Amphotericin B Nano-Assemblies Circumvent Intrinsic Toxicity and Ensure Superior Protection in Experimental Visceral
Fauzia Jamal1, Ishrat Altaf1, Ghufran Ahmed2
1Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202002, India.
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.
Insights
A novel nano-assembly of amphotericin B (AmB-NA) was developed using a green method. This formulation effectively treats leishmaniasis by inducing cell death and enhancing the host immune response, offering a promising alternative to conventional AmB.
Area of Science:
- Antimicrobial drug development
- Nanotechnology in medicine
- Parasitology and immunology
Background:
- Amphotericin B (AmB) is highly effective against leishmaniasis and fungal infections but limited by high toxicity and formulation issues.
- Existing AmB formulations face challenges including high cost, cold chain requirements, and parenteral administration, necessitating alternative delivery systems.
- Drug formulation at the nano-scale can significantly enhance the efficacy of the core therapeutic agent.
Purpose of the Study:
- To develop a novel, green-synthesized nano-assembly of amphotericin B (AmB-NA).
- To evaluate the pharmacokinetic properties, anti-leishmanial mechanism, and in vivo efficacy of AmB-NA.
- To assess the immunomodulatory effects of AmB-NA, specifically its impact on Th1 polarization.
Main Methods:
- A green chemistry approach was utilized to synthesize amphotericin B nano-assemblies (AmB-NA).
- Pharmacokinetic studies were conducted in treated animals to assess drug behavior.
- Mechanistic studies involved evaluating the effect of AmB-NA on *L. donovani* promastigotes, including mitochondrial membrane potential.
- In vivo efficacy was tested in BALB/c mice infected with *Leishmania donovani*, assessing parasite burden in spleen, liver, and bone marrow.
- Host immune response was analyzed, focusing on Th1 polarization.
Main Results:
- The synthesized AmB-NA exhibited favorable pharmacokinetics in animal models.
- AmB-NA induced necrosis-mediated cell death and mitochondrial dysfunction in *L. donovani* promastigotes.
- Significant reduction in parasite burden was observed in the spleen, liver, and bone marrow of infected mice.
- AmB-NA treatment promoted a Th1-polarized immune response, crucial for combating intracellular parasites.
Conclusions:
- Green synthesis of AmB-NA provides a viable alternative dosage form with improved properties.
- AmB-NA demonstrates potent anti-leishmanial activity through direct parasite toxicity and host immune modulation.
- The nano-formulation overcomes limitations of conventional AmB, offering therapeutic potential for leishmaniasis.
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