Peptide-functionalized and high drug loaded novel nanoparticles as dual-targeting drug delivery system for modulated and controlled release of paclitaxel to brain glioma
Peptide-functionalized and high drug loaded novel nanoparticles as dual-targeting drug delivery system for modulated and controlled release of paclitaxel to brain glioma
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DOI：
10.1016/j.ijpharm.2018.10.022
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发表时间：
2018-12-20
影响因子：
5.8
通讯作者：
Borros，Salvador
中科院分区：
文献类型：
--
作者：
Di Mauro，Primiano Pio;Cascante，Anna;Borros，Salvador
针对目前化疗药物的局限性，将对低密度脂蛋白受体（LDLR）具有特异亲和力的多肽功能化于新型聚酯纳米粒（NPs）上，构建紫杉醇（PTX）双靶向给药系统，将药物从血液转运至脑组织，进而靶向胶质瘤细胞。使用新型可生物降解的嵌段共聚物通过改进的纳米共沉淀法制备了（P和2 P）、PTX负载的和肽官能化的纳米颗粒，该方法仅在没有乳化剂的情况下在一个步骤中进行，允许获得球形纳米（<200 nm）、单分散的纳米颗粒。1）、聚（乙二醇）（PEG）涂覆的和高PTX负载的NP，具有缓慢和受控的释放速率，持续延长的时间段。通过荧光测定和HPLC氨基酸分析证实，与非官能化的PTX-NP相比，肽官能化增强了人原代胶质母细胞瘤细胞系（U-87 MG）和牛脑内皮细胞（BBMVEC）对官能化的PTX-NP的细胞摄取。为了证实双靶向效应，体外BBB模型中的跨内皮转运实验和针对U-87 MG的体外抗肿瘤活性显示肽功能化的PTX-NPs显著增加PTX跨BBB的转运比率，同时沿着提高的抗增殖效率。在大鼠体内进行的125 I放射性标记的双靶向PTX纳米粒体内实验的药代动力学和生物分布研究证实了纳米粒的隐形行为，并表明与已知能够穿过血脑屏障的肽相比，纳米粒渗透到脑组织中的水平略低。这些结果表明，双靶向给药系统在脑胶质瘤的治疗中具有很好的临床应用前景。
A dual-targeting drug delivery system for paclitaxel (PTX) was developed by functionalizing novel polyester-based nanoparticles (NPs) with peptides possessing special affinity for low-density lipoprotein receptor (LDLR), overcoming the limitations of the current chemotherapeutics, to transport drug from blood to brain, and then target glioma cells. Employing novel biodegradable block co-polymers (P and 2P), PTX loaded and peptide-functionalized nanoparticles were prepared by a modified nano-co-precipitation method, carried out in one step only without emulsifier, allowing to obtain spherical nanometric (<200 nm), monodisperse (PDI ∼ 0.1), Poly (Ethylene Glycol) (PEG)-coated and high PTX loaded NPs with a slow and controlled release rate for a prolonged period of time. Peptide functionalization, confirmed by fluorimetric assay and HPLC amino acids analysis, enhanced the cellular uptake of functionalized-PTX-NPs by human primary glioblastoma cell line (U-87 MG) and Bovine Brain Endothelial Cells (BBMVECs), compared with non-functionalized-PTX-NPs. To confirm dual-targeting effect, transendothelial transport experiments in anin vitroBBB model andin vitroanti-tumoral activity against U-87 MG revealed that peptide-functionalized-PTX-NPs significantly increased the transport ratio of PTX across the BBB along with an improved anti-proliferative efficiency. Pharmacokinetics and biodistribution studies in rats, carried out byin vivoexperiments with125I radiolabelled dual-targeting PTX-NPs, confirmed the stealthy behavior of NPs and indicated slightly lower levels of penetration into brain tissue in comparison with peptides known to be able to cross the BBB. These promising results suggested that the dual-targeting drug delivery system might have great potential for glioma therapy in clinical applications.