向性。纳米递送系统的表面修饰使其具有黏附性，应将纳米颗粒靶向膀胱肿瘤。研究目标是：1)研究聚合物的结构特征对载药纳米递送系统性能的影响；2)确定影响未经处理和表面修饰纳米递送系统与血液成分和膀胱组织相互作用的因素；3)在动物模型中评估经静脉或膀胱给药的选定配方的循环寿命、全身摄取、药代动力学和功效。

Amphiphilic molecules, such as diblock copolymers, are macromolecules with hydrophilic and hydrophobic blocks. Other macromolecules, called dendrimers, are highly branched macromolecules will a well-defined size, capable of binding drug molecules. These polymers all form nanometre size range, spherical particles: self-associating micelles (macromolecular aggregates), vesicles (an outer membrane composed of copolymer molecules and an inner aqueous core), dendrimers (unimolecular micelles) and nanospheres (solid core particles). These so-called nano-delivery systems can all be loaded with hydrophobic drugs, such as paclitaxel, and some will accommodate hydrophilic drugs, such as cisplatin. Few studies have explored the relationship between the properties of the polymer, the type of nanoparticles formed and the performance characteristics of the nano-delivery system, such as stability, drug release, interaction with blood components, interaction with mucosal tissue surfaces and pharmacokinetics. The goal of the proposed research is to compare the delivery characteristics, blood/tissue interactions and tumor targeting of drug loaded polymeric nanosphere, vesicle, micellar and dendritic formulations following both intravenous administration, and local instillation directly into the bladder for application in the treatment of bladder cancer. Surface modification of nano-delivery systems to confer mucoadhesiveness should target the nanoparticles to bladder tumors. The research objectives are: 1) to investigate the influence of structural features of the polymers on properties and performance characteristics of the drug loaded nano-delivery systems, 2) to determine the factors influencing the interactions of untreated and surface modified nano-delivery systems with blood components and bladder tissue, 3) to evaluate the circulation lifetime, systemic uptake, pharmacokinetics and efficacy of selected formulations administered via IV or into the bladders in animal models.