基于核苷类药物替换的反义核酸-药物缀合物抗肿瘤研究

Multi-drug resistance (MDR) in tumor is the main cause to the failure of chemo-therapy. Recently, developing high efficient drug delivery systems in order to reverse MDR has gained more and more interests. Up to date, both synergetic therapy by different anti-tumor drugs and co-delivery of drug resistance related protein inhibitors and anti-tumor drugs are widely used methods to reverse drug resistance. However, due to the diversity and complicate of the mechanism of MDR, the above mono-functional drug delivery nano-systems are hard to solve the problem of MDR efficiently. This project proposes the combinatory therapy of MDR tumor by self-assembly of antisense replaced by nucleotide drugs and hydrophobic anti-cancer drugs. We develop a brand-new simple and high efficiency nano-drug delivery system to reverse MDR through P-glycoprotein (P-gp) inhibitor and synergistic therapy of two different anti-tumor drugs. Amphiphilic nucleotide drugs replaced antisense and drugs conjugates are constructed by redox-responsive hydrophobic drug dimer and hydrophilic nucleotide drugs replaced antisense through click chemistry. It can self-assemble into spherical nucleus acid (SNA) nanoparticles with high charge density around surface in aqueous. This non-carrier nano-drug delivery system can make cancer cells more difficult to develop compensatory drug resistance mechanisms through synergetic therapy of different anti-tumor drugs. Meanwhile, the antisense can markedly reduce expression of P-gp and inhibit the pumping out of the anticancer drug. These non-carrier naono-drug delivery system can realize the co-delivery of P-gp inhibitor and synergetic therapy of two different anti-tumor drugs. This facile strategy will open a new way for reversing tumor multidrug resistance.

肿瘤耐药性是导致化疗失败的主要原因。通过不同抗癌药物联合给药或耐药蛋白抑制剂和抗癌药物联合给药，均可逆转肿瘤耐药。然而，肿瘤耐药机制的多样性和复杂性致使上述两种联合给药方式难以高效逆转肿瘤耐药性。本项目提出将碱基药物替换反义核苷酸与两亲性核酸-药物缀合物自组装相结合，通过P-糖蛋白抑制剂和两种抗癌药物的多药协同，发展一类全新的简单高效纳米输送系统逆转肿瘤耐药。首先利用点击化学将还原响应性的疏水性药物二聚体和亲水性类碱基药物替换的反义核苷酸偶联，制备类碱基药物替换的反义寡核酸-药物缀合物。借助反义核苷酸-药物缀合物的两亲性，在水中自组装形成表面高密度功能化取向的球形核酸纳米粒子多药自输送系统。该系统既能通过多种抗癌药物协同给药使癌细胞不容易发展补偿性耐药机制，同时抑制P-糖蛋白表达，减少亲脂性抗癌药物外排，实现抗细胞凋亡蛋白抑制剂及两种抗癌药物协同给药的共输送，为高效逆转肿瘤耐药提供新途径。

肿瘤耐药性是导致癌症化疗失败的主要原因。抗癌药物联合给药或耐药相关通路的蛋白抑制剂和抗癌药物联合给药可有效逆转肿瘤耐药。然而，肿瘤耐药机制的多样性和复杂性致使上述两种联合给药的方式难以高效逆转肿瘤耐药性。本项目提出临床使用的核苷类似物药物，如氯法拉滨、奈拉滨、吉西他滨和氟脲苷替换反义核苷酸或核酸适配体中对应的天然碱基，构建药物替换的反义核苷酸（化学基因药物）和全化疗药物替换的和核酸适配体（适配体药物）。设计合成的适配体药物可以高效的抑制肿瘤的生长，为核酸的靶向药物设计及肿瘤的靶向治疗提供了一种全新的思路。化学基因药物通过响应性的化学键可以和还原响应性的疏水性药物二聚体偶联得到化学基因药物-药物缀合物。借助化疗基因药物-药物缀合物的双亲性性能，在水中自组装形成表面高密度功能化取向的球形核酸纳米粒子多药自输送系统，为核酸的高效递送及治疗提供了新的方法。该方法提高了核酸输送的稳定性及细胞对核酸内吞的效率，同时，通过多种抗癌药物协同给药使癌细胞不容易发展补偿性耐药机制，抑制P-糖蛋白表达，减少亲脂性抗癌药物外排，提高耐药肿瘤细胞对化疗药物的敏感性，实现抗P-糖蛋白抑制剂及两种抗癌药物协同给药的共输送，为高效逆转肿瘤耐药提供新途径。