Reduction toxicity of Amphotericin B through loading into a novel nanoformulation of anionic linear globular dendrimer for improve treatment of leishmania major

Abstract

Amphotericin B (A) as an antileishmanial drug has limited clinical application owing to severe side-effects and low-water solubility. This is the first study reported using Anionic Linear Globular Dendrimer (ALGD) as A carrier for the increase of A solubility rate, decrease its toxicity, and improve its therapeutic effects. ALGD was synthesized and A was loaded into nanoparticles for the first time with the drug-loading efficiency of 82%. Drug loading was confirmed using characterization methods. The drug solubility rate was increased by 478-folds. The results of the study showed that the A toxicity was significantly decreased by 95% in vitro and in vivo environments, which was confirmed by pathology findings and enzymatic evaluation. Furthermore, the nanodrug caused that mortality rate was reached to zero. Moreover, the nanodrug was as potent as the free drug and glucantime (GUL) in reducing the parasite burden and parasite number. These findings indicated the potency of ALGD to decrease the drug side-effects, increase the drug solubility rate, and improve the drug efficacy. Moreover, the nanoformulation was a non-toxic and cost-effective formulation. The conformity between in vitro and in vivo results suggested that the A-loaded ALGD could be considered as a promising candidate in reducing the side-effects of A in leishmaniasis treatment.

In Vivo Therapeutic Effects of Four Synthesized Antileishmanial Nanodrugs in the Treatment of Leishmaniasis

“…However, they demonstrated an only negligible effect on inhibiting parasite in vivo environment, which is possibly due to a low dose of AK1 mg/kg (7- 10,12,13,15,16,24). In the present study, A was loaded into K synthesized by phase separation method (different from previous studies by using ionic gelation) and it was found that K decreased the toxicity effects of A and increased its solubility (14,18). As in previous studies, AK was not effective in inhibiting parasite in vivo in current dosage (1 mg/kg), then we increased the therapeutic dose of AK to 10 mg/kg by using phase separation method and a novel solvent (14).…”

“…In the present study, A was loaded into K synthesized by phase separation method (different from previous studies by using ionic gelation) and it was found that K decreased the toxicity effects of A and increased its solubility (14,18). As in previous studies, AK was not effective in inhibiting parasite in vivo in current dosage (1 mg/kg), then we increased the therapeutic dose of AK to 10 mg/kg by using phase separation method and a novel solvent (14). Our findings revealed that parasites were significantly inhibited in our mice model.…”

“…On the other hand, as B is a new compound with antileishmanial property, for the first time we considered to load B into a carrier such as K. This formulation increased solubility and decreased the toxicity, additionally, BK formulation was remarkably and significantly more effective on parasite inhibition in dosage of 20 mg/kg in comparison to our other formulations in recovery of L. major's pathological effects (14).…”

“…It has additionally immunomodulatory and wound healing effects and was synthesized with various methods including ionic gelation, phase separation, etc. (10,14). Some studies applied nanoformulation of amphotericin B-nanochitosan (AK) synthesized by ionic gelation on leishmaniasis treatment (7-10, 12, 13, 15, 16).…”

Dendrimers: Amazing Platforms for Bioactive Molecule Delivery Systems

“…Dendrimers as DDS can improve key points in transport and biodistribution such as prolongation of the drug circulation time, enhance drug solubility, enhance tumor permeation and retention, protection of the drug from surroundings, and the ability to target diseased tissue, among others. As a strategy to minimize the cytotoxicity of PAMAM dendrimers, the positive surface charge of its surface has been modified with carboxymethyl chitosan (CMCS) [90][91][92]. Considering that, CMCS is an amphoteric polymer, sensitive pH, and taking doxorubicin as a model drug for cancer, it is that the formulation of a nanoparticle between PAMAM dendrimer and CMCS based on electrostatic conjugation, can transport the drug and release it into the target tissue ( Figure 3A).…”