School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
Int J Pharm. 2019 May 1;562:162-171. doi: 10.1016/j.ijpharm.2019.03.031. Epub 2019 Mar 19.
Artesunate-heparin conjugate (ART-HEP) based nanocapsules as drug delivery vehicle was developed for intracellular release of ART in malaria therapy. Owing both hydrophobic and hydrophilic moieties, the conjugate was successfully self-assembled into artesunate-heparin nanocapsules (ART-HEP-NCPs) with lower critical micelle concentration (CMC) of about 20 µg/mL. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) revealed that ART-HEP-NCPs has an average hydrodynamic diameter of 112.1 nm with a negatively charged surface (-11.2 mV) and typical micellar nanostructure, respectively. Interestingly, such modification achieved high drug loading efficiency (DLE) of ART (29.3 wt%), which is significantly higher than already reported conventional ART-loaded nanoparticles. The nanocapsules demonstrated lower in vitro ART release under neutral physiological environment (33.81%) but higher release rate was observed in simulated acidic microenvironment (92.74%) in 70 h test. This behavior of ART-HEP-NCPs will facilitate the intracellular release of ART under slightly acidic parasitic food vacuole for effective antimalarial effect. Storage stability and hemolytic studies exhibited that ART-HEP based nanocapsules were stable and safe for intravenous (i.v) injection. Notably, ART-HEP-NCPs has promising internalization into Plasmodium infected red blood cells (iRBCs) and also displayed in vitro inhibitory effect against P. falciparum 3D7 with half-maximal inhibitory concentration (IC) of 10.16 nM, which was slightly higher than free ART (IC 6.27 nM). This expected slightly lower inhibitory effect of polymeric prodrug could be ascribed to the gradual release of ART from the polymer chain over time. More importantly, the in vivo pharmacokinetics study indicated that the nanoscale characteristic of nanocapsules substantially contributed to the extended circulation of ART in blood. In conclusion, such multifunctional ART-HEP-NCPs with higher ART loading and extended half-life could be a promising platform for targeted antimalarial drug delivery.
阿特柳酯-肝素缀合物（ART-HEP）纳米胶囊作为药物递送载体，用于疟疾治疗中阿特柳酯的细胞内释放。由于具有疏水性和亲水性部分，该缀合物成功地自组装成阿特柳酯-肝素纳米胶囊（ART-HEP-NCPs），其临界胶束浓度（CMC）约为 20μg/mL。动态光散射（DLS）和透射电子显微镜（TEM）显示，ART-HEP-NCPs 的平均水动力直径为 112.1nm，表面带负电荷（-11.2mV），具有典型的胶束纳米结构。有趣的是，这种修饰实现了 ART 的高载药量（DLE）（29.3wt%），明显高于已报道的常规 ART 负载纳米粒。纳米胶囊在中性生理环境下（33.81%）表现出较低的阿特柳酯体外释放，但在 70h 测试中模拟的酸性微环境中观察到更高的释放率（92.74%）。ART-HEP-NCPs 的这种行为将促进阿特柳酯在略酸性寄生食物泡中的细胞内释放，从而产生有效的抗疟效果。储存稳定性和溶血研究表明，基于阿特柳酯的纳米胶囊稳定且可安全用于静脉（i.v）注射。值得注意的是，ART-HEP-NCPs 具有良好的内化进入感染恶性疟原虫的红细胞（iRBCs）的能力，并且对恶性疟原虫 3D7 也表现出体外抑制作用，半数最大抑制浓度（IC）为 10.16nM，略高于游离 ART（IC 6.27nM）。这种聚合物前药的预期稍低的抑制作用可能归因于 ART 随时间从聚合物链上逐渐释放。更重要的是，体内药代动力学研究表明，纳米胶囊的纳米尺度特征极大地延长了 ART 在血液中的循环。总之，这种具有更高 ART 载药量和延长半衰期的多功能 ART-HEP-NCPs 可能成为靶向抗疟药物递送的有前途的平台。
