COMMUNICATION: Pharmacokinetics and Nephrotoxicity of Amphotericin B-Incorporated Poly(Ethylene Glycol)-Block-Poly(N-Hexyl Stearate l-aspartamide) Micelles

Diezi, Thomas A.; Takemoto, Jody K.; Davies, Neal M.; Kwon, Glen S.

doi:10.1002/jps.22445

Cited by 11 publications

(6 citation statements)

References 19 publications

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“…monomeric AmB, is dramatically less renal toxic than Fungizone ® , i.e. aggregated AmB after a one week course of treatment in a rat model, and they are consistent with an earlier single dose study in rats comparing mAmB and Fungizone ® , where the same conclusion was drawn [11]. In this earlier study, a change in kidney distribution of AmB as a factor in reduced renal toxicity was ruled out, showing no statistical difference in kidney distribution between mAmB and Fungizone ® .…”

Section: Resultssupporting

confidence: 88%

“…PEG- b -PHSA had a PEG block at 10,000 g/mole, a PHSA block with a degree of polymerization of 12, and a degree of stearic acid substitution at 50%, based on 1 H NMR spectroscopy. AmB was incorporated in PEG- b -PHSA micelles (2:1 molar ratio) using a thin film-hydration method as described previously [11]. Briefly, AmB dissolved in 6 mL of methanol (0.3 mg/mL) was added to PEG- b -PHSA dissolved in 10 mL of chloroform (6 mg/mL) in a round bottom flask.…”

Section: Methodsmentioning

confidence: 99%

“…Absorption spectra of mAmB and Fungizone ® were determined over the range of 300–450 nm by CARY ® 50 BIO UV-Vis Spectrophotometers (Varian, Palo Alto, CA) using a quartz cuvette (10 mm path length; Starna Cells Inc., Atascadero, CA). HPLC analytical method for AmB was adapted from a method reported previously [11]. …”

Section: Methodsmentioning

confidence: 99%

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Pharmacokinetics and Renal Toxicity of Monomeric Amphotericin B in Rats after a Multiple Dose Regimen

Kang

Gao

Shin

et al. 2016

PNT

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Background Delivery of monomeric Amphotericin B (AmB), i.e. deaggregated AmB, has been a major tactic in the reduction of renal toxicity at a membrane level, taking advantage of the selectivity of monomeric AmB for binding ergosterol over cholesterol. Objective The aim of this study was to characterize the pharmacokinetic (PK) and renal toxicity of monomeric AmB in rats following a multiple dose regimen. Method AmB existed primarily in a monomeric state in poly(ethylene glycol)-block-poly(N-hexyl stearate L-aspartamide) (PEG-b-PHSA) micelles (mAmB) at 2:1 ratio (mol:mol), whereas AmB as its standard formulation, Fungizone®, was highly self-aggregated based on absorption spectroscopy. Results After single intravenous injection, mAmB significantly (p < 0.001) increased the area under the plasma drug concentration-time curve (AUC) and reduced the volume of distribution (Vd) and total systemic clearance (CL) relative to Fungizone®. After daily intravenous injections at dose of 1.0 mg/kg for 7 days, PK parameters of mAmB and Fungizone® were similar to day 1. The treatment of Fungizone® also significantly (p < 0.05) increased levels of urinary enzymes, N-acetyl-β-D-glucosaminidase (NAG) and kidney injury molecule-1 (KIM-1) by 3.1- and 3.0 fold, respectively, whereas levels of NAG and KIM-1 were unchanged for mAmB, consistent with hematoxylin and eosin (H&E) staining of excised kidneys. Conclusion In summary, mAmB has less renal toxicity than AmB as Fungizone® in rats after a multiple dose regimen, validating the aggregation state hypothesis of AmB in vivo.

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Section: Resultssupporting

confidence: 88%

Section: Methodsmentioning

confidence: 99%

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Pharmacokinetics and Renal Toxicity of Monomeric Amphotericin B in Rats after a Multiple Dose Regimen

Kang

Gao

Shin

et al. 2016

PNT

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“…It suggests that, in addition to the controlled release of the cargos, PMs are safe nanocontainers for nephrotoxic drugs such as AmB. This is in concordance with in vivo studies which corroborate that micellar systems composed of polystyrene-block-polyethylene oxide [32], linoleic acid modified polyethylene glycol-block-polyethylenimine [33], polyethylene glycol-block-poly(N-hexyl stearate l-aspartamide) [34] and partially benzylated poly-L-aspartic acid [35] endow AmB lower toxicity.…”

Section: Introductionsupporting

confidence: 77%

Development of Amphotericin B Micellar Formulations Based on Copolymers of Poly(ethylene glycol) and Poly(ε-caprolactone) Conjugated with Retinol

et al. 2020

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Amphotericin B (AmB) is a broad spectrum of antifungal drug used to treat antifungal diseases. However, due to the high toxicity of AmB, treated patients may suffer the risk of side effects, such as renal failure. Nanoencapsulation strategies have been reported to elicit low toxicity, albeit most of them possess low encapsulation efficiency. The aim of this research is to develop micellar delivery systems for AmB with reduced toxicity while maintaining its affectivity by employing retinol (RET)-conjugated amphiphilic block copolymers (ABCs) as precursors. Copolymers composed of poly(ε-caprolactone) (A) and polyethylenglycol (B) of types AB and ABA were synthesized by ring opening polymerization and subsequently conjugated with RET by Steglich esterification. 1H-NMR spectroscopy was used to corroborate the structure of copolymers and their conjugates and determine their molecular weights. Analysis by gel permeation chromatography also found that the materials have narrow distributions. The resulting copolymers were used as precursors for delivery systems of AmB, thus reducing its aggregation and consequently causing a low haemolytic effect. Upon conjugation with RET, the encapsulation capacity was enhanced from approximately 2 wt % for AB and ABA copolymers to 10 wt %. AmB encapsulated in polymer micelles presented improved antifungal efficiency against Candida albicans and Candida auris strains compared with Fungizone®, as deduced from the low minimum inhibitory concentration.

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“…Deaggregation of AmB has been achieved with many different PEG-lipids, presumably due to a more favorable interaction with the lipid tail than with itself and sequestration of the hydrophobic molecule into the hydrophobic micelle core. Significant reductions in both in vitro hemolytic activity (26–29) and in vivo renal toxicity (30) have been demonstrated relative to AmB-SD. However, issues arise when the methods used to create these formulations are taken into consideration.…”

Section: Introductionmentioning

confidence: 99%

Reformulation of Fungizone by PEG-DSPE Micelles: Deaggregation and Detoxification of Amphotericin B

2016

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Purpose Fungizone® (AmB-SD), amphotericin B solubilized by sodium deoxycholate, contains a highly aggregated form of the antifungal agent that causes dose-limiting renal toxicity. With the aim of reducing the formulation’s toxicity by co-delivering monomeric amphotericin B (AmB) and sodium supplementation, we deaggregated AmB-SD with FDA-approved excipient PEG-DSPE in 0.9% NaCl-USP. Herein, we describe a reformulated AmB-SD with PEG-DSPE micelles that results in a less toxic drug with maintained antifungal activity. Methods We compared the aggregation state and particle size of AmB-SD alone or combined with PEG-DSPE micelles. In vitro hemolytic activity and in vivo renal toxicity were measured to determine the toxicity of different formulations. In vitro antifungal assays were performed to determine differences in efficacy among formulations. Results PEG-DSPE micelles in saline deaggregated AmB-SD. Deaggregated AmB-SD exhibited significantly reduced in vitro and in vivo toxicity. In vitro antifungal studies showed no difference in minimum inhibitory and fungicidal concentrations of AmB-SD combined with PEG-DSPE relative to the drug alone. Conclusions Reformulation of AmB-SD with PEG-DSPE micelles in saline facilitates co-delivery of monomeric AmB and sodium supplementation, potentially reducing the dose-limiting nephrotoxicity of AmB-SD. Ease of preparation and commercially available components lead us to acknowledge its potential for clinical use.

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COMMUNICATION: Pharmacokinetics and Nephrotoxicity of Amphotericin B-Incorporated Poly(Ethylene Glycol)-Block-Poly(N-Hexyl Stearate l-aspartamide) Micelles

Cited by 11 publications

References 19 publications

Pharmacokinetics and Renal Toxicity of Monomeric Amphotericin B in Rats after a Multiple Dose Regimen

Pharmacokinetics and Renal Toxicity of Monomeric Amphotericin B in Rats after a Multiple Dose Regimen

Development of Amphotericin B Micellar Formulations Based on Copolymers of Poly(ethylene glycol) and Poly(ε-caprolactone) Conjugated with Retinol

Reformulation of Fungizone by PEG-DSPE Micelles: Deaggregation and Detoxification of Amphotericin B

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