Dendritic Diblock Copolymer Micelles as New Targeted Drug Delivery Systems

描述(由申请人提供)：这项工作的主要目标是形成和检查定制的靶向纳米颗粒，包括树枝状外部，可以调整到包含广泛的配体密度和簇大小分布，以及用于癌症药物存储的宽敞的疏水内部区域。提出了通过在溶液中形成可作为两亲分子的线状-树枝状嵌段共聚物，通过形成含有树枝状物种N链聚集体的胶束来构建比传统树枝状大分子更大的纳米结构，同时更有效地利用了树枝状大分子体系的高功能密度。不同配基密度的混合胶束将被用来创造独特的纳米颗粒，具有不同的表面配基簇大小和密度，并安排与目标细胞受体进行最佳结合。通过交联线-树枝状两嵌段共聚物形成的胶束的内部，将有可能产生稳定的纳米粒子，其外表面具有基于聚集数和树枝状生成的异常密集的功能，以及可设计用于进行生物降解的大的、孤立的胶束内部区域，从而促进包裹后的药物释放。这些系统将具有比树枝状均聚物更大的容量，但将比典型的脂质体和微粒更小，从而使外渗和药物渗透更容易。在这些研究中，将被用于研究靶向药物传递中的配体簇效应的三个选定配体将包括叶酸和半乳糖，叶酸可以通过叶酸受体作为该系统的初步评估而被用于靶向卵巢癌细胞，半乳糖是一种具有良好特性的糖，它与ASGPR蛋白受体结合，已知对簇配体呈现高度敏感，并存在于肝细胞上。最后，作为一种直接适用的治疗系统的方法，针对肿瘤内皮细胞的RGD肽序列将被用作一种手段，通过α-v-β3整合素受体将细胞毒药物导向肿瘤的血管系统，从而通过抗血管生成途径促进肿瘤坏死。

DESCRIPTION (provided by applicant): The primary objective of this work is the formation and examination of tailored targeted nanoparticles consisting of a dendritic exterior that can be tuned to contain a broad distribution of ligand density and cluster size, and a spacious hydrophobic interior region for cancer drug storage. It is proposed that by creating linear-dendritic block copolymers which can act as amphiphiles in solution, much larger nanostructures than traditional dendrimers can be constructed through the formation of micelles containing N chain aggregates of dendritic species, while the high functional density of the dendrimer system is utilized more efficiently. Mixed micelles of varying ligand density will be used to create unique nanoparticles with variable surface ligand cluster size and density, arranged for optimal binding with the target cell receptor. By crosslinking the interior portion of micelles formed from linear-dendritic diblock copolymers, it will be possible to create stable nanoparticles with exterior surfaces that have unusually dense functionality based on the aggregation number and dendron generation, and large, isolated micelle interior regions which can be designed to undergo biodegradation, thus facilitating drug release following encapsulation. These systems will have larger capacities than dendritic homopolymers, but will be smaller than typical liposomes and microparticles, thus making extravasation and drug permeation more facile. In these studies, the three chosen ligands that will be used to investigate ligand-cluster effects in targeted drug delivery will include folate, which can be used to target cancer tumor cells in the ovary via the folate receptor as an initial evaluation of this system, and galactose, a well characterized saccharide which undergoes binding with the ASGPR protein receptor, known to exhibit high sensitivity to cluster ligand presentation and present on hepatocytes. Finally, as an approach to a directly applicable therapeutic system, the RGD peptide sequences which specifically target the endothelial cells of tumors will be used as a means of directing cytotoxic drugs to the vascular system of the tumor via the alpha-v-beta3 integrin receptor, and thus promoting tumor necrosis via anti-angiogenic approaches.