Hyaluronic Acid Engineered Nanomicelles Loaded with 3,4-Difluorobenzylidene Curcumin for Targeted Killing of CD44+Stem-Like Pancreatic Cancer Cells
Hyaluronic Acid Engineered Nanomicelles Loaded with 3,4-Difluorobenzylidene Curcumin for Targeted Killing of CD44+Stem-Like Pancreatic Cancer Cells
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DOI：
10.1021/acs.biomac.5b00941
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发表时间：
2015-09-01
影响因子：
6.2
通讯作者：
Iyer, Arun K.
中科院分区：
文献类型：
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作者：
Kesharwani, Prashant;Banerjee, Sanjeev;Iyer, Arun K.
肿瘤干细胞样细胞（CSLCs）在获得多药耐药（MDR）表型中起着关键作用。已经确定过表达CD 44受体（透明质酸的靶标; HA）的胰腺癌是引起MDR的主要因素之一。因此，使用基于HA的主动靶向策略靶向杀死表达CD 44的肿瘤细胞可能有利于根除MDR-胰腺癌。在这里，我们报告了一种新的HA共轭共聚物（苯乙烯马来酸）（HA-SMA）的合成，它可以被设计成与一种有效的抗癌剂，3，4-二氟亚苄基姜黄素（CDF）形成纳米胶束。CDF负载的纳米胶束对MiaPaCa-2和AsPC-1人胰腺癌细胞的抗癌活性显示出剂量依赖性的细胞杀伤。细胞内化的结果进一步证实了与三重标志物阴性（CD 44-/CD 133-/EpCAM-）对应物相比，HA工程化纳米胶束在三重标志物阳性（CD 44 +/CD 133 +/EpCAM+）胰腺CSLC中的更好摄取。更重要的是，HA-SMA-CDF对CD 44+胰腺CSLC表现出上级抗癌反应。结果进一步证实，用HA-SMA-CDF处理的三重标志物阳性细胞引起CD 44表达的显著降低和NF-κ B的显著抑制，这反过来可以减轻它们的增殖和侵袭行为。总之，这些结果表明，新开发的CD 44靶向纳米胶束可能在治疗胰腺癌，包括更具侵袭性的胰腺CSLCs方面具有重要意义。
Cancer stem-like cells (CSLCs) play a pivotal role in acquiring multidrug resistant (MDR) phenotypes. It has been established that pancreatic cancers overexpressing CD44 receptors (a target of hyaluronic acid; HA) is one of the major contributors for causing MDR Therefore, targeted killing of CD44 expressing tumor cells using HA based active targeting strategies may be beneficial for eradicating MDR-pancreatic cancers. Here, we report the synthesis of a new HA conjugate of copoly(styrene maleic acid) (HA-SMA) that could be engineered to form nanomicelles with a potent anticancer agent, 3,4-difluorobenzylidene curcumin (CDF). The anticancer activity of CDF loaded nanomicelles against MiaPaCa-2 and AsPC-1 human pancreatic cancer cells revealed dose-dependent cell killing. Results of cellular internalization further confirmed better uptake of HA engineered nanomicelles in triple-marker positive (CD44+/CD133+/EpCAM+) pancreatic CSLCs compared with triple-marker negative (CD44-/CD133-/EpCAM-) counterparts. More importantly, HA-SMA-CDF exhibited superior anticancer response toward CD44+ pancreatic CSLCs. Results further confirmed that triple-marker positive cells treated with HA-SMA-CDF caused significant reduction in CD44 expression and marked inhibition of NF-kappa B that in-turn can mitigate their proliferative and invasive behavior. Conclusively, these results suggest that the newly developed CD44 targeted nanomicelles may have great implications in treating pancreatic cancers including the more aggressive pancreatic CSLCs.