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，这些纳米颗粒由树突状外部组成，可以调整为包含广泛分布的配体密度和簇大小，以及用于癌症药物储存的宽敞疏水内部区域。本文提出，通过构建具有两亲性的线性枝状嵌段共聚物，通过形成含有N链枝状物质聚集体的胶束，可以构建比传统枝状大分子大得多的纳米结构，同时更有效地利用枝状大分子体系的高功能密度。不同配体密度的混合胶束将用于制造具有不同表面配体簇大小和密度的独特纳米颗粒，以最佳方式与靶细胞受体结合。通过交联由线性树突二嵌段共聚物形成的胶束的内部部分，将有可能创建稳定的纳米颗粒，其外表面具有基于聚集数和树突生成的异常密集的功能，以及可以设计用于进行生物降解的大的，孤立的胶束内部区域，从而促进药物在封装后的释放。这些系统将比树突均聚物具有更大的容量，但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，三种选择的配体将用于研究靶向药物递送中的配体-簇效应，包括叶酸，它可以通过叶酸受体用于靶向卵巢中的癌症肿瘤细胞，作为该系统的初步评估；半乳糖，一种特性良好的糖，可以与ASGPR蛋白受体结合，已知对簇配体呈现和肝细胞表现出高度敏感性。最后，作为一种直接适用的治疗系统，特异性靶向肿瘤内皮细胞的RGD肽序列将作为一种手段，通过α -v- β 3整合素受体将细胞毒性药物引导到肿瘤血管系统，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.