Vault Polymer Conjugates as Multi-Functional Nano Delivery Agents of Cancer Drugs

描述(申请人提供)：许多抗癌药物在水溶液中的溶解度低，缺乏组织特异性。这就需要使用载体制剂来增加可用性和减少副作用。纳米治疗性递送剂是一个理想的选择，因为它们表现出增强的血液循环时间，并优先在肿瘤中蓄积。这项研究的一个目标是开发一种高容量的疏水药物载体，方法是将合成的聚合物链连接到自然产生的纳米胶囊的内部，称为拱顶。第二个目标是开发一种拱形聚合物结合物，展示针对乳腺癌细胞表面受体的抗体，以增强对该细胞的靶向性。为实现这些目标，提出了两个具体目标。第一个目标是确定药物从内部用疏水聚合物修饰的蛋白质库中的载药量和释放情况。据推测，在内部用疏水聚合物改装的拱顶将包含疏水药物。为了实现这一点，将通过从拱顶内部的起始点聚合来合成疏水聚合物-拱顶连接物。药物的掺入和释放动力学将被量化。第二个目的是研究乳腺癌细胞培养中肿瘤药物载药库的细胞结合、摄取和体外细胞毒作用。据推测，在外部用靶向配体修饰的拱形聚合物药物负载结合物将降低乳腺癌细胞的活力。为了研究这一点，表面修饰了受体靶向配体的拱顶-聚合物药物负载结合物将与乳腺癌细胞培养，并将对细胞活力的抑制进行量化。结果将与空金库的结果和目前可用的配方技术进行比较。这项研究的一个潜在结果是开发了一种新的纳米胶囊，用于输送疏水性癌症药物。具体地说，将调查一种重要的治疗药物紫杉醇对乳腺癌细胞的输送情况。因此，这项工作有望与乳腺癌的治疗直接相关。这项研究的长期目标是创建一种通用的模块化纳米胶囊，以提供治疗各种疾病的疏水药物。 公共卫生相关性：隔离疏水药物并将疏水药物输送到靶细胞的拱顶聚合物纳米胶囊可能导致多功能治疗递送剂用于治疗癌症。

DESCRIPTION (provided by applicant): Many cancer drugs exhibit low solubility in aqueous solution and lack tissue specificity. This necessitates the use of carrier formulations to increase availability and reduce side effects. Nanometer-sized therapeutic delivery agents are an ideal choice because they exhibit enhanced blood circulation times and accumulate preferentially in tumors. One objective of this research is to develop a high capacity hydrophobic drug carrier by attaching synthetic polymer chains to the interior of a naturally occurring nanocapsule called a vault. A second objective is to develop a vault-polymer conjugate displaying an antibody to a breast cancer cell surface receptor to enhance targeting to the cell. Two specific aims are proposed to reach these objectives. The first aim is to determine drug loading and release from protein vaults modified in the interior with hydrophobic polymers. It is hypothesized that vaults modified at the interior with hydrophobic polymers will incorporate hydrophobic drugs. To accomplish this, hydrophobic polymer-vault conjugates will be synthesized by polymerizing from initiation sites on the interior of the vaults. Drug incorporation and release kinetics will be quantified. The second aim is to investigate cellular binding, uptake and in vitro cytotoxic effect of cancer drug-loaded vaults in breast cancer cell culture. It is hypothesized that vault- polymer drug loaded conjugates modified at the exterior with targeting ligands will reduce breast cancer cell viability. To investigate this, vault-polymer drug loaded conjugates modified on the exterior with receptor targeting ligands will be incubated in culture with breast cancer cells and inhibition of cell viability will be quantified. Results will be compared to that of empty vaults and to currently available formulation technology. One potential outcome of this research is the development of a new nanocapsule for delivery of hydrophobic cancer drugs. Specifically, delivery of an important therapeutic, paclitaxel, to breast cancer cells will be investigated. Thus, this work is expected to be directly relevant to breast cancer therapy. The long term goal of this research is to create a general modular nanocapsule to deliver hydrophobic drugs to treat a variety of diseases. PUBLIC HEALTH RELEVANCE: Vault-polymer nanocapsules that sequester and deliver hydrophobic drugs to targeted cells can lead to multifunctional therapeutic delivery agents to treat cancer.