Reducing the toxicity of amphotericin B by encapsulation using methoxy poly(ethylene glycol)-b-poly(L-glutamic acid-co-L-phenylalanine)
Reducing the toxicity of amphotericin B by encapsulation using methoxy poly(ethylene glycol)-b-poly(L-glutamic acid-co-L-phenylalanine)
复制标题
甲氧基聚乙二醇-b-聚(L-谷氨酸-co-L-苯丙氨酸)封装降低两性霉素B的毒性
DOI：
10.1039/c8bm00506k
复制
发表时间：
2018-08-01
影响因子：
6.6
通讯作者：
Chen, Xuesi
中科院分区：
文献类型：
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作者：
Yang, Chenguang;Xue, Baiji;Chen, Xuesi
两性霉素 B (AmB) 是一种抗真菌药物，用于治疗严重的真菌感染和利什曼病。但因其毒性较大，其临床应用受到限制。为了解决这个问题，我们通过静电、疏水和p-p相互作用将AmB负载到甲氧基聚(乙二醇)-b-聚(L-谷氨酸-co-L-苯丙氨酸)(mPEG-b-P(Gluco-Phe))纳米颗粒(L-AmB)中。 L-AmB 在 PBS 和血浆中均具有优异的稳定性，并且与游离 AmB（94.2 +/- 5.3%，6 小时）相比，溶血显着减少（17.1 +/- 1.5%，6 小时）。 L-AmB的肾毒性明显低于游离AmB。 L-AmB的最大耐受剂量(MTD)为3.0 mg kg(-1)，是游离AmB的3.75倍(MTD = 0.8 mg kg(-1))。结合物的抗菌活性在体内得以保留，L-AmB 被证明比单独的 AmB 对小鼠烟曲霉感染具有更强的保护性治疗作用。这些表明L-AmB是一种低副作用的AmB制剂。
Amphotericin B (AmB) is an antifungal drug used for serious fungal infections and leishmaniosis. However, its clinical application is limited because of its high toxicity. To resolve this problem, herein we loaded AmB into methoxy poly(ethylene glycol)-b-poly(L-glutamic acid-co-L-phenylalanine) (mPEG-b-P(Gluco-Phe)) nanoparticles (L-AmB) via electrostatic, hydrophobic and p-p interactions. The L-AmB has excellent stability both in PBS and in plasma and shows a remarkably reduced hemolysis (17.1 +/- 1.5%, 6 h) compared to the free AmB (94.2 +/- 5.3%, 6 h). The nephrotoxicity of L-AmB is significantly lower than that of free AmB. The maximum tolerance dose (MTD) of L-AmB is 3.0 mg kg(-1), which is 3.75 fold that of free AmB (MTD = 0.8 mg kg(-1)). The antimicrobial activity of the conjugate was retained in vivo, with L-AmB proving to be a more protective treatment for Aspergillus fumigatus infections in mice than AmB alone. These indicate that L-AmB is a formulation of AmB with low side effects.