RNA/Peptide双重适配体介导腺病毒/阿霉素肿瘤靶向递药系统构建及抑癌机制研究

项目名称： RNA/Peptide双重适配体介导腺病毒/阿霉素肿瘤靶向递药系统构建及抑癌机制研究

项目编号： No.81202479

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 钟志容

作者单位： 泸州医学院

项目金额： 23万元

中文摘要： 肿瘤靶向治疗致力于将药物定向浓集至肿瘤部位，定向彻底消灭癌细胞。高效靶向性、药物有效性是关键。RNA和Peptide适配体是一种可基于肿瘤膜表位，具有高亲和力、高特异性的小分子核苷酸片段。我们已证明腺病毒介导的抑癌基因PTEN与化疗药阿霉素体外具有协同抑瘤效应。因此，本课题拟用功能性PEG为连接臂，将基于前列腺特异性膜抗原（PSMA）阳性癌的RNA适配体和PSMA阴性癌的Peptide适配体同时连接到携载抑癌基因PTEN的腺病毒表面，再利用阿霉素能与RNA双链CG序列牢固结合的特点，将基因治疗和化学治疗巧妙地整合为一体，制备由RNA和Peptide双重适配体介导的既能靶向PSMA阳性癌又能靶向PSMA阴性癌的腺病毒/阿霉素肿瘤靶向给药系统。阐明适配体与腺病毒偶联方法、体外靶向性、体外促凋亡效应、体内分布、肿瘤靶向性和抑瘤效应，探讨其抑瘤机制。对发展前列腺癌分子靶向治疗具有重要的指导作用。

中文关键词： 双重适配体；靶向给药系统；前列腺癌；细胞抑制；体内毒性

英文摘要： Tumor-targeted therapy focused on the subjects that if the drugs were concentrated directly in the tumor site and that if the cancer cells excluding the formal cells were killed thoroughly, in which the key problems are the high targeting efficiency and the high effects of therapeutical agents. RNA and peptide aptamers are the small molecule nucleotide fragments with high affinity and highly specificity which might be designed according to the tumor membrane epitope. In the previous study, we found that the adenovirus-mediated tumor suppressor gene of PTEN and the chemotherapy drug of doxorubicin have synergistic effect on inhibition of tumor cells in vitro. Therefore, this project intends to prepare the complexes of Ad5-PTEN and doxorubicin (ADDP-Ad5) targeted to prostate cancers by aptamers of A10-3.2 and DUP-1, in which doxorubicin could bind onto the stem part of double-strand nucleotides with CG sequences in the RNA aptamer and the Ad5-PTEN was modified with the RNA aptamer of the prostate-specific membrane antigen (PSMA) positive cancer and the peptide aptamers of the PSMA-negative cancer by taking the functional PEG as the arm's linkers. Therefore, this tumor-targeted drug delivery system combined the gene therapy and the chemical therapy as a whole body. We will clarify the method of aptamers conjugating

英文关键词： double adapter；targeting drug delivery system；prostatic cancer；growth inhibition；vivo toxicity