Development of Disease-Specific Drug Delivery Vehicles

疾病特异性给药载体的开发

• 批准号: 7650196
• 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 2011-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7650196
• 关键词: Achievement; Affinity; Amino Acid Sequence; Antibodies; Antigen Targeting; Antigens; Antineoplastic Agents; Binding; Cell Line; Cell surface; Characteristics; Classification; DNA; Detection; Development; Diagnostic; Disease; Dose; Drug Delivery Systems; Effectiveness; Encapsulated; Endocytosis; Ethylene Glycols; Evaluation; Evolution; Future; Goals; Human; Image; Immunohistochemistry; In Vitro; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Methodology; Methods; Modality; Modeling; Molecular Target; Normal tissue morphology; Nucleic Acids; PC3 cell line; Pathologic; Pattern; Pharmaceutical Preparations; Polymers; Prostate; Proteins; Research; Research Proposals; Screening procedure; Specificity; Surface Antigens; Surface of the Prostate; System; Techniques; Technology; Testing; Tissues; Tumor Antigens; antigen binding; aptamer; cancer cell; cancer diagnosis; controlled release; copolymer; cytotoxic; disease diagnosis; ethylene glycol; extracellular; human disease; in vivo; killings; mouse model; nanoparticle; novel; novel therapeutics; outcome forecast; poly(lactic acid); prognostic; protein purification; research study; therapeutic target; tool; tumor; Achievement; Affinity; Amino Acid Sequence; Antibodies; Antigen Targeting; Antigens; Antineoplastic Agents; Binding; Cell Line; Cell surface; Characteristics; Classification; DNA; Detection; Development; Diagnostic; Disease; Dose; Drug Delivery Systems; Effectiveness; Encapsulated; Endocytosis; Ethylene Glycols; Evaluation; Evolution; Future; Goals; Human; Image; Immunohistochemistry; In Vitro; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Methodology; Methods; Modality; Modeling; Molecular Target; Normal tissue morphology; Nucleic Acids; PC3 cell line; Pathologic; Pattern; Pharmaceutical Preparations; Polymers; Prostate; Proteins; Research; Research Proposals; Screening procedure; Specificity; Surface Antigens; Surface of the Prostate; System; Techniques; Technology; Testing; Tissues; Tumor Antigens; antigen binding; aptamer; cancer cell; cancer diagnosis; controlled release; copolymer; cytotoxic; disease diagnosis; ethylene glycol; extracellular; human disease; in vivo; killings; mouse model; nanoparticle; novel; novel therapeutics; outcome forecast; poly(lactic acid); prognostic; protein purification; research study; therapeutic target; tool; tumor

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K08建议的核心目的是开发一种使用核酸配体（Aptamers）作为护送分子的疾病特异性靶向释放聚合物系统的技术。受控释放聚合物系统的靶向是可取的，尤其是在治疗诸如癌症之类的疾病时，重要的是，在不杀死周围的非癌组织的情况下将细胞毒性剂量递送到癌细胞中。为了检查和证明我们方法的可行性，我们建议将前列腺癌（PCA）特异性适体分离出来，用于靶向药物封装的纳米颗粒受控释放的释放聚合物递送车辆，以靶向PCA。我们的研究具有4个具体目标：1）PCA特异性适体的隔离； 2）表征与每个适体结合的靶抗原； 3）开发PCA药物输送车辆，由PCA特异性适体组成，这些适体与受控释放的聚合物纳米颗粒相结合； 4）评估所得的PCA特异性输送车辆在体外和体内。我们将使用一种新颖的筛选方法来分离与PCA细胞表达的抗原结合的适体。我们方法的成功发展可能会导致分离出其他疾病的其他特异性适体，只要患病组织及其正常组织对应物之间的抗原表达差异。其次，作为我们策略的一部分的适体将用作使用配体介导的蛋白质纯化纯化其靶标的工具，这可能导致鉴定新型疾病特异性标记物。第三，在该提案的范围内，特异性适体将用作伴游分子，用于将药物输送到各自的患病组织中。但是，特定适体的效用远远超出了我们建议的应用。例如，特定于疾病的适体对于产生未来的诊断和预后方式很有价值。具有成像对比度的疾病特异性适体的结合物可用于检测疾病的焦点。疾病特异性的适体也可用于以类似于确定疾病诊断和预后的抗体方式对病理组织的组织学评估。因此，用于针对靶向治疗和诊断应用的孤立疾病特异性适体具有广泛的意义，并可能影响无数重要的人类疾病。