Qu Wenhao, Yang Quanjun, Wang Guanchun, Wang Zhaohong, Huang Ping, Huang Wei, Zhang Rong, Yan Deyue
School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University 800 Dongchuan Road Shanghai 200240 China
Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital 600 Yishan Road Shanghai 200233 China.
RSC Adv. 2020 Mar 2;10(15):8958-8966. doi: 10.1039/d0ra00912a. eCollection 2020 Feb 27.
Melampomagnolide B (MMB) is a natural sesquiterpene lactone product structurally related to parthenolide (PTL). Although MMB has been widely used to treat various types of cancers, such as glioma, leukemia and colon cancer, the effective delivery of MMB to cancer cells remains a challenge. An amphiphilic drug-drug conjugate (ADDC) strategy has been proposed and developed as a promising drug self-delivery system for cancer therapy because of its simple preparation, carrier-free nature, and high therapeutic activity. Herein, we present a new ADDC, which is synthesized by linking the hydrophilic anticancer drug irinotecan (Ir) and the hydrophobic anticancer drug MMB through a carbonate bond. The obtained amphiphilic irinotecan-melampomagnolide B conjugate (Ir-C-MMB) can self-assemble in water into stable nanoparticles with an average diameter of around 122.1 nm. After cellular uptake, the carbonate bond between the hydrophilic drug and hydrophobic drug can be cleaved to release free Ir and MMB under acidic conditions, which exhibit a synergistic effect in tumor cells. MTT results reveal that the Ir-C-MMB nanoparticles can effectively inhibit proliferation of cancer cells. The apoptosis data indicate that the apoptosis rate of cells treated with Ir-C-MMB nanoparticles is about 50% within 24 h, which is much higher than that of free Ir or MMB. Our results suggest that this ADDC strategy could be used as a drug delivery platform for MMB and its derivatives, and that it offers effective synergistic therapeutic efficacy.
美兰厚朴内酯B（MMB）是一种天然倍半萜内酯产物，其结构与小白菊内酯（PTL）相关。尽管MMB已被广泛用于治疗各种类型的癌症，如神经胶质瘤、白血病和结肠癌，但将MMB有效递送至癌细胞仍然是一个挑战。由于其制备简单、无载体性质和高治疗活性，一种两亲性药物-药物缀合物（ADDC）策略已被提出并开发为一种有前景的癌症治疗药物自递送系统。在此，我们展示了一种新的ADDC，它是通过将亲水性抗癌药物伊立替康（Ir）和疏水性抗癌药物MMB通过碳酸酯键连接而合成的。所得到的两亲性伊立替康-美兰厚朴内酯B缀合物（Ir-C-MMB）在水中可自组装成平均直径约为122.1 nm的稳定纳米颗粒。细胞摄取后，亲水性药物和疏水性药物之间的碳酸酯键在酸性条件下可被裂解以释放游离的Ir和MMB，它们在肿瘤细胞中表现出协同作用。MTT结果表明，Ir-C-MMB纳米颗粒可有效抑制癌细胞的增殖。凋亡数据表明，用Ir-C-MMB纳米颗粒处理的细胞在24小时内的凋亡率约为50%，远高于游离的Ir或MMB。我们的结果表明，这种ADDC策略可作为MMB及其衍生物的药物递送平台，并提供有效的协同治疗效果。
