Carreño Heider, Osorio Jorge, Mejía-Ospino Enrique, Escobar Patricia
Centro de Investigación de enfermedades tropicales (CINTROP-UIS), Departamento de Ciencias Básicas, Escuela de Medicina, Universidad Industrial de Santander, Bucaramanga, Colombia.
Laboratorio de Espectroscopia Atómica Y Molecular (LEAM), Escuela de Química, Universidad Industrial de Santander, Bucaramanga, 680002, Colombia.
J Exp Pharmacol. 2025 May 30;17:269-286. doi: 10.2147/JEP.S511808. eCollection 2025.
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 . 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.
目的：关于金属有机框架（MOF）作为抗利什曼原虫药物的局部给药系统（DDS）的信息有限。本研究概述了我们开发MOF-药物偶联物作为感染利什曼原虫的小鼠皮肤利什曼病（CL）局部治疗方法的策略。 方法：我们从两种商业MOF（ZIF-8和Fe-BTC）和七种抗利什曼原虫化合物中选择偶联物。选择两性霉素B（AmB）和沸石咪唑酯骨架-8（AmB@ZIF-8），并使用浸渍法以AmB:ZIF-8比例1.5:1.0制备。使用动态光散射、紫外可见光谱、傅里叶变换红外光谱和扫描电子显微镜对偶联物进行表征。制备水凝胶并评估其在CL-BALB/c小鼠中的毒性和疗效。 结果：AmB@ZIF-8表现出59.6%的载药量、6.67%的包封率和2%的体外药物释放（IVR）。AmB@ZIF-8的粒径比ZIF-8小且多分散性更高（1370 nm对2537 nm）。证明了AmB与ZIF-8的偶联。AmB@ZIF-8对前鞭毛体表现出与AmB相似的抗利什曼原虫活性。局部应用0.5% AmB@ZIF-8和0.5% AmB水凝胶30天，未能减小病变大小或寄生虫负荷。最初，病变大小稳定；然而，在30天的随访期内，病变随后显著增大。MOF-水凝胶治疗无刺激性。 结论：包封率（EE%）和AmB的IVR非常低。发现AmB@ZIF-8和AmB水凝胶对感染CL的小鼠安全但无效。几个因素可能解释这些负面结果，包括商业ZIF-8的大尺寸、AmB在溶液中的聚集、用于浸渍的过量AmB以及IVR测定的条件。由于其对酸性pH水平敏感，我们建议继续将ZIF-8用作DDS；然而，我们建议减小粒径并降低药物与ZIF-8的比例。本文讨论了其他替代方案。我们还主张研究替代的抗利什曼原虫药物作为负载物，如米替福新或喷他脒。
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