Amphotericin B Nano-Assemblies Circumvent Intrinsic Toxicity and Ensure Superior Protection in Experimental Visceral Leishmaniasis with Feeble Toxic Manifestation

Abstract

In spite of its high effectiveness in the treatment of both leishmaniasis as well as a range of fungal infections, the free form of the polyene antibiotic amphotericin B (AmB) does not entertain the status of the most preferred drug of choice in clinical settings. The high intrinsic toxicity of the principal drug could be considered the main impedance in the frequent medicinal use of this otherwise very effective antimicrobial agent. Taking into consideration this fact, the pharma industry has introduced many novel dosage forms of AmB to alleviate its toxicity issues. However, the limited production, high cost, requirement for a strict cold chain, and need for parenteral administration are some of the limitations that explicitly compel professionals to look for the development of an alternate dosage form of this important drug. Considering the fact that the nano-size dimensions of drug formulation play an important role in increasing the efficacy of the core drug, we employed a green method for the development of nano-assemblies of AmB (AmB-NA). The as-synthesized AmB-NA manifests desirable pharmacokinetics in the treated animals. The possible mechanistic insight suggested that as-synthesized AmB-NA induces necrosis-mediated cell death and severe mitochondrial dysfunction in L. donovani promastigotes by triggering depolarization of mitochondrial membrane potential. In vivo studies demonstrate a noticeable decline in parasite burden in the spleen, liver, and bone marrow of the experimental BALB/c mice host. In addition to successfully suppressing the Leishmania donovani, the as-formed AmB-NA formulation also modulates the host immune system with predominant Th1 polarization, a key immune defender that facilitates the killing of the intracellular parasite.

Disclosing the Antifungal Mechanisms of the Cyclam Salt H4[H2(4-CF3PhCH2)2Cyclam]Cl4 against Candida albicans and Candida krusei

“…Various strategies have been developed to avoid the haemolytic and cytotoxic activity of the compounds, such as their molecular modification [39] or the use of drug delivery systems, some already in clinical use and others being evaluated in clinical trials [40]. Amphotericin B is a good example of an antifungal drug widely used in the treatment of serious systemic infections, with a broad spectrum of action and a very low level of resistance, but which is very toxic to humans [41][42][43][44]. The toxicity associated with amphotericin B has implications for its clinical use, which is limited to inpatients due to the need, among other factors, for slow continuous intravenous infusion and the permanent need to monitor renal toxicity and body temperature [41][42][43][44].…”

“…Amphotericin B is a good example of an antifungal drug widely used in the treatment of serious systemic infections, with a broad spectrum of action and a very low level of resistance, but which is very toxic to humans [41][42][43][44]. The toxicity associated with amphotericin B has implications for its clinical use, which is limited to inpatients due to the need, among other factors, for slow continuous intravenous infusion and the permanent need to monitor renal toxicity and body temperature [41][42][43][44]. For this reason, new therapeutic systems have been developed for administering this drug, and it continues to be used in therapy [41][42][43].…”

“…The effect of compound 1 on yeast mitochondrial membrane potential was evaluated through the JC-1 assay [44]. Suspension of yeasts (C. krusei ATCC 6258 and C. albicans ATCC 10231) with a final cell density of 0.5-2.5 × 10 3 CFU/mL were prepared in RPMI-1640 medium, and these working suspensions were placed into micro tubes (1 mL), and incubated for 24 h at 37 • C. Then, micro tubes were centrifuged at 15,493× g for 5 min.…”

Developing nanosize carrier systems for Amphotericin‐B: A review on the biomedical application of nanoparticles for the treatment of leishmaniasis and fungal infections

“…[ 18 ] This scientific study revealed that the new formulation of Am‐B has minimal toxicity on living cells (erythrocytes, RBCs). [ 18 ] Furthermore, Singh et al., 2022 showed the promising antileishmanial activity of carboxymethyl chitosan (CMC)‐Am‐B‐LV (with no toxicity) against L. donovani infected macrophages. [ 19 ] These data indicated that newly designed carrier systems for drug delivery can increase efficacy and also reduce cytotoxicity of Am‐B (Table 1).…”

“…This formulation of Am‐B is highly effective against both promastigotes and amastigotes of Leishmania donovani . [ 18 ] This scientific study revealed that the new formulation of Am‐B has minimal toxicity on living cells (erythrocytes, RBCs). [ 18 ] Furthermore, Singh et al., 2022 showed the promising antileishmanial activity of carboxymethyl chitosan (CMC)‐Am‐B‐LV (with no toxicity) against L. donovani infected macrophages.…”