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

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.