NanoDisk containing super aggregated amphotericin B: a high therapeutic index antifungal formulation with enhanced potency.
NanoDisk containing super aggregated amphotericin B: a high therapeutic index antifungal formulation with enhanced potency.
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DOI：
10.2147/ijn.s50113
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发表时间：
2013
影响因子：
8
通讯作者：
Oda MN
中科院分区：
文献类型：
--
作者：
Burgess BL;He Y;Baker MM;Luo B;Carroll SF;Forte TM;Oda MN
纳米盘两性霉素B （ND-AMB）是一种蛋白质磷脂生物颗粒，含有抗真菌AMB的“超聚集体”形式。虽然脂基AMB制剂，包括脂质体AMB (L-AMB)，比脱氧胆酸盐（DOC）溶解形式（DOC-AMB）更安全，但脂基制剂的效力减弱。我们已经开发出一种基于amb的治疗方法，耐受性良好且完全有效。通过肉汤培养生长抑制试验和定量培养电镀的念珠菌动力学来确定效力。在健康小鼠中进行了毒理学研究。使用免疫能力和白细胞减少的小鼠模型对全身性白色念珠菌感染进行疗效评估。ND-AMB对白色念珠菌和烟曲霉的最低抑菌浓度分别比L-AMB低4倍和6倍。ND-AMB的候选菌活性为0.125 mg/L，比L- amb低16倍。在小鼠试验中，最高剂量为15 mg/kg的ND-AMB对肾脏或肝脏没有显著的毒性。当在感染白色念珠菌的免疫能力小鼠中进行评估时，ND-AMB至少与DOC-AMB或L-AMB一样有效。在白细胞减少的念珠菌病模型中，ND-AMB的50%有效剂量比L-AMB低约三倍。这些结果表明，与DOC-AMB和L-AMB相比，ND-AMB表现出更有利的安全性，同时保持了不受影响的抗真菌性能。ND-AMB是治疗侵袭性真菌感染的一种很有前景的疗法。
NanoDisk–amphotericin B (ND-AMB) is a protein-phospholipid bioparticle containing a “super aggregate” form of antifungal AMB. While lipid-based formulations of AMB, including liposomal AMB (L-AMB), are safer than the deoxycholate (DOC) solubilized form (DOC-AMB), the potency of lipid-based formulations is attenuated. We have developed an AMB-based therapy that is both well tolerated and fully efficacious. Potency was determined using broth culture growth-inhibition assays and candidacidal kinetics by quantitative culture plating. Toxicology studies were performed in healthy mice. Efficacy was assessed using both immune-competent and leukopenic murine models of systemic Candida albicans infection. ND-AMB C. albicans and Aspergillus fumigatus minimum inhibitory concentrations were fourfold and sixfold lower, respectively, than that observed for L-AMB. ND-AMB exhibited candidacidal activity at 0.125 mg/L, 16-fold lower than L-AMB. In mice, ND-AMB produced no statistically significant kidney or liver toxicity at 15 mg/kg, the highest dose tested. When evaluated in immune-competent mice infected with C. albicans, ND-AMB was at least as effective as DOC-AMB or L-AMB. In a leukopenic model of candidiasis, the 50% effective dose of ND-AMB was around threefold lower than L-AMB. These results indicate that ND-AMB exhibits a more favorable safety profile while maintaining uncompromised antifungal properties compared to both DOC-AMB and L-AMB. ND-AMB is a promising therapy for the treatment of invasive fungal infections.