A dendrimer-based dual delivery system for artesunate and fluconazole: Effective malaria treatment in a murine model of Plasmodium berghei

IF 2.1 3区医学 Q2 PARASITOLOGY

Acta tropica Pub Date : 2025-05-21 DOI:10.1016/j.actatropica.2025.107663

Fatemeh Babapour , Faride Khanabadi , Shohreh Fahimirad , Seyedeh Shaghayegh Hosseini , Taher Elmi

{"title":"A dendrimer-based dual delivery system for artesunate and fluconazole: Effective malaria treatment in a murine model of Plasmodium berghei","authors":"Fatemeh Babapour , Faride Khanabadi , Shohreh Fahimirad , Seyedeh Shaghayegh Hosseini , Taher Elmi","doi":"10.1016/j.actatropica.2025.107663","DOIUrl":null,"url":null,"abstract":"<div><h3>Purpose</h3><div>The increasing prevalence of <em>Plasmodium</em> resistance to conventional artemisinin-based combination therapies (ACTs) presents a significant threat to global malaria control. To address this, we developed a nanocarrier-based co-delivery system (ND-ARS/FLZ) encapsulating artesunate (ARS) and fluconazole (FLZ), aimed at enhancing therapeutic efficacy and overcoming drug resistance in a murine model of <em>Plasmodium berghei</em> infection. The rationale for combining ARS, an antimalarial, with FLZ, an antifungal, stems from recent studies indicating potential synergistic effects on <em>Plasmodium</em> metabolism and drug resistance mechanisms.</div></div><div><h3>Methods</h3><div>The ND-ARS/FLZ nanocarrier was synthesized using a second-generation dendrimer platform, and its structural characteristics were analyzed using Fourier-transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), and scanning electron microscopy (SEM). Encapsulation efficiency and drug loading were also determined. Antiplasmodial efficacy was assessed by quantifying parasitemia on day 4 post-treatment in infected mice. Histopathological analysis of liver tissue was performed to evaluate safety and biocompatibility. Statistical significance was determined using SPSS.</div></div><div><h3>Results</h3><div>The ND-ARS/FLZ nanocarrier exhibited a spherical morphology with a mean diameter of 137 nm and demonstrated sustained drug release, achieving 98 % FLZ and 92 % ARS release within 42 h. At a dose of 400 mg/kg (80 mg ARS + 44 mg FLZ), ND-ARS/FLZ achieved complete parasitemia clearance (100 %), significantly outperforming monotherapies (<em>P</em> < 0.01). The estimated ED₅₀ was 146 mg/kg, indicating potent antimalarial activity. No histopathological signs of hepatotoxicity were observed (<em>P</em> > 0.05), supporting the formulation’s favorable safety profile. The PEGylated dendrimer core, combined with a citric acid-functionalized surface, enhanced the antimalarial efficacy of encapsulated drugs while concurrently minimizing off-target toxicity.</div></div><div><h3>Conclusion</h3><div>The ND-ARS/FLZ nanocarrier exhibits potent antimalarial activity and a promising safety profile, positioning it as a potential candidate for treating drug-resistant malaria. The synergistic drug combination, coupled with nanocarrier-mediated delivery, offers a novel approach to overcoming resistance. Future studies should further explore the pharmacokinetics, host-parasite interactions, and mechanisms of action using techniques such as mass spectrometry, NMR, and in vivo imaging to facilitate preclinical advancement.</div></div>","PeriodicalId":7240,"journal":{"name":"Acta tropica","volume":"267 ","pages":"Article 107663"},"PeriodicalIF":2.1000,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta tropica","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0001706X25001391","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PARASITOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Purpose

The increasing prevalence of Plasmodium resistance to conventional artemisinin-based combination therapies (ACTs) presents a significant threat to global malaria control. To address this, we developed a nanocarrier-based co-delivery system (ND-ARS/FLZ) encapsulating artesunate (ARS) and fluconazole (FLZ), aimed at enhancing therapeutic efficacy and overcoming drug resistance in a murine model of Plasmodium berghei infection. The rationale for combining ARS, an antimalarial, with FLZ, an antifungal, stems from recent studies indicating potential synergistic effects on Plasmodium metabolism and drug resistance mechanisms.

Methods

The ND-ARS/FLZ nanocarrier was synthesized using a second-generation dendrimer platform, and its structural characteristics were analyzed using Fourier-transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), and scanning electron microscopy (SEM). Encapsulation efficiency and drug loading were also determined. Antiplasmodial efficacy was assessed by quantifying parasitemia on day 4 post-treatment in infected mice. Histopathological analysis of liver tissue was performed to evaluate safety and biocompatibility. Statistical significance was determined using SPSS.

Results

The ND-ARS/FLZ nanocarrier exhibited a spherical morphology with a mean diameter of 137 nm and demonstrated sustained drug release, achieving 98 % FLZ and 92 % ARS release within 42 h. At a dose of 400 mg/kg (80 mg ARS + 44 mg FLZ), ND-ARS/FLZ achieved complete parasitemia clearance (100 %), significantly outperforming monotherapies (P < 0.01). The estimated ED₅₀ was 146 mg/kg, indicating potent antimalarial activity. No histopathological signs of hepatotoxicity were observed (P > 0.05), supporting the formulation’s favorable safety profile. The PEGylated dendrimer core, combined with a citric acid-functionalized surface, enhanced the antimalarial efficacy of encapsulated drugs while concurrently minimizing off-target toxicity.

Conclusion

The ND-ARS/FLZ nanocarrier exhibits potent antimalarial activity and a promising safety profile, positioning it as a potential candidate for treating drug-resistant malaria. The synergistic drug combination, coupled with nanocarrier-mediated delivery, offers a novel approach to overcoming resistance. Future studies should further explore the pharmacokinetics, host-parasite interactions, and mechanisms of action using techniques such as mass spectrometry, NMR, and in vivo imaging to facilitate preclinical advancement.

查看原文本刊更多论文

基于树突状分子的青蒿琥酯和氟康唑双重递送系统：有效治疗伯氏疟原虫小鼠模型中的疟疾。

目的：疟原虫对传统青蒿素为基础的联合疗法（ACTs）的耐药性日益普遍，对全球疟疾控制构成重大威胁。为了解决这一问题，我们开发了一种基于纳米载体的共递送系统（ND-ARS/FLZ），该系统包封了青蒿琥酯（ARS）和氟康唑（FLZ），旨在提高伯氏疟原虫感染小鼠模型的治疗效果并克服耐药性。将ARS（一种抗疟疾药物）与FLZ（一种抗真菌药物）联合使用的理由源于最近的研究，这些研究表明，在疟原虫代谢和耐药机制方面存在潜在的协同作用。方法：采用第二代树状大分子平台合成ND-ARS/FLZ纳米载体，并利用傅里叶变换红外光谱（FTIR）、动态光散射（DLS）和扫描电镜（SEM）对其结构特征进行分析。测定包封率和载药量。在治疗后第4天，通过定量寄生虫率评估感染小鼠的抗疟原虫效果。对肝组织进行组织病理学分析以评估安全性和生物相容性。采用SPSS统计软件进行统计学意义分析。结果：ND-ARS/FLZ纳米载体呈球形，平均直径为137 nm，具有较好的缓释效果，42 h内可达到98%的FLZ和92%的ARS缓释。在400 mg/kg （80 mg ARS + 44 mg FLZ）剂量下，ND-ARS/FLZ完全清除寄生虫（100%），显著优于单一治疗（P < 0.01）。估计的ED₅0为146 mg/kg，表明有效的抗疟疾活性。未观察到肝毒性的组织病理学迹象（P < 0.05），支持该配方良好的安全性。聚乙二醇化的树状大分子核与柠檬酸功能化的表面结合，增强了包封药物的抗疟疾功效，同时最大限度地减少了脱靶毒性。结论：ND-ARS/FLZ纳米载体具有强大的抗疟活性和良好的安全性，是治疗耐药疟疾的潜在候选药物。协同药物组合，加上纳米载体介导的递送，提供了一种克服耐药性的新方法。未来的研究应利用质谱、核磁共振和体内成像等技术进一步探索药代动力学、宿主-寄生虫相互作用和作用机制，以促进临床前研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Acta tropica 医学-寄生虫学

CiteScore

5.40

自引率

11.10%

发文量

383

审稿时长

37 days

期刊介绍： Acta Tropica, is an international journal on infectious diseases that covers public health sciences and biomedical research with particular emphasis on topics relevant to human and animal health in the tropics and the subtropics.