Drugcarts to Combat Drug Resistance

对抗耐药性的药车

• 批准号: 7479763
• 负责人: Marit Nilsen-Hamilton
• 金额: $ 15.77万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7479763
• 关键词: Affinity; Antibodies; Base Sequence; Binding; Biochemistry; Bystander Effect; Cell Death; Cell membrane; Cell surface; Cells; Cellular biology; Cleaved cell; Development; Drug Delivery Systems; Drug resistance; Gleevec; Glutamate Carboxypeptidase II; Goals; Imatinib mesylate; Inflammatory Response; Link; Malignant neoplasm of prostate; Molecular Biology; Nucleic acid sequencing; PD 173955; Peptides; Permeability; Pharmaceutical Preparations; Predisposition; Prodrugs; Prostate Cancer therapy; Prostate-Specific Antigen; RNA; RNA Binding; Range; Reagent; Research; Scientist; Serine Protease; Specificity; Staging; Surface; Synthesis Chemistry; Testing; Tissues; Toxic effect; Work; analog; aptamer; base; bone; cancer cell; cancer therapy; cell injury; cell killing; concept; design; experience; killings; nanoparticle; receptor; uptake

DESCRIPTION (provided by applicant): The current proposal focuses on the development of an aptamer-based reagent for prostate cancer therapy. The proposed reagent, called a Drugcart (Drug carrying aptamers for receptor targeting), is a unique design composed of aptamers with two binding specificities in a single stranded nucleic acid sequence. The Drugcarts will have the following functions: 1) encase and solubilize hydrophobic drugs, 2) target the drugs to the appropriate cells, 3) release the drugs at the target cell surface, and 4) pick up other drug molecules to be shuttled into the cell membrane. For this proposed work, we will link the PSMA aptamer to an aptamer that recognizes PD173955, a drug with similar actions as imatinib mesylate (Gleevec). PD173955 will be further modified to the form of a prodrug with covalently linked peptides that are susceptible to cleavage by the serine protease, prostate specific antigen (PSA). Thus, further specificity for prostate cancer cells will be achieved by the requirement for PSA to cleave the drug and make it permeable to the cell. To develop this promising new drug delivery molecule, we have assembled a team of experienced scientists with expertise in biochemistry, molecular biology, cell biology, cancer therapy, and organic synthetic chemistry. The team has already synthesized a PD173955 analog, isolated two PD173955-binding RNA aptamers, and is ready for the next stage of reagent development as defined by the following specific aims: 1 Synthesize PD173955 derivatives that can be cleaved by PSA to form a permeable PD173955 product. The synthesized derivatives of PD173955 will be tested for their cell permeability, susceptibility to cleavage by PSA, and increased permeability of the product PD173955 after PSA cleavage. 2 Create Drugcarts that bind PSMA and PD173955 for delivering PD173955 to cells. Stabilized RNA Drugcarts containing the PSMA and PD173955 aptamers will be synthesized. Binding activity and stability will be evaluated. 3 Establish that the Drugcarts specifically promote PD173955 uptake by cells that express PSMA on their surfaces. Optimized Drugcarts will be used to deliver the PD173955 prodrug to prostate cancer cells. The specificity of this delivery mechanism for cells that express PSMA and to promote cell death will be investigated.

描述（由申请人提供）：目前的提案侧重于开发一种基于适配体的前列腺癌治疗试剂。该试剂被称为Drugcart（用于受体靶向的携带药物的适体），是一种独特的设计，由单链核酸序列中具有两种结合特异性的适体组成。药物车将具有以下功能：1)包裹和溶解疏水药物，2)将药物靶向到合适的细胞，3)在靶细胞表面释放药物，4)携带其他药物分子穿梭到细胞膜中。对于这项拟议的工作，我们将把PSMA适配体连接到识别PD173955的适配体上，PD173955是一种与甲酸伊马替尼（格列卫）作用相似的药物。PD173955将被进一步修饰为具有共价连接肽的前药，易被丝氨酸蛋白酶前列腺特异性抗原（PSA）切割。因此，对前列腺癌细胞的进一步特异性将通过要求PSA切割药物并使其可渗透到细胞中来实现。为了开发这种有前景的新型药物传递分子，我们组建了一支经验丰富的科学家团队，他们在生物化学、分子生物学、细胞生物学、癌症治疗和有机合成化学方面具有专业知识。该团队已经合成了PD173955类似物，分离了两个PD173955结合RNA适配体，并准备进行试剂开发的下一阶段，具体目标如下：1合成PD173955衍生物，可以通过PSA切割形成可渗透的PD173955产物。我们将测试合成的PD173955衍生物的细胞通透性、对PSA裂解的敏感性以及PSA裂解后产物PD173955的通透性增加。创建结合PSMA和PD173955的drugcart，以便将PD173955递送到细胞。将合成含有PSMA和PD173955适配体的稳定RNA药车。将评估结合活性和稳定性。3 .确定药物特异性促进在其表面表达PSMA的细胞对PD173955的摄取。优化后的drugcart将用于将PD173955前药输送到前列腺癌细胞。这种传递机制对表达PSMA并促进细胞死亡的细胞的特异性将被研究。