Drugcarts to Combat Drug Resistance

对抗耐药性的药车

• 批准号: 7290802
• 负责人: Marit Nilsen-Hamilton
• 金额: $ 15.61万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7290802
• 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）：当前的提案着重于开发基于适体癌症治疗的适体试剂。所提出的试剂称为药房（携带用于受体靶向的药物的药物），是一种独特的设计，由单个链核酸序列中具有两个结合特异性的适体组成。药车将具有以下功能：1）包含并溶解疏水性药物，2）将药物靶向适当的细胞，3）在靶细胞表面释放药物，4）捡起其他药物分子以将其穿梭为细胞膜。对于这项提议的工作，我们将将PSMA适体剂与识别PD173955的适体联系起来，PD173955是一种类似于伊马替尼梅赛酸酯（Gleevec）的药物。 PD173955将进一步修改为使用丝氨酸蛋白酶，前列腺特异性抗原（PSA）裂解的前药的形式。因此，通过PSA裂解药物并使其可渗透到细胞的要求将实现前列腺癌细胞的进一步特异性。为了开发这种有希望的新药物分子，我们组建了一支经验丰富的科学家团队，具有生物化学，分子生物学，细胞生物学，癌症治疗和有机合成化学方面的专业知识。该团队已经合成了PD173955模拟，隔离了两个PD173955结合RNA Aptamers，并准备好用于下一阶段的试剂开发阶段，这是由以下具体目的定义的：1合成PD173955衍生剂，可以由PSA固定以形成PSA以形成PSA以形成允许的PD17393939555555555555555。 PD173955的合成衍生物的细胞渗透性，PSA裂解的敏感性以及PSA裂解后产物PD173955的渗透性提高。 2创建与PSMA和PD173955结合的药房，用于将PD173955传递到细胞。将合成包含PSMA和PD173955适体的稳定RNA药房。将评估结合活性和稳定性。 3确定药房专门促进了在其表面上表达PSMA的细胞摄取的PD173955。优化的药房将用于提供PD173955前列腺癌细胞的PD173955前药。该输送机制对于表达PSMA并促进细胞死亡的细胞的特异性将得到研究。