Dendritic Diblock Copolymer Micelles as New Targeted Drug Delivery Systems

描述（由申请人提供）：这项工作的主要目的是形成和检查定制的靶向纳米颗粒，其由树枝状外部和宽敞的疏水内部区域组成，所述树枝状外部可以被调节以包含配体密度和簇大小的广泛分布，所述内部区域用于癌症药物储存。有人提出，通过创建线性树枝状嵌段共聚物，可以作为两亲物在溶液中，更大的纳米结构比传统的树枝状聚合物可以通过形成胶束含有N链聚集体的树枝状物种，而高功能密度的树枝状聚合物系统被更有效地利用。不同配体密度的混合胶束将用于产生具有可变表面配体簇大小和密度的独特纳米颗粒，其被布置用于与靶细胞受体的最佳结合。通过交联由线性-树枝状二嵌段共聚物形成的胶束的内部部分，将有可能产生具有外表面的稳定纳米颗粒，所述外表面具有基于聚集数和树枝化基元生成的异常致密的官能度，以及可以被设计为进行生物降解的大的隔离胶束内部区域，从而促进包封后的药物释放。这些系统将具有比树枝状均聚物更大的容量，但将小于典型的脂质体和微粒，从而使外渗和药物渗透更容易。在这些研究中，将用于研究靶向药物递送中的配体簇效应的三种所选配体将包括叶酸和半乳糖，叶酸可用于通过叶酸受体靶向卵巢中的癌症肿瘤细胞作为该系统的初始评估，半乳糖是一种充分表征的糖，其与ASGPR蛋白受体结合，已知对簇配体呈递表现出高敏感性并存在于肝细胞上。最后，作为直接应用的治疗系统的方法，特异性靶向肿瘤内皮细胞的RGD肽序列将用作通过α-v-β 3整联蛋白受体将细胞毒性药物导向肿瘤血管系统的手段，从而通过抗血管生成方法促进肿瘤坏死。

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.