Glutathione-Sensitive Hyaluronic Acid-Mercaptopurine Prodrug Linked via Carbonyl Vinyl Sulfide: A Robust and CD44-Targeted Nanomedicine for Leukemia,Biomacromolecules

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Glutathione-Sensitive Hyaluronic Acid-Mercaptopurine Prodrug Linked via Carbonyl Vinyl Sulfide: A Robust and CD44-Targeted Nanomedicine for Leukemia
Biomacromolecules ( IF 5.5 ) Pub Date : 2017-09-01 00:00:00 , DOI: 10.1021/acs.biomac.7b00846
Jie Qiu ₁ , Ru Cheng ₁ , Jian Zhang ₁ , Huanli Sun ₁ , Chao Deng ₁ , Fenghua Meng ₁ , Zhiyuan Zhong ₁

Affiliation

6-Mercaptopurine (6-MP) is an essential medicine used for treating leukemia in the clinics. 6-MP suffers, however, from poor water solubility, low bioavailability, and significant side effects. Here, we designed CD44-targeted glutathione-sensitive hyaluronic acid-mercaptopurine prodrug (HA-GS-MP) linked via carbonyl vinyl sulfide for safer and enhanced treatment of acute myeloid leukemia (AML). HA-GS-MP obtained with 50 kDa HA and 6-MP conjugation content of 6.9 wt % showed excellent water solubility with a hydrodynamic size of ca. 15 nm. Intriguingly, HA-GS-MP was extremely stable, without any drug leakage, under physiological environment while rapidly releasing 6-MP in response to 10 mM glutathione. HA-GS-MP exhibited obvious targetability and markedly enhanced antitumor effect to OCI/AML-2 human AML cells (IC₅₀ = 16.9 μg 6-MP equiv./mL). The pharmacokinetic studies displayed that Cy5-labeled HA-GS-MP had a long circulation time in mice (elimination half-life = 4.37 h). The in vivo fluorescence images demonstrated strong and persistent accumulation of Cy5-labeled HA-GS-MP from 4 to 48 h post injection in the subcutaneous OCI/AML-2 tumor in nude mice. Notably, HA-GS-MP while causing little side effects induced significantly enhanced growth inhibition of OCI/AML-2 tumor and better survival rate of OCI/AML-2 tumor-bearing mice as compared to free 6-MP. Carbonyl vinyl sulfide-linked hyaluronic acid-mercaptopurine prodrug has appeared to be a simple and smart nanomedicine for targeted treatment of AML.

中文翻译：

谷胱甘肽敏感性透明质酸-巯基嘌呤前药通过羰基乙烯基硫化物连接：一种针对白血病的稳健且以CD44为靶标的纳米药物。

6-巯基嘌呤（6-MP）是临床上用于治疗白血病的基本药物。但是，6-MP的水溶性差，生物利用度低以及明显的副作用。在这里，我们设计了靶向CD44的谷胱甘肽敏感性透明质酸-巯基嘌呤前药（HA-GS-MP），通过羰基乙烯基硫醚连接，可更安全，更有效地治疗急性髓细胞性白血病（AML）。用50kDa HA和6-MP缀合含量为6.9wt％获得的HA-GS-MP显示出优异的水溶性，其流体力学尺寸为约1。15纳米有趣的是，HA-GS-MP在生理环境下非常稳定，没有任何药物泄漏，同时响应10 mM谷胱甘肽迅速释放6-MP。HA-GS-MP对OCI / AML-2人AML细胞表现出明显的靶向性并显着增强了其抗肿瘤作用（IC ₅₀＝ 16.9μg6-MP当量/ mL）。药代动力学研究表明，Cy5标记的HA-GS-MP在小鼠中具有较长的循环时间（消除半衰期= 4.37 h）。体内荧光图像表明，裸鼠皮下注射OCI / AML-2肿瘤后，注射后4至48 h，Cy5标记的HA-GS-MP强烈且持久地蓄积。值得注意的是，与游离6-MP相比，HA-GS-MP几乎不会引起副作用，但可以显着增强对OCI / AML-2肿瘤的生长抑制作用，并可以提高带有OCI / AML-2肿瘤的小鼠的存活率。羰基乙烯基硫醚连接的透明质酸-巯基嘌呤前药似乎是一种用于靶向治疗AML的简单而智能的纳米药物。

更新日期：2017-09-04

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