Mitomycin C-Soybean Phosphatidylcholine Complex-Loaded Self-Assembled PEG-Lipid-PLA Hybrid Nanoparticles for Targeted Drug Delivery and Dual-Controlled Drug Release
Mitomycin C-Soybean Phosphatidylcholine Complex-Loaded Self-Assembled PEG-Lipid-PLA Hybrid Nanoparticles for Targeted Drug Delivery and Dual-Controlled Drug Release
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DOI：
10.1021/mp500254j
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发表时间：
2014-08-01
影响因子：
4.9
通讯作者：
Hou, Zhenqing
中科院分区：
文献类型：
--
作者：
Li, Yang;Wu, Hongjie;Hou, Zhenqing
目前大多数药物磷脂传递系统是基于水不溶性药物磷脂复合物，但很少水溶性药物磷脂复合物。丝裂霉素C（MMC）是一种广泛用于一线化疗的水溶性抗癌药物，但其体外水稳定性差、从体内快速消除以及缺乏靶点特异性等限制了其应用。本文报道了一种叶酸功能化的MMC-大豆磷脂酰胆碱复合物PEG-脂质-PLA杂化纳米粒（FA-PEG-PE-PLA NPs@MMC-SPC），用于靶向给药和药物双控释放。FA-PEG-PE-PLA NPs@MMC-SPC包含负载MMC-SPC的疏水核（PLA）、两亲性脂质界面层（PE）、亲水壳（PEG）和表面上的靶向配体（FA），具有球形形状、纳米级粒径和几乎95%的高药物包封率。新型药物递送系统的优点在于通过药物磷脂复合物的早期药物控制释放和通过pH敏感的聚合物脂质杂化纳米粒的晚期药物控制释放。体外细胞毒性和溶血试验表明，药物载体具有细胞相容性和血液相容性。大鼠体内药代动力学研究表明FA-PEG-PE-PLA NPs@MMC-SPC较游离MMC显著延长血液循环时间。更重要的是，FA-PEG-PE-PLA NP @MMC-SPC在体外表现出增强的细胞摄取/细胞毒性，在体内表现出上级的肿瘤积聚/治疗功效，同时降低全身毒性。在FA-PEG-PE-PLA NPs@MMC-SPC中实现的MMC作用位点即MMC在核中的显著积累使其成为MMC药物递送的理想选择。本研究为水溶性药物磷脂复合物靶向给药和药物缓控释的设计和开发提供了有效的策略。
Most present drug phospholipid delivery systems were based on a water-insoluble drug phospholipid complex but rarely water-soluble drug phospholipid complex. Mitomycin C (MMC) is a water-soluble anticancer drug extensively used in first-line chemotherapy but is limited by its poor aqueous stability in vitro, rapid elimination from the body, and lack of target specificity. In this article, we report the MMC-soybean phosphatidylcholine complex-loaded PEG-lipid-PLA hybrid nanoparticles (NPs) with Folate (FA) functionalization (FA-PEG-PE-PLA NPs@MMC-SPC) for targeted drug delivery and dual-controlled drug release. FA-PEG-PE-PLA NPs@MMC-SPC comprise a hydrophobic core (PLA) loaded with MMC-SPC, an amphiphilic lipid interface layer (PE), a hydrophilic shell (PEG), and a targeting ligand (FA) on the surface, with a spherical shape, a nanoscaled particle size, and high drug encapsulation efficiency of almost 95%. The advantage of the new drug delivery systems is the early phase controlled drug release by the drug phospholipid complex and the late-phase controlled drug release by the pH-sensitive polymer lipid hybrid NPs. In vitro cytotoxicity and hemolysis assays demonstrated that the drug carriers were cytocompatible and hemocompatible. The pharmacokinetics study in rats showed that FA-PEG-PE-PLA NPs@MMC-SPC significantly prolonged the blood circulation time compared to that of the free MMC. More importantly, FA-PEG-PE-PLA NPs@MMC-SPC presented the enhanced cell uptake/cytotoxicity in vitro and superior tumor accumulation/therapeutic efficacy in vivo while reducing the systemic toxicity. A significant accumulation of MMC in the nuclei as the site of MMC action achieved in FA-PEG-PE-PLA NPs@MMC-SPC made them ideal for MMC drug delivery. This study may provide an effective strategy for the design and development of the water-soluble drug phospholipid complex-based targeted drug delivery and sustained/controlled drug release.