Instituto de Investigação e Inovação em Saúde (i3S) and Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Rua Alfredo Allen, 208, 4200-393, Porto, Portugal.
Instituto de Química de São Carlos, Universidade de São Paulo, Avenida Trabalhador São-Carlense, São Carlos, SP, 400-13560-970, Brazil.
Drug Deliv Transl Res. 2018 Apr;8(2):387-397. doi: 10.1007/s13346-017-0357-8.
In this work, self-assembled amphiphilic micelles based on chitosan (CS) and polycaprolactone (PCL) were produced and used as carriers of paclitaxel (PTX) to improve its intestinal pharmacokinetic profile. Chitosan-grafted-polycaprolactone (CS-g-PCL) was synthesized through a carbodiimide reaction by amidation and confirmed by Fourier transform infrared spectroscopy (FTIR), hydrogen nuclear magnetic resonance analysis (H NMR), and contact angle evaluation. Micelles were produced by solvent evaporation method, and the critical micelle concentration was investigated by conductimetry. The obtained micelles were of 408-nm mean particle size, narrow size distribution (polydispersity index of 0.335) and presented positive surface charge around 30 mV. The morphology of micelles assessed by transmission electron microscopy (TEM) revealed round and smooth surface, in agreement with dynamic light scattering measurements. The association efficiency determined by high-performance liquid chromatography (HPLC) was as high as 82%. The in vitro cytotoxicity of the unloaded and PTX-loaded micelles was tested against Caco-2 and HT29-MTX intestinal epithelial cells, resulting in the absence of cell toxicity for all formulations. Moreover, the permeability of PTX-loaded micelles in Caco-2 monolayer and Caco-2/HT29-MTX co-culture model was determined. Results showed that the permeability of PTX was higher in Caco-2/HT29-MTX co-culture model compared with Caco-2 monolayer due to the mucoadhesive character of micelles, acting as a platform to deliver PTX at the sites of absorption. Therefore, it can be concluded that the PTX-loaded CS-g-PCL micelles, employed for the first time as PTX carriers, may be a potential drug carrier for the intestinal delivery of hydrophobic drugs, particularly anticancer agents.
在这项工作中，制备了基于壳聚糖（CS）和聚己内酯（PCL）的自组装两亲性胶束，并将其用作紫杉醇（PTX）的载体，以改善其肠道药代动力学特征。通过碳二亚胺反应通过酰胺化合成壳聚糖接枝聚己内酯（CS-g-PCL），并通过傅里叶变换红外光谱（FTIR）、氢核磁共振分析（H NMR）和接触角评估进行确认。通过溶剂蒸发法制备胶束，并通过电导率法研究临界胶束浓度。所得到的胶束的平均粒径为 408nm，粒径分布较窄（多分散指数为 0.335），表面带正电荷约 30mV。通过透射电子显微镜（TEM）评估的胶束形态显示出圆形和光滑的表面，与动态光散射测量结果一致。通过高效液相色谱（HPLC）测定的结合效率高达 82%。对未负载和负载 PTX 的胶束进行了 Caco-2 和 HT29-MTX 肠上皮细胞的体外细胞毒性测试，结果表明所有制剂均无细胞毒性。此外，还测定了载 PTX 胶束在 Caco-2 单层和 Caco-2/HT29-MTX 共培养模型中的渗透性。结果表明，由于胶束的粘膜粘附特性，载 PTX 胶束在 Caco-2/HT29-MTX 共培养模型中的渗透性高于 Caco-2 单层，作为在吸收部位递药的平台。因此，可以得出结论，首次用作 PTX 载体的载 PTX CS-g-PCL 胶束可能是用于肠道递释疏水性药物（特别是抗癌药物）的潜在药物载体。
