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）：当前提案的重点是开发用于前列腺癌治疗的基于适体的试剂。所提出的试剂称为 Drugcart（用于受体靶向的药物携带适体），是一种独特的设计，由在单链核酸序列中具有两种结合特异性的适体组成。药车将具有以下功能：1）包裹并溶解疏水性药物，2）将药物靶向适当的细胞，3）在靶细胞表面释放药物，4）拾取其他药物分子以穿梭进入细胞膜。对于这项拟议的工作，我们将把 PSMA 适体与识别 PD173955 的适体连接起来，PD173955 是一种与甲磺酸伊马替尼 (Gleevec) 具有相似作用的药物。 PD173955 将被进一步修饰为具有共价连接肽的前药形式，这些肽易于被丝氨酸蛋白酶、前列腺特异性抗原 (PSA) 裂解。因此，通过需要 PSA 裂解药物并使其可渗透到细胞中，将实现对前列腺癌细胞的进一步特异性。为了开发这种有前途的新型药物输送分子，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拥有专业知识。该团队已经合成了PD173955类似物，分离了两种PD173955结合RNA适体，并为下一阶段的试剂开发做好了准备，具体目标如下： 1 合成可被PSA裂解形成可渗透的PD173955的PD173955衍生物产品。将测试合成的PD173955衍生物的细胞渗透性、对PSA裂解的敏感性以及PSA裂解后产物PD173955的渗透性增加。 2 创建结合 PSMA 和 PD173955 的 Drugcarts，以将 PD173955 递送至细胞。将合成含有 PSMA 和 PD173955 适体的稳定 RNA 药车。将评估结合活性和稳定性。 3 确定 Drugcarts 特异性促进表面表达 PSMA 的细胞摄取 PD173955。优化的 Drugcarts 将用于将 PD173955 前药递送至前列腺癌细胞。将研究这种递送机制对于表达 PSMA 的细胞和促进细胞死亡的特异性。