School of Pharmacy, Shanxi Medical University, Taiyuan 030001, China.
Shanxi Provincial Key Laboratory of Drug Synthesis and Novel Pharmaceutical Preparation Technology, Shanxi Medical University, Taiyuan 030001, China.
Mol Pharm. 2024 Nov 4;21(11):5551-5564. doi: 10.1021/acs.molpharmaceut.4c00520. Epub 2024 Oct 8.
Targeted nanodrug delivery systems are highly anticipated for the treatment of malaria. It is known that can induce new permeability pathways (NPPs) on the membrane of infected red blood cells (iRBCs) for their nutrient uptake. The NPPs also enable the uptake of nanoparticles (NPs) smaller than 80 nm. Additionally, maintains a stable, slightly acidic, and reductive internal environment with higher glutathione (GSH) levels. Based on this knowledge, methyl artelinate (MA, a prodrug-like derivative of dihydroartemisinin) nanoparticles (MA-PCL-NPs) were developed using poly(ethylene glycol)--poly(ε-caprolactone) (mPEG-PCL) by a thin-film dispersion method and were further coated with polydopamine (PDA) to obtain MA-PCL@PDA-NPs with a particle size of ∼30 nm. The biomaterial PDA can be degraded in slightly acidic and reductive environments, thereby serving as triggers for drug release. MA could generate reactive oxygen species and decrease GSH levels, consequently causing parasite damage. The in vitro release experiment results indicated that the cumulative release percentage of MA from MA-PCL@PDA-NPs was considerably higher in phosphate buffer with 10 mM GSH at pH 5.5 (88.10%) than in phosphate buffer without GSH at pH 7.4 (16.98%). The green fluorescence within iRBCs of coumarin 6, the probe of NPs (C6-PCL@PDA-NPs), could be reduced significantly after adding the NPP inhibitor furosemide ( < 0.001), which demonstrated that MA-PCL@PDA-NPs could be ingested into iRBCs through NPPs. In vivo antimalarial pharmacodynamics in K173-bearing mice showed that the inhibition ratio of MA-PCL@PDA-NPs (93.96%) was significantly higher than that of commercial artesunate injection (AS-Inj, 63.33%). The above results showed that the developed MA-PCL@PDA-NPs possessed pH-GSH dual-responsive drug release characteristics and targeting efficacy for iRBCs, leading to higher antimalarial efficacy against .
载药纳米递药系统被高度期待用于疟疾的治疗。已知 可在感染的红细胞（iRBC）的膜上诱导新的通透性途径（NPPs），从而摄取营养物质。这些 NPPs 还允许吸收小于 80nm 的纳米颗粒（NPs）。此外， 维持一个稳定的、略带酸性和还原性的内部环境，具有较高的谷胱甘肽（GSH）水平。基于这一知识，通过薄膜分散法用聚乙二醇-聚（ε-己内酯）（mPEG-PCL）制备了二氢青蒿素的前药类似物甲氧基阿替林酸（MA）纳米颗粒（MA-PCL-NPs），并进一步用聚多巴胺（PDA）进行涂层，得到粒径约为 30nm 的 MA-PCL@PDA-NPs。生物材料 PDA 可以在略酸性和还原性环境中降解，因此可以作为药物释放的触发物。MA 可以产生活性氧物质并降低 GSH 水平，从而导致寄生虫损伤。体外释放实验结果表明，在 pH5.5 、含有 10mM GSH 的磷酸盐缓冲液中，MA-PCL@PDA-NPs 的 MA 累积释放百分比（88.10%）明显高于在不含 GSH 的 pH7.4 的磷酸盐缓冲液中（16.98%）。加入 NPP 抑制剂呋塞米（<0.001）后，iRBC 内香豆素 6（NPs 的探针）的绿色荧光明显减少，这表明 MA-PCL@PDA-NPs 可以通过 NPP 被摄取到 iRBC 中。在 K173 携带的小鼠体内抗疟药效学研究中，MA-PCL@PDA-NPs 的抑制率（93.96%）明显高于市售青蒿琥酯注射液（AS-Inj，63.33%）。上述结果表明，所开发的 MA-PCL@PDA-NPs 具有 pH-GSH 双重响应药物释放特性和靶向 iRBC 的效果，从而对 表现出更高的抗疟疗效。
