Th-1 biased immunomodulation and synergistic antileishmanial activity of stable cationic lipid-polymer hybrid nanoparticle: Biodistribution and toxicity assessment of encapsulated amphotericin B
Th-1 biased immunomodulation and synergistic antileishmanial activity of stable cationic lipid-polymer hybrid nanoparticle: Biodistribution and toxicity assessment of encapsulated amphotericin B
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DOI：
10.1016/j.ejpb.2014.11.019
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发表时间：
2015-01-01
影响因子：
4.9
通讯作者：
Chourasia, Manish K.
中科院分区：
文献类型：
--
作者：
Asthana, Shalini;Jaiswal, Anil K.;Chourasia, Manish K.
为了解决两性霉素B（Amp B）临床应用的相关问题，我们开发了巨噬细胞靶向的阳离子硬脂胺脂质聚合物杂化纳米粒（LPNPs），该纳米粒具有聚合物纳米粒和脂质体的互补特性，以增强封装的Amp B的治疗效果并降低毒性作用。LPNPs（尺寸198.3 +/- 3.52 nm，PDI 0.135 +/- 0.03，zeta电位+31.6 +/- 1.91 mV）提供核-壳型结构，其具有以较高量包封两亲性AmpB（包封效率96.1 +/- 2.01%）、持续药物释放和极大地稳定制剂的能力。LPNPs的减毒红细胞和J774A.1毒性证明了胃肠外给药的安全适用性。LPNP的巨噬细胞摄取升高、快速血浆清除和在巨噬细胞丰富的肝脏和脾脏中较高的药物分配说明AmpB-LPNP在体外（IC 50，0.16 +/- 0.04 μ g AmpB/ml）和体内（89.41 +/- 3.58%寄生虫抑制）对内脏利什曼病模型的令人钦佩的抗利什曼病功效。由于无药物LPNPs介导的Th-1偏向性免疫改变导致抗利什曼原虫活性增强，其升高了巨噬细胞的杀微生物介质。此外，对肾组织的最小分布和低水平的肾毒性标志物（肌酐和BUN）证明了AmpB-LPNP的安全性特征。总之，AmpB-LPNP的可靠安全性和巨噬细胞导向的治疗性能表明其作为用于根除巨噬细胞内疾病的商业AmpB制剂的有希望的替代品。(C)2014爱思唯尔有限公司版权所有。
To address issues related to Amphotericin B (AmpB) clinical applications, we developed macrophage targeted cationic stearylamine lipid-polymer hybrid nanoparticles (LPNPs) with complementary characteristics of both polymeric nanoparticles and liposomes, for enhancement of therapeutic efficacy and diminishing toxic effect of encapsulated AmpB. The LPNPs (size 198.3 +/- 3.52 nm, PDI 0.135 +/- 0.03, zeta potential +31.6 +/- 1.91 mV) provide core-shell type structure which has the ability to encapsulate amphiphilic AmpB in higher amount (Encapsulation efficiency 96.1 +/- 2.01%), sustain drug release and stabilize formulation tremendously. Attenuated erythrocytes and J774A.1 toxicity of LPNPs demonstrated safe applicability for parenteral administration. Elevated macrophage uptake of LPNPs, rapid plasma clearance and higher drug allocation in macrophage abundant liver and spleen illustrated admirable antileishmanial efficacy of AmpB-LPNPs in vitro (IC50, 0.16 +/- 0.04 mu g AmpB/ml) and in vivo (89.41 +/- 3.58% parasite inhibition) against visceral leishmaniasis models. Augmentation in antileishmanial activity due to Th-1 biased immune-alteration mediated by drug-free LPNPs which elevated microbicidal mediators of macrophages. Moreover, minimal distribution to kidney tissues and low level of nephrotoxicity markers (creatinine and BUN) demonstrated the safety profile of AmpB-LPNPs. Conclusively, reliable safety and macrophage directed therapeutic performance of AmpB-LPNPs suggest it as promising alternative to commercial AmpB-formulations for the eradication of intra-macrophage diseases. (C) 2014 Elsevier B.V. All rights reserved.