新颖姜黄素脂质体修饰的透明质酸靶向CD44剧在急性髓性白血病的抗白血病作用<i>的体外</i>和<i>体内</i>,ACS Applied Materials & Interfaces

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新颖姜黄素脂质体修饰的透明质酸靶向CD44剧在急性髓性白血病的抗白血病作用的体外和体内
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2017-05-10 00:00:00 , DOI: 10.1021/acsami.7b02863
Dan Sun ₁ , Jian-Kang Zhou ₁ , Linshu Zhao ₂ , Zhe-Yu Zheng ₁ , Jiao Li ₁ , Wenchen Pu ₁ , Shaoyang Liu ₁ , Xue-Sha Liu ₁ , Shu-Jun Liu ₃ , Yu Zheng ₁ , Yun Zhao ₁ , Yong Peng ₁

Affiliation

姜黄素已被广泛用作食品添加剂已有数百年历史，并且最近因其抗炎和抗肿瘤特性而得到研究。尽管姜黄素对某些癌症在药理学上安全有效，但其对急性髓细胞性白血病（AML）的作用仍不清楚，并且由于水溶性低和体内活性低而缺乏临床应用生物利用度。为了解决这些问题，我们开发了一种用透明质酸（HA-Cur-LPs）修饰的新型姜黄素脂质体，可通过靶向AML细胞表面的CD44将姜黄素特异地递送至AML。与游离姜黄素和非靶向脂质体（Cur-LPs）相比，HA-Cur-LPs表现出良好的稳定性，对CD44的高亲和力，增加的细胞摄取以及更强的抑制AML细胞增殖的活性。植入KG-1细胞的AML小鼠每2天用HA-Cur-LPs中的50 mg / kg姜黄素剂量治疗2周后，AML的进展显着延迟，甚至被预防。从机理上讲，HA-Cur-LP的抗AML作用是通过抑制Akt / ERK途径并激活caspase依赖性凋亡来实现的。此外，HA-Cur-LP在AML中DNMT1表达的下调中起着至关重要的作用，导致DNA甲基化不足和肿瘤抑制基因（如miR-223）的重新激活。使用HA-Cur-LP作为单一治疗剂或与其他治疗组合使用，本研究中HA-Cur-LP的开发和评估为AML治疗提供了另一种潜在选择。

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Novel Curcumin Liposome Modified with Hyaluronan Targeting CD44 Plays an Anti-Leukemic Role in Acute Myeloid Leukemia in Vitro and in Vivo

Curcumin has been widely used as a food additive for centuries and has been recently explored for its anti-inflammatory and antitumor properties. Although curcumin is pharmacologically safe and efficacious to certain cancers, its role against acute myeloid leukemia (AML) still remains unclear, and it lacks clinical application due to low water solubility and low in vivo bioavailability. To address these issues, we developed a novel curcumin liposome modified with hyaluronan (HA-Cur-LPs) to specifically deliver curcumin to AML by targeting CD44 on AML cell surface. When compared with free curcumin and nontargeted liposome (Cur-LPs), the HA-Cur-LPs exhibited good stability, high affinity to CD44, increased cellular uptake, and more potent activity on inhibiting AML cell proliferation. The KG-1 cell implanted AML mice had significantly delayed, or even prevented, AML progression following treatment with 50 mg/kg of curcumin dose in the HA-Cur-LPs every 2 days for 2 weeks. Mechanistically, the anti-AML effects of HA-Cur-LPs were achieved by inhibiting Akt/ERK pathways and activating caspase-dependent apoptosis. Moreover, HA-Cur-LPs played a critical role in downregulation of DNMT1 expression in AML, leading to DNA hypomethylation and reactivation of tumor suppressor genes such as miR-223. The development and assessment of the HA-Cur-LPs in this study provide another potential choice for AML therapy, using HA-Cur-LPs as either a single treatment agent or in combination with other treatments.

更新日期：2017-05-10

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