基于两亲性药-抑制剂缀合物的还原响应性纳米药物逆转肿瘤多药耐药性研究

Cancer is the leading disease of mortality in many countries all over the world. Among various cancer treatments, chemotherapy is an indispensable choice for most cancer cases because of its high efficiency. However, chemotherapy usually has a high rate of failure due to the multidrug resistence (MDR) of tumor. To address the multidrug resistance, a highly efficient and reduction-responsive self-delivery drug system will be developed in this project. In detail, we will design and synthesize an amphiphilic drug-inhibitor conjugate, which used a linkage containing disulfide bond to combine a hydrophilic anticancer and a hydrophobic P-gp protein inhibitor. Based on the amphiphilic characteristic, this amphiphilic drug-inhibitor conjugate can self-assemble into nanoparticles in water to construct a nanodrug self-delivery system. It shows longer blood retention half-life compared with that of free drugs, which facilitates the accumulation of drugs in tumor site via EPR effect. After cellular internalization, the disulfide bond in the linkage is cleaved rapidly under the stimulus of intracellular glutathione (GSH) to release the anticancer drug and the inhibitor synchronally. The released inhibitor can markedly reduce expression of P-gp and inhibit the pumping out of the anticancer drug. The concentration of anticancer drugs was increased in the drug-resistant cells to greatly improve therapeutic efficacy. Therefore, the reduction-responsive amphiphilic drug-inhibitor conjugate system can efficiently reverse the multidrug resistance of tumor. This facile strategy will open a new way for reversing tumor multidrug resistance in clinic cancer therapy.

目前，癌症已成为多数国家人口死亡率上升的一个主要因素。在癌症治疗方法中，化疗是最常用且高效的方法之一，但由于癌症对化疗药物易产生耐药性而导致化疗失败。针对癌症治疗中化疗药物易产生耐药性以及药物输送和可控释放中存在的关键科学问题，本项目拟通过含二硫键连接基将亲水性化疗药物和疏水性P-gp蛋白抑制剂偶联起来，制备具有还原响应性的两亲性药-抑制剂缀合物。通过在水中自组装构建还原响应性纳米药物自输送系统，实现化疗药物和蛋白抑制剂共输送。由于纳米药物可提高化疗药物和蛋白抑制剂的血液保留时间，并通过EPR效应被动靶向富集到肿瘤部位。当纳米药物进入肿瘤细胞后，在谷胱甘肽酶作用下，二硫键发生断裂，释放出化疗药物和抑制剂，抑制剂可抑制P-gp蛋白表达，防止化疗药物被泵出，保证其在细胞内的浓度，从而杀死癌细胞，逆转肿瘤耐药性。本项目构建的还原响应性自输送纳米药物系统有望为临床治疗中逆转肿瘤耐药性提供新的思路。

在化疗的过程中，大多数小分子抗肿瘤药物常常会产生严重的多药耐药性，导致化疗失败。本项目将含有还原响应连接基的两亲性药物抑制剂缀合物（ADIC）通过自组装构建了一类纳米药用于逆转肿瘤细胞的多药耐药性（MDR）。具体地，将亲水性抗癌药伊立替康（Ir）和疏水性P-gp蛋白抑制剂奎宁（Qu）通过还原响应连接基连接起来。Ir-ss-Qu能在水中自组装成纳米颗粒（NPs），该纳米颗粒比游离Ir和Qu具有更长的血液停留时间，有利于药物在肿瘤部位的富集。耐药性肿瘤细胞内吞Ir-ss-Qu NPs后，在谷胱甘肽（GSH）的刺激下，Ir与Qu之间的二硫键迅速断裂，同时释放抗癌药物Ir和抑制剂Qu。释放的Qu能显著降低耐药肿瘤细胞中P-gp蛋白的表达，防止Ir被泵出耐药性肿瘤细胞外，有效提高细胞内Ir浓度，达到杀死耐药性肿瘤细胞。这种还原响应的Ir-ss-Qu NPs作为一种药物输送系统，在体外和体内均表现出很高的细胞毒性和对耐药乳腺癌生长最有效的抑制作用。我们相信这种基于还原响应的两亲性药-抑制剂缀合物的策略为逆转肿瘤的多药耐药性提供一条新的途径并最终实现临床上的应用。