Combination of using prodrug-modified cationic liposome nanocomplexes and a potentiating strategy via targeted co-delivery of gemcitabine and docetaxel for CD44-overexpressed triple negative breast cancer therapy
Combination of using prodrug-modified cationic liposome nanocomplexes and a potentiating strategy via targeted co-delivery of gemcitabine and docetaxel for CD44-overexpressed triple negative breast cancer therapy
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DOI：
10.1016/j.actbio.2017.08.034
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发表时间：
2017-10-15
影响因子：
9.7
通讯作者：
Ding, Tingting
中科院分区：
文献类型：
--
作者：
Fan, Yang;Wang, Qingjie;Ding, Tingting
在该研究中，报道了用于吉西他滨（GEM）和多西他赛（DTX）共递送的新型前药修饰的阳离子脂质体纳米复合物（Combo NC）。该纳米平台具有一步化学反应的“绿色”制造、合适的尺寸（类似于200 nm）和分布（PDI < 0.2）、低zeta电位（-31.1 mv）、高载药效率（9.3%GEM +3.1%DTX，wt%）以及pH和酶促双刺激响应释放特性。免疫荧光和细胞摄取研究表明，Combo NC有效靶向MDA-MB-231癌中过表达的CD 44。体外研究表明，Combo NCs在协同诱导细胞毒性、细胞凋亡和抑制伤口愈合中发挥关键作用。与空白对照相比，Combo NC通过将CDA的mRNA表达降低至0.09倍并将dCK的mRNA表达增加1.36倍，显著增加dCK/CDA比率至15.3倍，证实其表现出增加S期阻滞和重塑CDA和dCK平衡的巨大效力。在体内获得的生物分布结果显示在肿瘤病灶中有效蓄积。Combo NC的所有这些优点有助于其显著的抗肿瘤功效而无全身毒性以及其促增殖和抗增殖能力，如通过体内TUNEL和Ki 67免疫组织化学测定的。因此，这种合理考虑的共递送系统展示了用于三阴性乳腺癌治疗的临床应用的有希望的潜力。显著性状态Combo NC创新地应用于亲水性GEM和疏水性DTX的共递送。体外释药实验表明，HA-GEM的酯键连接和屏蔽作用使载体具有同步释药特性。由于HA修饰，载体具有阳性靶向CD 44过表达的三阴性乳腺癌细胞MDA-MB-231的巨大效力。细胞毒性和凋亡研究证实了两种药物之间的靶向作用和协同作用。有趣的是，我们在细胞周期研究中发现，药物组合（自由组合或Combo NC）没有显示G2 M期的上升，当单独处理DTX时，G2 M期显著更高。我们进一步发现，DTX在组合中的作用可能涉及调节GEM相关酶，从而增强GEM的功效。因此，这种纳米平台提供了一种新的解决方案，用于实现靶向共递送和增强癌症治疗的效果。(C)2017 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
In this study, novel prodrug-modified cationic liposome nanocomplexes (Combo NCs) were reported for gemcitabine (GEM) and docetaxel (DTX) co-delivery. This nanoplatform exhibited multiple favorable characteristics, such as a 'green' fabrication with a one-step chemical reaction, appropriate size (similar to 200 nm) and distribution (PDI < 0.2), low zeta potential (-31.1 mv), high drug-loading efficiency (9.3% GEM plus 3.1% DTX, wt%) and pH and enzymatic dual-stimulus-responsive release properties. Immunofluorescence and cellular uptake studies showed that Combo NCs efficiently targeted overexpressed CD44 in MDA-MB-231 carcinoma. In vitro studies revealed that Combo NCs played a critical role in the synergistic induction of cytotoxicity, apoptosis and inhibition of wound healing. Combo NCs were confirmed to exhibit great potency for increasing S phase arrest and remodeling the CDA and dCK balance by decreasing the mRNA expression of CDA down to 0.09-fold and increasing the mRNA expression of dCK by 1.36-fold, remarkably increasing the dCK/CDA ratio to 15.3-fold compared with the blank control. The biodistribution results obtained in vivo revealed an effective accumulation in tumor foci. All of these advantages of Combo NCs contributed to their remarkable anti-tumor efficacy without systemic toxicity as well as their apoptosis-enhancing and anti-proliferative capacities, as determined by TUNEL and Ki67 immunohistochemistry in vivo. Consequently, such a rationally contemplated co-delivery system demonstrated the promising potential of clinical applications for triple-negative breast cancer therapy.State of SignificanceThe Combo NCs were innovatively applied for co-delivery of hydrophilic GEM and hydrophobic DTX. The ester bond linking and shielding effect of HA-GEM made the carriers achieve synchronous release properties, which was determined in in vitro release study. Due to the HA modification, the vectors own great potency for positive targeting to CD44 overexpressed triple-negative breast cancer cells MDA-MB-231. Cytotoxicity and apoptosis studies confirmed the targeting effect and synergism between two drugs. Interestingly, we found in cell cycle study, drug combinations (free combination or Combo NCs) didn't show a rise in G2M phase, which was significantly higher when treated DTX alone. We further discovered the role of DTX in combinations may involve in modulating GEM associated enzymes thus enhancing the efficacy of GEM. Consequently, this nanoplatform provided a novel solution for achieving targeted co-delivery and potentiating effect in cancer therapy. (C) 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.