Characterization of a Polyethylene Glycol-Amphotericin B Conjugate Loaded with Free AMB for Improved Antifungal Efficacy

Tan, Tessa Rui Min; Hoi, Kong Meng; Zhang, Peiqing; Ng, Say Kong

doi:10.1371/journal.pone.0152112

Cited by 25 publications

(21 citation statements)

References 38 publications

(44 reference statements)

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“…The spectral modifications induced by aggregation may be represented by the ratio of the first (340 nm) to the fourth (410 nm) peaks, I/IV (A 340 /A 410 ) 13 , indicative of the aggregated versus monomeric ratio. In accordance with previous reports 42 , 52 , the A 340 /A 410 ratio was >2 for AmB-NA, indicating the presence of super-aggregated forms 13 of AmB in AmB-NA. Absorption peaks at a lower wavelength are generally observed when aggregated AmB is complexed with deoxycholate 53 , or upon formation of superaggregates by heat treatment of AmB alone 15 .…”

Section: Discussionsupporting

confidence: 93%

Biomimetically engineered Amphotericin B nano-aggregates circumvent toxicity constraints and treat systemic fungal infection in experimental animals

Zia

Owais

Rauf

et al. 2017

Sci Rep

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Biomimetic synthesis of nanoparticles offers a convenient and bio friendly approach to fabricate complex structures with sub-nanometer precision from simple precursor components. In the present study, we have synthesized nanoparticles of Amphotericin B (AmB), a potent antifungal agent, using Aloe vera leaf extract. The synthesis of AmB nano-assemblies (AmB-NAs) was established employing spectro-photometric and electron microscopic studies, while their crystalline nature was established by X-ray diffraction. AmB-nano-formulation showed much higher stability in both phosphate buffer saline and serum and exhibit sustained release of parent drug over an extended time period. The as-synthesized AmB-NA possessed significantly less haemolysis as well as nephrotoxicity in the host at par with Ambisome®, a liposomized AmB formulation. Interestingly, the AmB-NAs were more effective in killing various fungal pathogens including Candida spp. and evoked less drug related toxic manifestations in the host as compared to free form of the drug. The data of the present study suggest that biomimetically synthesized AmB-NA circumvent toxicity issues and offer a promising approach to eliminate systemic fungal infections in Balb/C mice.

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Section: Discussionsupporting

confidence: 93%

Biomimetically engineered Amphotericin B nano-aggregates circumvent toxicity constraints and treat systemic fungal infection in experimental animals

Zia

Owais

Rauf

et al. 2017

Sci Rep

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“…The resulting cardiomyocytes were maintained for three weeks in serum-free RPMI-1640 (R8758, Sigma-Aldrich), supplemented with B27 and Antibiotic-Antimycotic (Thermo Fisher). The final concentration of amphotericin B was 270 nM, well below the threshold concentrations reported for toxicity of this compound 76,77 . The IMR90 cardiomyocytes were reseeded at a density of 12,500 cells well −1 onto half-area 96-well plates (675096, Grenier Bio-One), coated as above, for 1 week prior to treatment.…”

Section: Methods Cell Linesmentioning

confidence: 65%

Selective protection of human cardiomyocytes from anthracycline cardiotoxicity by small molecule inhibitors of MAP4K4

Golforoush

Narasimhan

Guerrero

et al. 2020

Sci Rep

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Given the poor track record to date of animal models for creating cardioprotective drugs, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have been proposed as a therapeutically relevant human platform to guide target validation and cardiac drug development. Mitogen-Activated Protein Kinase Kinase Kinase Kinase-4 (MAP4K4) is an "upstream" member of the MAPK superfamily that is implicated in human cardiac muscle cell death from oxidative stress, based on gene silencing and pharmacological inhibition in hPSC-CMs. A further role for MAP4K4 was proposed in heart muscle cell death triggered by cardiotoxic anti-cancer drugs, given its reported activation in failing human hearts with doxorubicin (DOX) cardiomyopathy, and its activation acutely by DOX in cultured cardiomyocytes. Here, we report successful protection from DOX in two independent hPSC-CM lines, using two potent, highly selective MAP4K4 inhibitors. The MAP4K4 inhibitors enhanced viability and reduced apoptosis at otherwise lethal concentrations of DOX, and preserved cardiomyocyte function, as measured by spontaneous calcium transients, at sub-maximal ones. Notably, in contrast, no intereference was seen in tumor cell killing, caspase activation, or mitochondrial membrane dissipation by DOX, in human cancer cell lines. Thus, MAP4K4 is a plausible, tractable, selective therapeutic target in DOX-induced human heart muscle cell death. With earlier diagnosis and improved treatments for cancer, cardiovascular disease has become the main alternative cause of death in cancer survivors 1-4. This heightened risk is ascribable to the cardiac toxicity of several routine anti-cancer agents including, especially, anthracyclines like doxorubicin (DOX) 5. Though some relief can result from standard heart failure medications, no approved therapy apart from the iron chelator dexrazoxane addresses the responsible cytotoxic mechanisms and effector pathways operating in the damaged cardiomyocytes. For anthracyclines, these include diverse reported mediators-binding to nuclear topoisomerase 2β, thereby triggering DNA double-strand breaks, p53-dependent apoptosis, mitochondrial dysfunction, reactive oxygen species, and programmed iron-dependent cell death (ferroptosis) 1,6,7. Cardiotoxicity can be acute, early, or late; early intervention based on subclinical abnormalities may be key to averting the delayed or cumulative effects 8. Notably, acute toxicity is seen in up to 30% of patients receiving anthracyclines, soon after infusion 4. Current cardioprotection trials in cancer rely chiefly on routine heart failure medications (ACE inhibitors, β-blockers, angiotensin receptor blockers), which mitigate the symptoms and signs, with little or no demonstrated impact on cardiomyocyte death. Therapeutic progress has been hampered, in part, by the failure of animal models alone to predict clinical success in cardioprotection. For instance, nearly all strategies for protection in ischemic heart disease, a more intensively studied indication, have failed between phases I and I...

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“…Nephrotoxicity has been the most studied side effect induced by polymeric-based drug delivery systems containing AmB. The majority of the studies related to the fabrication of these vehicles have focused on evaluating their in vitro toxicity in human kidney cells, demonstrating their ability to significantly decrease the main side effects of AmB [ 25 , 26 , 42 , 52 , 53 ]. Nevertheless, the toxicity caused by polymeric formulations in lung cells has not been a focus of study.…”

Section: Resultsmentioning

confidence: 99%

“…Because the majority of the studies related to the fabrication of polymeric vehicles have focused on evaluating their in vitro toxicity in human kidney cells, demonstrating their ability to significantly decrease the main side effects of AmB [ 25 , 26 , 42 , 52 , 53 ]; this study will only focus on lung cell toxicity which is one of the main side effects related to commercial formulations containing AmB. Immortalized or cancer cells lines are widely used for in vitro toxicology studies [ 54 ].…”

Section: Methodsmentioning

confidence: 99%

Preparation and In Vitro Evaluation of Alginate Microparticles Containing Amphotericin B for the Treatment of Candida Infections

Alvarez-Berríos

Aponte-Reyes

Diaz-Figueroa

et al. 2020

International Journal of Biomaterials

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Invasive candidiasis (IC) remains as a major cause of morbidity and mortality in critically ill patients. Amphotericin B (AmB) is one of the most effective antifungal agents commonly used to treat this infection. However, it induces severe side effects such as nephrotoxicity, cardiac alterations, nausea, fever, and liver damage. The utilization of drug delivery systems has been explored to overcome these limitations. Several AmB lipid formulations have been developed and are currently available in the market. Although they have the ability to reduce the main side effects of free AmB, their high cost, necessity of repeated intravenous injections for successful treatment, and incidence of pulmonary toxicity have limited their use. In the last decades, alginate has gained significant interest in drug delivery applications as a cost-effective strategy to improve the safety and therapeutic effect of toxic drugs. In this work, the clinically relevant drug AmB was encapsulated into alginate microparticles using the emulsification/external gelation method. We hypothesize that this synthesis strategy may positively impact the antifungal efficacy of AmB-loaded MCPs toward Candida albicans cells while reducing the toxicity in human lung cells. To prove this hypothesis, the ability of the microplatform to disrupt the cellular membrane potential was tested and its antifungal effectiveness toward Candida albicans cells was evaluated using the cell counting and plate count methods. Moreover, the toxicity of the microplatform in human lung cells was evaluated using CellTiter 96® AQueous cell viability assay and qualitative diffusion analysis of acridine orange. Our results demonstrated that the platform developed in this work was able to induce antifungal toxicity against Candida albicans yeast cells at the same level of free AmB with minimal toxicity to lung cells, which is one of the main side effects induced by commercial drug delivery systems containing AmB. Overall, our data provides convincing evidence about the effectiveness of the alginate-based microplatform toward Candida albicans cells. In addition, this vehicle may not require several infusions for a successful treatment while reducing the pulmonary toxic effect induced by commercial lipid formulations.

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Characterization of a Polyethylene Glycol-Amphotericin B Conjugate Loaded with Free AMB for Improved Antifungal Efficacy

Cited by 25 publications

References 38 publications

Biomimetically engineered Amphotericin B nano-aggregates circumvent toxicity constraints and treat systemic fungal infection in experimental animals

Biomimetically engineered Amphotericin B nano-aggregates circumvent toxicity constraints and treat systemic fungal infection in experimental animals

Selective protection of human cardiomyocytes from anthracycline cardiotoxicity by small molecule inhibitors of MAP4K4

Preparation and In Vitro Evaluation of Alginate Microparticles Containing Amphotericin B for the Treatment of Candida Infections

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