Abstract：
Artemisinin and its derivatives have been commonly used to treat malaria. However, the emergence of resistance against artemisinin derivatives has posed a critical challenge in malaria management. In the present study, we have proposed a combinatorial approach, utilizing pH-responsive acetal-dextran nanoparticles (Ac-Dex NPs) as carriers for the delivery of withaferin-A (WS-3) and artesunate (Art) to improve treatment efficacy of malaria. The optimized WS-3 and Art Ac-Dex NPs demonstrated enhanced pH-responsive release profiles under parasitophorous mimetic conditions (pH 5.5). Computational molecular modeling reveals that Ac-Dex\'s polymeric backbone strongly interacts with merozoite surface protein-1 (MSP-1), preventing erythrocyte invasion. In-vitro antimalarial activity of drug-loaded Ac-Dex NPs reveals a 1-1.5-fold reduction in IC50 values compared to pure drug against the 3D7 strain of Plasmodium falciparum. Treatment with WS-3 Ac-Dex NPs (100 mg/kg) and Art Ac-Dex NPs (30 mg/kg) to Plasmodium berghei-infected mice resulted in 78.11 % and 100 % inhibition of parasitemia. Notably, the combination therapy comprised of Art and WS-3 Ac-Dex NPs achieved complete inhibition of parasitemia even at a half dose of Art, indicating the synergistic potential of the combinations. However, further investigations are necessary to confirm the safety and effectiveness of WS-3 and Art Ac-Dex NPs for their successful clinical implications.
摘要：
青蒿素及其衍生物通常用于治疗疟疾。然而,对青蒿素衍生物的耐药性的出现给疟疾管理带来了严峻的挑战。在本研究中,我们提出了一种组合方法，利用pH响应性缩醛-葡聚糖纳米颗粒（Ac-DexNPs）作为载体，用于递送withaferin-A（WS-3）和青蒿琥酯（Art），以提高疟疾的治疗效果。优化的WS-3和ArtAc-DexNP在寄生虫模拟条件（pH5.5）下显示出增强的pH响应性释放曲线。计算分子模型表明，Ac-Dex的聚合物主链与裂殖子表面蛋白1（MSP-1）强烈相互作用，防止红细胞入侵。载药Ac-DexNP的体外抗疟活性显示，与纯药物相比，抗恶性疟原虫3D7菌株的IC50值降低了1-1.5倍。用WS-3Ac-DexNP（100mg/kg）和ArtAc-DexNP（30mg/kg）对伯氏疟原虫感染的小鼠进行治疗可导致78.11％和100％的寄生虫血症抑制。值得注意的是,由Art和WS-3Ac-DexNP组成的联合治疗即使在一半剂量的Art下也能完全抑制寄生虫血症，表明组合的协同潜力。然而,有必要进一步研究以确认WS-3和ArtAc-DexNP的安全性和有效性,证明其成功的临床意义.
