Development and characterization of sorafenib-loaded PLGA nanoparticles for the systemic treatment of liver fibrosis
Development and characterization of sorafenib-loaded PLGA nanoparticles for the systemic treatment of liver fibrosis
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DOI：
10.1016/j.jconrel.2015.11.003
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发表时间：
2016-01-10
影响因子：
10.8
通讯作者：
Chen, Yunching
中科院分区：
文献类型：
--
作者：
Lin, Ts-Ting;Gao, Dong-Yu;Chen, Yunching
索拉非尼是一种酪氨酸激酶抑制剂，最近被证明是一种潜在的抗纤维化药物。然而，狭窄的治疗窗口限制了索拉非尼的临床应用和治疗效果。在此，我们开发和优化了由聚乙二醇-b-聚乳酸-乙醇酸共聚物(PEG-PLGA)和聚乳酸-乙醇酸共聚物(PLGA)的混合物制备的纳米颗粒(NP)，用于系统地将索拉非尼输送到CCl4诱导的纤维化小鼠的肝纤维化模型中。我们表征并比较了两种不同的PLGA纳米粒--聚乙二醇-聚乙二醇酯纳米粒(PEGPLGA/PLGA=10/0)和聚乙二醇聚乳酸/聚乙醇酸纳米粒(PEGPLGA/PLGA=5/5)的药学和生物学特性。随着聚乙二醇聚乳酸/聚乙醇酸共混物中PLGA含量的增加，微球的粒径增大，药物包封率提高，药物释放速率降低。PEGPLGA和PEGPLGA/PLGA纳米粒均显著延长了货物的血液循环，并增加了肝纤维化组织的摄取。每周两次全身注射含索拉非尼的聚乙二醇聚乳酸或聚乙二醇聚乳酸/聚乙二醇胺纳米粒，持续4周，可有效地改善肝纤维化，表现为肝组织中α-平滑肌肌动蛋白(α-SMA)含量和胶原生成减少。此外，负载索拉非尼的PLGA纳米粒显著收缩异常血管，降低微血管密度(MVD)，导致纤维化肝脏血管正常化。总之，我们的结果反映了索拉非尼PLGA纳米粒在预防和治疗肝纤维化方面的临床潜力。(C)2015爱思唯尔B.V.保留所有权利。
Sorafenib is a tyrosine kinase inhibitor that has recently been shown to be a potential antifibrotic agent. However, a narrow therapeutic window limits the clinical use and therapeutic efficacy of sorafenib. Herein, we have developed and optimized nanoparticle (NP) formulations prepared from a mixture of poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (PEG-PLGA) copolymers with poly(lactic-co-glycolic acid) (PLGA) for the systemic delivery of sorafenib into the fibrotic livers of CCl4-induced fibrosis mouse models. We characterized and compared the pharmaceutical and biological properties of two different PLGA nanoparticles (NPs) - PEG-PLGA NPs (PEG-PLGA/PLGA = 10/0) and PEG-PLGA/PLGA NPs (PEG-PLGA/PLGA = 5/5). Increasing the PLGA content in the PEG-PLGA/PLGA mixture led to increases in the particle size and drug encapsulation efficacy and a decrease in the drug release rate. Both PEG-PLGA and PEG-PLGA/PLGA NPs significantly prolonged the blood circulation of the cargo and increased the uptake by the fibrotic livers. The systemic administration of PEG-PLGA or PEG-PLGA/PLGA NPs containing sorafenib twice per week for a period of 4 weeks efficiently ameliorated liver fibrosis, as indicated by decreased alpha-smooth muscle actin (alpha-SMA) content and collagen production in the livers of CCl4-treated mice. Furthermore, sorafenib-loaded PLGA NPs significantly shrank the abnormal blood vessels and decreased microvascular density (MVD), leading to vessel normalization in the fibrotic livers. In conclusion, our results reflect the clinical potential of sorafenib-loaded PLGA NPs for the prevention and treatment of liver fibrosis. (C) 2015 Elsevier B.V. All rights reserved.