In Vitro and In Vivo Study of Amphotericin B Formulation with Quaternized Bioreducible Lipidoids

Abstract

Invasive fungal infections are well-known causes of morbidity and mortality in immunocompromised patients. Amphotericin B (AmB) is a polyene fungicidal agent with excellent properties of the broad antifungal spectrum, high activity, and relatively rare drug resistance. However, significant toxicities limit the clinical application of AmB and its conventional formulation AmB deoxycholate (Fungizone). Here we investigated nanoparticle formulations of AmB using synthetic biodegradable lipidoids and evaluated their stability, in vitro antifungal efficacy, and in vivo toxicity and pharmacokinetics. We found that the AmB formulated using a mixture of quaternized lipidoid (Q78-O14B) and DSPE-PEG2000 has the size around 70–100 nm and is stable during storage. The formulation showed no hemotoxicity to red blood cells (RBCs) in vitro. It also possesses the highest antifungal activity (in vitro) and lowest toxicity (both in vitro and in vivo). These metrics are significantly superior to the commercial antifungal product Fungizone. Meanwhile, AmB/Q78-O14B-P exhibited prolonged blood circulation in comparison to Fungizone in vivo. In AmB/Q78-O14B-P formulation, AmB was still detectable in the liver, spleen, and lung tissues with a concentration above the minimum inhibitory concentrations 72 h after low-dose intravenous injection. Based on these results, AmB in lipidoid nanoparticle formulation may produce sustained antifungal activity against blood-borne and systemic organ infections. Moreover, the new AmB formulation showed low nephrotoxicity and hepatotoxicity in rats even at high doses, allowing a dramatically wider and safer therapeutic window than Fungizone. This method provides a means to develop much needed antifungal agents that will be more therapeutically efficacious, more affordable (than AmBisome), and less toxic (than Fungizone) for the treatment of systemic fungal infections.

Neurotransmitter-derived lipidoids (NT-lipidoids) for enhanced brain delivery through intravenous injection

“…The AmB encapsulates were prepared according to our previous report ( 27 ). Briefly, 1 mg of each lipidoid (solid) was mixed with 1 mg of AmB in 300 μl of dimethyl sulfoxide (DMSO).…”

“…The DLCs (drug loading content) of AmB were calculated according to our previous report ( fig. S7D) (27). TEM images were captured by a FEI Tecnai Spirit transmission electron microscope ( fig.…”

“…The tissue biodistributions of AmB were measured using HPLC analysis with a modular liquid chromatograph system (Agilent) according to our previous report (27). The calibration curve of AmB concentration measured using HPLC was shown in fig.…”

Intracellular Antibody Delivery Mediated by Lipids, Polymers, and Inorganic Nanomaterials for Therapeutic Applications

“…[40,41] Lipids are amphiphilic small molecules, either naturally occurring or synthetically constructed, which self-assemble into nanoparticles in selective solvents. The combinatorial library strategy has been particularly useful in synthesizing and identifying novel lipid formulations for small molecule drug, [42,43] protein, [44][45][46] and gene [47][48][49] deliveries. Many types of lipids have been tested for intracellular antibody delivery.…”

mRNA Delivery Using Bioreducible Lipidoid Nanoparticles Facilitates Neural Differentiation of Human Mesenchymal Stem Cells

“…[ 6 ] In our group, a combinatorial library strategy is used to develop novel lipidoids for high efficacy mRNA delivery in vitro and in vivo. [ 7 ] This strategy uses simple Michael addition chemistry to synthesize a library of lipidoids with diverse structures [ 8 ] which can then be screened for delivering different types of therapeutic cargos, including small molecules, [ 9 ] nucleic acids, [ 10 ] and proteins. [ 11 ] Besides, these lipidoids contain degradable bond such as ester and disulfide bond, and have shown great biocompatibility both in vitro and in vivo.…”