腫瘤普遍存在耐藥現(xiàn)象,，耐藥是腫瘤臨床化療失敗的主要原因之一,，即使分子靶向藥物使用幾個月后也產生耐藥,，導致療效降低或無效,。據(jù)美國癌癥協(xié)會的統(tǒng)計顯示，90%以上的癌癥患者死于不同程度的多藥耐藥,。迄今國內外尚未找到克服腫瘤耐藥的有效策略,，如何降低腫瘤多藥耐藥已成為國內外腫瘤治療的研究熱點之一。
中科院上海藥物所李亞平課題組的博士研究生段曉品和肖計生設計構建了一種智能化時序控制釋藥的共輸送納米載藥系統(tǒng)（DSM）,，通過合成具有pH響應性的阿霉素（DOX）與聚合物的偶聯(lián)物（SAD）自組裝包載雙硫侖（DSF）,；發(fā)現(xiàn)該載藥系統(tǒng)具有較高的載藥量及確定的藥物比例，能夠保證足夠量的藥物以最優(yōu)比例輸送至腫瘤組織,。特別是該載藥系統(tǒng)能夠保證兩種藥物以不同的速率釋放：包載于疏水內核的DSF釋放較快,，發(fā)揮先抑制藥物外排泵的活性，同時恢復耐藥細胞的凋亡信號通路,，而通過共價偶聯(lián)于聚合物上的DOX釋放較慢,，且具有pH響應性，只有在低pH條件下才能被釋放出來,。
由于DSF提前抑制了藥物外排泵的活性,，導致DOX能夠大量蓄積于耐藥細胞中并與DSF產生協(xié)同作用，抑制腫瘤細胞增殖,，誘導細胞凋亡,，最終降低腫瘤多藥耐藥。動物體內研究結果顯示,，DSM幾乎完全抑制了耐藥腫瘤的生長,，并顯著降低DOX的系統(tǒng)毒性。該研究提出了時序控制釋藥降低腫瘤多藥耐藥的新思路,，對提高耐藥腫瘤治療效果具有重要參考價值,，研究工作發(fā)表于國際權威期刊ACS Nano（http：//pubs.acs.org/doi/abs/10.1021/nn4010796， IF=11.421）上,。
該項研究得到了國家自然科學基金,，國家重大科學研究計劃項目的資助。中科院上海藥物所李亞平課題組最近幾年在采用納米藥物降低腫瘤耐藥研究方面取得了一系列重要進展，相關研究分別發(fā)表在ACS Nano,， Small,， Biomaterials， J Control Release等國際重要學術期刊上,，并應邀為Adv Drug Deliv Rev (IF=11.502)撰寫相關綜述（http：//dx.doi.org/10.1016/j.addr.2013.04.011）,，該課題組擁有自主知識產權的1項顯著降低腫瘤耐藥并具開發(fā)前景的納米藥物已進入臨床前研究,。（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.
