Biocompatibility and Effectiveness of Amphotericin B-Loaded Metal-Organic Structures (AmB-ZIF-8) as Dermal Drug Transporters in Experimental Cutaneous Leishmaniasis

Purpose: Information on metal-organic frameworks (MOFs) as topical drug delivery systems (DDS) for antileishmanial drugs is limited. This study outlines our strategies for developing MOF-drug conjugate as a topical treatment for cutaneous leishmaniasis (CL) in mice infected with Leishmania (L). amazonensis . Methods: We selected conjugates from two commercial MOFs (ZIF-8 and Fe-BTC) and seven antileishmanial compounds. Amphotericin B (AmB) and zeolitic imidazolate framework-8 (AmB@ZIF-8) were chosen and prepared at an AmB: ZIF-8 ratio of 1.5:1.0 using the impregnation method. Conjugates were characterised using dynamic light scattering, UV-Vis, FTIR, and SEM. Hydrogels were prepared and evaluated for toxicity and efficacy in CL-BALB/c mice. Results: AmB@ZIF-8 exhibited a 59.6% loading capacity, 6.67% encapsulation efficiency, and 2% in vitro drug release (IVR). The particle size of AmB@ZIF-8 was smaller and more polydisperse than ZIF-8 (1370 nm vs 2537 nm). The conjugation of AmB to ZIF-8 was demonstrated. AmB@ZIF-8 exhibited similar antileishmanial activity to AmB against promastigotes. Topical 0.5% AmB@ZIF-8 and 0.5% AmB hydrogels, administered for 30 days, were unable to decrease lesion sizes or parasite loads. Initially, there was stabilisation of the lesion size; however, the lesions subsequently increased considerably during the 30-day follow-up period. The MOF-hydrogel treatment was non-irritating. Conclusion: There were very low EE% and AmB IVR. AmB@ZIF-8 and AmB hydrogels were found to be safe but ineffective against CL-infected mice. Several factors may explain these negative results, including the large size of the commercial ZIF-8, the aggregation of AmB in solution, the excess AmB used for impregnation, and the conditions of the IVR assay. We suggest continuing to use ZIF-8 as a DDS due to its sensitivity to acidic pH levels; however, we recommend reducing the particle size and lowering the drug-to-ZIF-8 ratio. Other alternatives are discussed in the present paper. We also advocate investigating alternative antileishmanial drugs as cargo, such as miltefosine or pentamidine.