Enhancing Safety and Efficacy by Altering the Toxic Aggregated State of Amphotericin B in Lipidic Nanoformulations

Abstract

The toxicity of Amphotericin B (AmB) is contributed by the small, water-soluble aggregates of the drug. Hence, AmB lipid polymer hybrid nanoparticles (LIPOMER), comprising stearate lipids with a hydrophilic polymer Gantrez (GZ), and solid lipid nanoparticles (SLN), comprising only stearates, were prepared with the objective of monomerizing AmB. While intercalation of stearates with the hydrophobic polyene chain could hinder AmB–AmB interactions, enabling monomerization, it was hypothesized that GZ could aid in the stabilization of the monomers through hydrophilic interactions. AmB LIPOMERs and SLNs, prepared by nanoprecipitation, exhibited an average size of 350–500 nm with negative ζ potential. Polyglyceryl-6-distearate (PGDS) SLN exhibited maximum monomerization, with the highest peak IV (410 nm) to peak I (350 nm) ratio in the UV–visible spectrum. In total contrast, LIPOMERs and GZ nanoparticles revealed a hypsochromic shifted peak I between 321 and 324 nm, indicative of AmB super-aggregate formation. Super-aggregates, which result due to condensation of multiple aggregates with monomers, were attributed to extensive GZ–AmB and GZ–GZ interactions and could provide advantages of enhanced thermodynamic stability, with safety and efficacy similar to the monomeric form. Safety was confirmed by low and comparable erythrocyte toxicity exhibited by the LIPOMERs and SLNs. An in vitro efficacy study of PGDS LIPOMER and SLN against intracellular amastigotes revealed significantly lower IC50 values, which translated to a 7.1- and 6.1-fold enhancement in efficacy compared to commercial nanoformulations Amfocare (micellar AmB) and 1.79- and 1.54-fold enhancement in efficacy compared to Fungisome (liposomal AmB). High efficacy coupled with a higher selectivity index indicated the superiority of the developed AmB nanoformulations and substantiated that altering the toxic aggregated state of AmB can offer a promising approach for the design of safe and efficacious AmB lipidic nanoformulations.

The Fate of Sialic Acid and PEG Modified Epirubicin Liposomes in Aged versus Young Cells and Tumor Mice Models

“…In the experiment of 8-week-old mice and 8-month-old mice, different drug delivery system (harnessing PBMs and evading immune system) produced different therapeutic effects [ 32 ]. With the increase of PBMs, the administration routes using PBMs drug delivery system increased the accumulation of EPI-SL in tumors [ 33 ]. For EPI-PL, the accumulation of EPI-PL at the tumor site is reduced.…”

Potential lipid-based strategies of amphotericin B designed for oral administration in clinical application

“…Some experiments have been conducted to investigate the aggregation of AmB in lipid excipients. The strategy to use lipids for stabilizing the monomer state of AmB had focused on not only limiting the hydrophobic interactions of the drug, but also masking the polar regions of the macrolide ring, and increasing the solubilization capacity (Das and Devarajan, 2020 ). Fujii et al.…”

Polyene Antibiotics Physical Chemistry and Their Effect on Lipid Membranes; Impacting Biological Processes and Medical Applications

“…Since the 1990s, some of these formulations went into clinical use: AmB lipid complex with the commercial name Abelcet ® [ 183 , 184 ], which is formed in a ribbon-like shape [ 185 ]; there is also a colloidal dispersion of AmB and cholesteryl sulfate that forms disk complexes and is sold under the commercial name of Amphotec ® or Amphocil ® [ 186 , 187 , 188 , 189 , 190 ]; a liposomal formulation of AmB in cholesterol-containing lipid vesicles sold under the name of Ambisome ® [ 191 , 192 , 193 , 194 ]; and a multilamellar vesicle formulation, with a different lipid mixture and sold under the name Fungisome TM [ 195 , 196 , 197 , 198 , 199 , 200 ]. In the case of Nys, a liposomal formulation called Nyotran ® [ 201 , 202 , 203 , 204 , 205 ] is currently undergoing phase III clinical trials [ 178 ], and the available results are promising.…”