Oral administration of amphotericin B nanoparticles: antifungal activity, bioavailability and toxicity in rats

Radwan, Mahasen A.; AlQuadeib, Bushra T.; Šiller, Lidija; Wright, Matthew C.; Horrocks, Benjamin R.

doi:10.1080/10717544.2016.1228715

Cited by 88 publications

(55 citation statements)

References 71 publications

(128 reference statements)

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“…However, TNF-␣ did not show significant changes after CAmB treatment in infected animals, and IL-6 showed small reductions, in contrast to large increases demonstrated in previous studies using older formulations of AmB (33,34). Such inflammatory reactions have been related to AmB-related liposome impurities, resulting in toxicities such as fever and renal toxicity (35,36), and may help to explain the absence of observed toxicity with CAmB, similar to other nanoparticle delivery formulations (37). More inflammationneutral preparations may thus help to reduce inflammatory syndromes such as cIRIS or postinfectious inflammatory response syndrome (PIIRS) in these patients, potentially improving outcome.…”

Section: Discussionmentioning

confidence: 65%

Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis

Lu¹,

Hollingsworth

Qiu

et al. 2019

mBio

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Cryptococcus neoformans is an encapsulated yeast responsible for approximately a quarter of a million deaths worldwide annually despite therapy, and upwards of 11% of HIV/AIDS-related deaths, rivaling the impact of tuberculosis and malaria. However, the most effective antifungal agent, amphotericin B, requires intravenous delivery and has significant renal and hematopoietic toxicity, making it difficult to utilize, especially in resource-limited settings. The present studies describe a new nanoparticle crystal encapsulated formulation of amphotericin B known as encochleated amphotericin B (CAmB) that seeks to provide an oral formulation that is low in toxicity and cost. Using a 3-day delayed model of murine cryptococcal meningoencephalitis and a large inoculum of a highly virulent strain of serotype A C. neoformans, CAmB, in combination with flucytosine, was found to have efficacy equivalent to parental amphotericin B deoxycholate with flucytosine and superior to oral fluconazole without untoward toxicity. Transport of fluorescent CAmB particles to brain as well as significant brain levels of amphotericin drug was demonstrated in treated mice, and immunological profiles were similar to those of mice treated with conventional amphotericin B. Additional toxicity studies using a standardized rat model showed negligible toxicity after a 28-day treatment schedule. These studies thus offer the potential for an efficacious oral formulation of a known fungicidal drug against intrathecal cryptococcal disease. IMPORTANCE Cryptococcus neoformans is a significant global fungal pathogen that kills an estimated quarter of a million HIV-infected individuals yearly and has poor outcomes despite therapy. The most effective therapy, amphotericin B, is highly effective in killing the fungus but is available only in highly toxic, intravenous formulations that are unavailable in most of the developing world, where cryptococcal disease in most prevalent. For example, in Ethiopia, reliance on the orally available antifungal fluconazole results in high mortality, even when initiated as preemptive therapy at the time of HIV diagnosis. Thus, alternative agents could result in significant saving of lives. Toward this end, the present work describes the development of a new formulation of amphotericin B (CAmB) that encapsulates the drug as a crystal lipid nanoparticle that facilitates oral absorption and prevents toxicity. Successful oral absorption of the drug was demonstrated in a mouse model that, in combination with the antifungal flucytosine, provided efficacy equal to a parental preparation of amphotericin B plus flucytosine. These studies demonstrate the potential for CAmB in combination with flucytosine to provide an effective oral formulation of a well-known, potent fungicidal drug combination.

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Section: Discussionmentioning

confidence: 65%

Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis

Lu¹,

Hollingsworth

Qiu

et al. 2019

mBio

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“…Using the help of the nanosized particles, the drugs for treatment may access to the target easier (Ahmed et al 2016). Silver nanoparticles help to improve the ability of the compounds use for treatment as the drugs have poor bioavailability, therefore the conjugation with silver nanoparticles are likely to improve the transportation of the drugs to infected areas (Radwan et al 2017). Recently, natural products coated nanoparticles have shown potent antiacanthamoebic effects.…”

Section: Discussionmentioning

confidence: 99%

Antiamoebic activity of plant-based natural products and their conjugated silver nanoparticles against Acanthamoeba castellanii (ATCC 50492)

et al. 2020

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Acanthamoeba spp. are the causative agent of Acanthamoeba keratitis and granulomatous amoebic encephalitis (GAE). The current options to treat Acanthamoeba infections have limited success. Silver nanoparticles show antimicrobial effects and enhance the efficacy of their payload at the specific biological targets. Natural folk plants have been widely used for treating diseases as the phytochemicals from several plants have been shown to exhibit amoebicidal effects. Herein, we used natural products of plant or commercial sources including quercetin (QT), kolavenic acid (PGEA) isolated from plant extracts of Polyalthia longifolia var pendula and crude plant methanolic extract of Caesalpinia pulcherrima (CPFLM) as antiacanthamoebic agents. Furthermore, these plant-based materials were conjugated with silver nanoparticles (AgNPs) to determine the effects of the natural compounds and their nanoconjugates against a clinical isolate of A. castellanii from a keratitis patient (ATCC 50492) belonging to the T4 genotype. The compounds were conjugated with AgNPs and characterized by using ultraviolet visible spectrophotometry and atomic force microscopy. Quercetin coated silver nanoparticles (QT-AgNPs) showed characteristic surface plasmon resonance band at 443 nm and the average size distribution was found to be around 45 nm. The natural compounds alone and their nanoconjugates were tested for the viability of amoebae, encystation and excystation activity against A. castellanii. The natural compounds showed significant growth inhibition of A. castellanii while QT-AgNPs specifically exhibited enhanced antiamoebic effects as well as interrupted the encystation and excystation activity of the amoebae. Interestingly, these compounds and nanoconjugates did not exhibit in vitro cytotoxic effects against human cells. Plantbased compounds and extracts could be an interesting strategy in development of alternative therapeutics against Acanthamoeba infections.

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“…The plasma was separated from the collected samples by centrifugation at 4000 rpm for 15 min and stored at À20 C until further use. AmB was extracted from the plasma and quantified by using a validated highperformance liquid chromatography (HPLC) method [20].…”

Section: Permeation Enhancingmentioning

confidence: 99%

Design of mannosylated oral amphotericin B nanoformulation: efficacy and safety in visceral leishmaniasis

Sarwar

Sohail

Saljoughian

et al. 2018

Artificial Cells, Nanomedicine, and Biotechnology

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The aim of this study was to evaluate mannose-anchored thiolated chitosan (MTC) based nanocarriers (NCs) for enhanced permeability, improved oral bioavailability and anti-parasitic potential of amphotericin B (AmB). Transgenic Leishmania donovani parasites expressing red fluorescent protein DsRed2 and imaging-flow cytometry was used to investigate parasitic burdens inside bone marrow-derived macrophages ex vivo. Cytokine estimation revealed that MTC nanocarriers activated the macrophages to impart an explicit immune response by higher production of TNF-α and IL-12 as compared to control. Cells treated with MTC NCs showed a significantly higher magnitude of nitrite and propidium iodide (PI) fluorescence intensity in contrast to cells treated with AmB. Concerning to apparent permeability coefficient (P) results, the MTC NCs formulation displayed more specific permeation across the Caco-2 cell monolayer as compared to AmB. The half-life of MTC NCs was about 3.3-fold persistent than oral AmB used as positive control. Also, t oral bioavailability of AmB was increased to 6.4-fold for MTC NCs compared to AmB for positive control. Acute oral evaluation indicated that MTC NCs were significantly less toxic compared to the AmB. Based on these findings, MTC NCs seems to be promising for significant oral absorption and improved oral bioavailability of AmB in leishmaniasis chemotherapy.

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Oral administration of amphotericin B nanoparticles: antifungal activity, bioavailability and toxicity in rats

Cited by 88 publications

References 71 publications

Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis

Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis

Antiamoebic activity of plant-based natural products and their conjugated silver nanoparticles against Acanthamoeba castellanii (ATCC 50492)

Design of mannosylated oral amphotericin B nanoformulation: efficacy and safety in visceral leishmaniasis

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