期刊
JOURNAL OF CONTROLLED RELEASE
卷 324, 期 -, 页码 657-668出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2020.05.026
关键词
Nanoassembly; Amphotericin B; Albumin; Nanomedicine; Nephrotoxicity; Redistribution
资金
- National Natural Science Foundation of China [81671989, 81601745, 81903670, 81471924]
- Scientific research projects of the Shanghai Science and Technology Committee [18411951300]
- Shanghai Youth Medical Talents Training Program (Laboratory Medicine) [[2018]02]
As the gold standard treatment for invasive fungal infection, amphotericin B (AmB) is limited by its severe nephrotoxicity. It has been shown that AmB complex with albumin in vivo forms a sub-10 nm nanocomplex within kidney excretion size range and eventually induces the nephrotoxicity. This study presents an approach to take advantage of the weakness of such unique interaction between AmB and albumin to form AmB nanocomplex beyond the size range of kidney excretion. Herein, a novel strategy was developed by directly assembling molecular BSA into larger-sized nanostructures with the reconstructed intermolecular disulfide bond and hydrophobic interaction. The rich binding sites of AmB within BSA nanostructures enabled the efficient AmB loading and forming nanoparticle (AmB-NP) which exceeds the size range of kidney excretion (similar to 60 nm). We found nanoassembly with BSA redirected biodistribution of AmB with a 2.8-fold reduction of drug accumulation in the kidney and significantly improved its renal impairment in mice. Furthermore, we found that nanoassembly with BSA significantly increased the biodistribution of AmB in brain and endowed it 100-folds increase in pharmacological effect against meningoencephalitis caused by common fungal pathogen Cryptococcus neoformans. Together, this study not merely overcomes the nephrotoxicity of AmB using its weakness by a nanoassembly method, and provides a new strategy for reducing toxicity of drugs with high albumin binding rate in vivo.
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