Development of Disease-Specific Drug Delivery Vehicles

疾病特异性给药载体的开发

• 批准号: 6867511
• 负责人: OMID C FAROKHZAD
• 金额: $ 19.26万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6867511
• 关键词: athymic mouse; bioengineering /biomedical engineering; copolymer; drug delivery systems; human tissue; immunoconjugates; immunocytochemistry; immunofluorescence technique; lactates; nanotechnology; oligonucleotides; prostate neoplasms; slow release drug; technology /technique development; tumor antigens; xenotransplantation

DESCRIPTION (provided by candidate): The central aim of this K08 proposal is to develop a technology for disease-specific targeting of controlled release polymer systems using nucleic acid ligands (aptamers) as escort molecules. The targeting of controlled-release polymer systems is desirable especially when treating a condition such as cancer where it is important that a cytotoxic dose of the drug is delivered to cancer cells without killing the surrounding noncancerous tissue. To examine and demonstrate the feasibility of our approach, we propose to isolate Prostate Cancer (PCa)-specific aptamers for targeting of drug encapsulated nanoparticle-aptamer controlled release polymer delivery vehicles to PCa. Our research has 4 specific aims: 1) isolation of PCa-specific aptamers; 2) characterization of the target antigen that binds to each aptamer; 3) development of PCa drug delivery vehicles comprised of PCa-specific aptamers conjugated to controlled release polymer nanoparticles; and 4) evaluation of the resulting PCa-specific delivery vehicles in-vitro and in-vivo. We will use a novel screening method to isolate aptamers that bind to antigens expressed on PCa cells. The successful development of our methodology could result in isolating other disease-specific aptamers for virtually any disease as long as there is a differential expression of antigens between the diseased tissue and its normal tissue counterpart. Second, aptamers isolated as part of our strategy would be used as tools to purify their targets using ligand mediated protein purification which could result in the identification of novel disease-specific markers. Third, within the scope of this proposal, disease-specific aptamers would serve as escort molecules for delivering drugs to their respective diseased tissue. However, the utility of disease specific aptamers can extend far beyond our proposed application. For example, disease-specific aptamers will be valuable for generating future diagnostic and prognostic modalities. A conjugate of a disease-specific aptamers with an imaging contrast may be used for detection of a disease focus. Disease-specific aptamers could also be used for histological evaluation of pathologic tissue in a similar manner as antibodies for determining disease diagnosis and prognosis. Therefore, isolating disease-specific aptamers for use in targeted therapeutic and diagnostic applications has broad significance and may impact a myriad of important human diseases.

描述（由候选人提供）： 该K 08提案的中心目标是开发一种使用核酸配体（适体）作为护送分子的控制释放聚合物系统的疾病特异性靶向技术。控释聚合物系统的靶向是期望的，尤其是当治疗诸如癌症的病症时，其中重要的是将细胞毒性剂量的药物递送至癌细胞而不杀死周围的非癌组织。为了检查和证明我们的方法的可行性，我们建议分离前列腺癌（PCa）特异性适体，用于将药物包封的纳米颗粒-适体控释聚合物递送载体靶向PCa。我们的研究有4个具体目标：1）分离PCa特异性适体; 2）表征与每个适体结合的靶抗原; 3）开发由PCa特异性适体与控释聚合物纳米颗粒缀合组成的PCa药物递送载体;以及4）在体外和体内评价所得的PCa特异性递送载体。我们将使用一种新的筛选方法来分离与PCa细胞上表达的抗原结合的适体。我们的方法的成功开发可以导致分离几乎任何疾病的其他疾病特异性适体，只要在患病组织和其正常组织对应物之间存在抗原的差异表达。其次，作为我们策略的一部分分离的适体将用作使用配体介导的蛋白质纯化来纯化其靶标的工具，这可能导致鉴定新的疾病特异性标记。第三，在这个提议的范围内，疾病特异性适体将作为护送分子，将药物输送到各自的病变组织。然而，疾病特异性适体的效用可以远远超出我们提出的应用。例如，疾病特异性适体对于产生未来的诊断和预后模式将是有价值的。疾病特异性适体与成像造影剂的缀合物可用于检测疾病病灶。疾病特异性适体也可用于病理组织的组织学评价，其方式与用于确定疾病诊断和预后的抗体类似。因此，分离用于靶向治疗和诊断应用的疾病特异性适体具有广泛的意义，并且可以影响无数重要的人类疾病。