Development of Disease-Specific Drug Delivery Vehicles

疾病特异性给药载体的开发

• 批准号: 7020645
• 负责人: OMID C FAROKHZAD
• 金额: $ 19.29万
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7020645
• 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）： K08 提案的中心目标是开发一种使用核酸配体（适体）作为护航分子的控释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理想的，尤其是在治疗癌症等病症时，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是很重要的。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，用于将药物封装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) 与每个适体结合的靶抗原的表征； 3) 开发由与控释聚合物纳米颗粒缀合的 PCa 特异性适体组成的 PCa 药物递送载体； 4) 对由此产生的 PCa 特异性运载工具进行体外和体内评估。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。只要患病组织与其正常组织对应物之间的抗原表达存在差异，我们方法的成功开发就可以分离出几乎任何疾病的其他疾病特异性适体。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，这可能导致新的疾病特异性标记物的鉴定。第三，在该提案的范围内，疾病特异性适体将作为护送分子，将药物递送至各自的患病组织。然而，疾病特异性适体的用途可以远远超出我们提出的应用范围。例如，疾病特异性适体对于生成未来的诊断和预后模式非常有价值。疾病特异性适体与成像对比的缀合物可用于检测疾病病灶。疾病特异性适体还可以以与确定疾病诊断和预后的抗体类似的方式用于病理组织的组织学评估。因此，分离疾病特异性适体用于靶向治疗和诊断应用具有广泛的意义，并可能影响多种重要的人类疾病。