Ji Weiping, Wang Bo, Fan Qiuping, Xu Chao, He Youwu, Chen Youfen
Department of Orthopedics, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, China.
Department of hematology and oncology, Ningbo University affiliated Yangming Hospital, Yuyao, China.
PLoS One. 2017 Jul 7;12(7):e0180037. doi: 10.1371/journal.pone.0180037. eCollection 2017.
Multidrug resistance (MDR) against chemotherapeutic agents has become the major obstacle to successful cancer therapy and multidrug resistance-associated proteins (MRPs) mediated drug efflux is the key factor for MDR. Indomethacin (IND), one of the non-steroidal anti-inflammatory agents, has been demonstrated to increase cytotoxic effects of anti-tumor agents as MRP substrates. In this study, dextran-g-indomethacin (DEX-IND) polymeric micelles were designed to delivery paclitaxel (PTX) for the treatment of MDR tumors. The DEX-IND polymer could effectively encapsulate PTX with high loading content and DEX-IND/PTX micelles present a small size distribution. Compared with free PTX, the release of PTX from DEX-IND/PTX micelles could be prolonged to 48 h. Cellular uptake test showed that the internalization of DEX-IND/PTX micelles by drug-sensitive MCF-7/ADR cells was significantly higher than free PTX benefiting from the inhibitory effect of IND on MRPs. In vitro cytotoxicity test further demonstrated that DEX-IND/PTX micelles could enhance the cytotoxicity of PTX against MCF-7/ADR tumor cells. In vivo pharmacokinetic results showed that DEX-IND/PTX micelles had longer systemic circulation time and slower plasma elimination rate in comparison to PTX. The anti-tumor efficacy test showed that DEX-IND/PTX micelles exhibited greater tumor growth-inhibition effects on MDR tumor-bearing mice, with good correlation between in vitro and in vivo. Overall, the cumulative evidence indicates that DEX-IND/PTX micelles hold significant promise for the treatment of MDR tumors.
对化疗药物的多药耐药性（MDR）已成为癌症治疗成功的主要障碍，而多药耐药相关蛋白（MRP）介导的药物外排是MDR的关键因素。吲哚美辛（IND）作为非甾体抗炎药之一，已被证明可增加作为MRP底物的抗肿瘤药物的细胞毒性作用。在本研究中，设计了葡聚糖-g-吲哚美辛（DEX-IND）聚合物胶束来递送紫杉醇（PTX）以治疗MDR肿瘤。DEX-IND聚合物能够以高载药量有效包封PTX，并且DEX-IND/PTX胶束呈现出较小的粒径分布。与游离PTX相比，PTX从DEX-IND/PTX胶束中的释放可延长至48小时。细胞摄取试验表明，由于IND对MRP的抑制作用，药物敏感的MCF-7/ADR细胞对DEX-IND/PTX胶束的内化作用显著高于游离PTX。体外细胞毒性试验进一步证明，DEX-IND/PTX胶束可增强PTX对MCF-7/ADR肿瘤细胞的细胞毒性。体内药代动力学结果表明，与PTX相比，DEX-IND/PTX胶束具有更长的全身循环时间和更慢的血浆消除率。抗肿瘤疗效试验表明，DEX-IND/PTX胶束对荷MDR肿瘤小鼠具有更强的肿瘤生长抑制作用，体内外结果具有良好的相关性。总体而言，累积证据表明DEX-IND/PTX胶束在治疗MDR肿瘤方面具有巨大潜力。
