"Click" amphotericin B in prodrug nanoformulations for enhanced systemic fungemia treatment

Dandan Guo; Changying Shi; Liye Suo; Xiaotian Ji; Hao Yue; Dekai Yuan; Juntao Luo

doi:10.1016/j.jconrel.2024.05.003

"Click" amphotericin B in prodrug nanoformulations for enhanced systemic fungemia treatment

J Control Release. 2024 May 15:370:626-642. doi: 10.1016/j.jconrel.2024.05.003. Online ahead of print.

Authors

Dandan Guo¹, Changying Shi¹, Liye Suo², Xiaotian Ji¹, Hao Yue¹, Dekai Yuan¹, Juntao Luo³

Affiliations

¹ Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
² Department of Pathology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
³ Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA; Department of Surgery, State University of New York Upstate Medical University, Syracuse, NY 13210, USA; Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, State University of New York Upstate Medical University, Syracuse, NY 13210, USA; Sepsis Interdisciplinary Research Center (SIRC), State University of New York Upstate Medical University, Syracuse, NY 13210, USA. Electronic address: luoj@upstate.edu.

PMID: 38734314
DOI: 10.1016/j.jconrel.2024.05.003

Abstract

Severe nephrotoxicity and infusion-related side effects pose significant obstacles to the clinical application of Amphotericin B (AmB) in life-threatening systemic fungal infections. In pursuit of a cost-effective and safe formulation, we have introduced multiple phenylboronic acid (PBA) moieties onto a linear dendritic telodendrimer (TD) scaffold, enabling effective AmB conjugation via boronate chemistry through a rapid, high yield, catalysis-free and dialysis-free "Click" drug loading process. Optimized AmB-TD prodrugs self-assemble into monodispersed micelles characterized by small particle sizes and neutral surface charges. AmB prodrugs sustain drug release in circulation, which is accelerated in response to the acidic pH and Reactive Oxygen Species (ROS) in the infection and inflammation. Prodrugs mitigate the AmB aggregation status, reduce cytotoxicity and hemolytic activity compared to Fungizone®, and demonstrate superior antifungal activity to AmBisome®. AmB-PEG^5kBA₄ has a comparable maximum tolerated dose (MTD) to AmBisome®, while over 20-fold increase than Fungizone®. A single dose of AmB-PEG^5kBA₄ demonstrates superior efficacy to Fungizone® and AmBisome® in treating systemic fungal infections in both immunocompetent and immunocompromised mice.

Keywords: Amphotericin B prodrug; Click boronate chemistry; Immunocompromised fungal infection; Reduced nephrotoxicity; Telodendrimer nanoformulation; pH-/ROS-responsive release.