肿瘤普遍存在耐药现象，耐药是肿瘤临床化疗失败的主要原因之一，即使分子靶向药物使用几个月后也产生耐药，导致疗效降低或无效。据美国癌症协会的统计显示，90%以上的癌症患者死于不同程度的多药耐药。迄今国内外尚未找到克服肿瘤耐药的有效策略，如何降低肿瘤多药耐药已成为国内外肿瘤治疗的研究热点之一。
中科院上海药物所李亚平课题组的博士研究生段晓品和肖计生设计构建了一种智能化时序控制释药的共输送纳米载药系统（DSM），通过合成具有pH响应性的阿霉素（DOX）与聚合物的偶联物（SAD）自组装包载双硫仑（DSF）；发现该载药系统具有较高的载药量及确定的药物比例，能够保证足够量的药物以最优比例输送至肿瘤组织。特别是该载药系统能够保证两种药物以不同的速率释放：包载于疏水内核的DSF释放较快，发挥先抑制药物外排泵的活性，同时恢复耐药细胞的凋亡信号通路，而通过共价偶联于聚合物上的DOX释放较慢，且具有pH响应性，只有在低pH条件下才能被释放出来。
由于DSF提前抑制了药物外排泵的活性，导致DOX能够大量蓄积于耐药细胞中并与DSF产生协同作用，抑制肿瘤细胞增殖，诱导细胞凋亡，最终降低肿瘤多药耐药。动物体内研究结果显示，DSM几乎完全抑制了耐药肿瘤的生长，并显著降低DOX的系统毒性。该研究提出了时序控制释药降低肿瘤多药耐药的新思路，对提高耐药肿瘤治疗效果具有重要参考价值，研究工作发表于国际权威期刊ACS Nano（http：//pubs.acs.org/doi/abs/10.1021/nn4010796， IF=11.421）上。
该项研究得到了国家自然科学基金，国家重大科学研究计划项目的资助。中科院上海药物所李亚平课题组最近几年在采用纳米药物降低肿瘤耐药研究方面取得了一系列重要进展，相关研究分别发表在ACS Nano， Small， Biomaterials， J Control Release等国际重要学术期刊上，并应邀为Adv Drug Deliv Rev (IF=11.502)撰写相关综述（http：//dx.doi.org/10.1016/j.addr.2013.04.011），该课题组拥有自主知识产权的1项显著降低肿瘤耐药并具开发前景的纳米药物已进入临床前研究。（生物谷Bioon.com）
doi:10.1021/nn4010796
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Smart pH-Sensitive and Temporal-Controlled Polymeric Micelles for Effective Combination Therapy of Doxorubicin and Disulfiram
Xiaopin Duan †‡, Jisheng Xiao †, Qi Yin †, Zhiwen Zhang †, Haijun Yu †, Shirui Mao ‡, and Yaping Li †*
The combination of a chemotherapeutic drug with a multidrug resistance (MDR) modulator has emerged as a promising strategy for treating MDR cancer. To ensure two drugs could be simultaneously delivered to tumor region at the optimum ratio, and the MDR modulator could be released earlier and faster than the chemotherapeutic drug to inactivate P-glycoprotein (P-gp) and subsequently inhibit the pumping out of the chemotherapeutic drug, a smart pH-sensitive polymeric micelles system with high drug loading and precise drug ratio was designed and prepared by conjugating doxorubicin (DOX) to poly(styrene-co-maleic anhydride) (SMA) derivative with adipic dihydrazide (ADH) through a acid-cleavable hydrazone bond, and then encapsulating disulfiram (DSF), a P-gp inhibitor as well as an apoptosis inducer, into the micelles formed by the self-assembly of SMA-ADH-DOX (SAD) conjugate. The pH-sensitive polymeric micelles system enabled a temporal release of two drugs: encapsulated DSF was released fast to inhibit the activity of P-gp and restore cell apoptotic signaling pathways, while conjugated DOX was released in a sustained and pH-dependent manner and highly accumulated in drug resistant cells to exert therapeutic effect, due to the inactivation of P-gp by DSF. The smart co-delivery system was very effective in enhancing the cytotoxicity by increasing the intracellular accumulation of DOX and promoting the apoptotic response, and showed the most effective inhibitory effect on the growth of drug-resistant breast cancer xenografts as compared to other combinations of both drugs. In a word, this smart co-delivery system has significant promise for the clinical therapy of MDR cancer.
