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

描述（由申请人提供）：许多癌症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并减少副作用。纳米尺寸的治疗递送剂是理想的选择，因为它们表现出增强的血液循环时间并且优先在肿瘤中积累。本研究的一个目的是通过将合成聚合物链连接到称为拱顶的天然存在的纳米胶囊的内部来开发高容量疏水性药物载体。第二个目的是开发展示针对乳腺癌细胞表面受体的抗体以增强对细胞的靶向的拱顶-聚合物缀合物。为实现这些目标，提出了两个具体目标。第一个目的是确定药物装载和释放从蛋白质拱顶修改的内部与疏水性聚合物。假设在内部用疏水聚合物修饰的拱顶将掺入疏水药物。为了实现这一点，疏水聚合物-拱顶缀合物将通过从拱顶内部上的起始位点聚合来合成。将定量药物掺入和释放动力学。第二个目的是研究载药穹窿在乳腺癌细胞培养中的细胞结合、摄取和体外细胞毒作用。假设在外部用靶向配体修饰的穹窿-聚合物载药缀合物将降低乳腺癌细胞活力。为了研究这一点，将在外部用受体靶向配体修饰的拱顶聚合物载药缀合物与乳腺癌细胞一起在培养物中孵育，并定量细胞活力的抑制。结果将与空拱顶和目前可用的配方技术进行比较。这项研究的一个潜在成果是开发一种新的纳米胶囊，用于递送疏水性癌症药物。具体而言，将研究向乳腺癌细胞递送重要的治疗剂紫杉醇。因此，这项工作预计将与乳腺癌治疗直接相关。这项研究的长期目标是创造一种通用的模块化纳米胶囊，以提供疏水药物来治疗各种疾病。 公共卫生相关性：拱顶聚合物纳米胶囊，螯合和提供疏水性药物靶向细胞，可以导致多功能的治疗递送剂治疗癌症。

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.