Nano- and Microformulations to Advance Therapies for Visceral Leishmaniasis

Varma, Devika M.; Redding, Elizabeth A; Bachelder, Eric M.; Ainslie, Kristy M.

doi:10.1021/acsbiomaterials.0c01132

Cited by 18 publications

(13 citation statements)

References 104 publications

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“…Generation of new AmB derivatives 43 , 44 or its nano-formulation with reduced toxicity 24 , 45 – 47 was reported with some success. But due to the lack of vaccine 48 and drug resistance and toxicity associated with AmB, the idea of nano and micro-formulation 49 , natural product-based drug-delivery 6 using flavonoids or its formulation 50 , 51 , marine products 52 and even drug-repurposing 53 have gained significant attention for the treatment of various forms of leishmaniasis. In this study, we have confirmed the antileishmanial efficacy of CA, a natural FA that is already known to have antibacterial/antifungal efficacy.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic insight into the role of mevalonate kinase by a natural fatty acid-mediated killing of Leishmania donovani

Prasad

Kumar

Mandal

et al. 2022

Sci Rep

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We evaluated the anti-leishmanial efficacy of different saturated medium-chain fatty acids (FAs, C8–C18) where FA containing C8 chain, caprylic acid (CA), was found to be most potent against Leishmania donovani, the causative agent for visceral leishmaniasis (VL). Different analogs of CA with C8 linear chain, but not higher, along with a carboxyl/ester group showed a similar anti-leishmanial effect. Ergosterol depletion was the major cause of CA-mediated cell death. Molecular docking and molecular dynamic simulation studies indicated the enzyme mevalonate kinase (MevK) of the ergosterol biosynthesis pathway as a possible target of CA. Enzyme assays with purified recombinant MevK and CA/CA analogs confirmed the target with a competitive inhibition pattern. Using biochemical and biophysical studies; strong binding interaction between MevK and CA/CA analogs was established. Further, using parasites with overexpressed MevK and proteomics studies of CA-treated parasites the direct role of MevK as the target was validated. We established the mechanism of the antileishmanial effect of CA, a natural product, against VL where toxicity and drug resistance with current chemotherapeutics demand an alternative. This is the first report on the identification of an enzymatic target with kinetic parameters and mechanistic insights against any organism for a natural medium-chain FA.

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Section: Discussionmentioning

confidence: 99%

Mechanistic insight into the role of mevalonate kinase by a natural fatty acid-mediated killing of Leishmania donovani

Prasad

Kumar

Mandal

et al. 2022

Sci Rep

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“…The neglected tropical disease leishmaniasis (caused by around 20 species of the genus Leishmania) is the second most common parasitic disease after malaria and affects close to 1 million people yearly. 176 It is endemic in places like Bihar, the second poorest state in India. 177,178 Although there are several FDA approved and preclinical treatments for leishmaniasis, 176 amphotericin B is the first-line treatment in endemic areas.…”

Section: Success Can Come In Small Packagesmentioning

confidence: 99%

Micro and nanotechnologies: The little formulations that could

Stiepel

Duggan

Batty

et al. 2022

Bioengineering & Transla Med

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The first publication of micro‐ and nanotechnology in medicine was in 1798 with the use of the Cowpox virus by Edward Jenner as an attenuated vaccine against Smallpox. Since then, there has been an explosion of micro‐ and nanotechnologies for medical applications. The breadth of these micro‐ and nanotechnologies is discussed in this piece, presenting the date of their first report and their latest progression (e.g., clinical trials, FDA approval). This includes successes such as the recent severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccines from Pfizer, Moderna, and Janssen (Johnson & Johnson) as well as the most popular nanoparticle therapy, liposomal Doxil. However, the enormity of the success of these platforms has not been without challenges. For example, we discuss why the production of Doxil was halted for several years, and the bankruptcy of BIND therapeutics, which relied on a nanoparticle drug carrier. Overall, the field of micro‐ and nanotechnology has advanced beyond these challenges and continues advancing new and novel platforms that have transformed therapies, vaccines, and imaging. In this review, a wide range of biomedical micro‐ and nanotechnology is discussed to serve as a primer to the field and provide an accessible summary of clinically relevant micro‐ and nanotechnology platforms.

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“…31 The applications of nanoparticles (NPs), due to their biodegradability, biocompatibility, stability, surface-modifiable abilities, and facilitating pharmacokinetics, 33 have gained much attention in the development of effective conjugated nanotherapeutics in the management of parasitic infections through intracellular delivery, particularly against Leishmania infections. 34 It has been reported that in achieving effective leishmaniasis therapy, macrophage-targeted drug delivery plays a crucial role, and this strategy could be accomplished through mannose receptor-mediated endocytosis of the nanoparticulate systems. 35 Among the various kinds of nanomaterials, nanoemulsions have shown safety, biodegradability, stability, and drug targetability, and thus have evolved as a novel strategy for targeting ALA in leishmaniasis therapy.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Potential of Quercetin-Loaded Nanoemulsion against Experimental Visceral Leishmaniasis: In Vitro/Ex Vivo Studies and Mechanistic Insights

et al. 2022

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Visceral leishmaniasis (VL) is one of the most fatal and neglected tropical diseases caused by Leishmania donovani (L. donovani). The applications of currently available chemotherapy (amphotericin B, miltefosine, and others) in VL treatment have been limited due to their poor bioavailability, unfavorable toxicity profile, and prolonged parenteral dosing. Quercetin (QT), a potent natural antioxidant, is a prominent target when conducting investigations on alternative therapies against L. donovani infections. However, the therapeutic applications of QT have been restricted due to its low solubility and bioavailability. In the present study, we developed and evaluated the antileishmanial activity (ALA) of quercetin-loaded nanoemulsion (QTNE) against L. donovani clinical strains. In vitro anti-promastigote assay results demonstrated that QTNE (IC50 6.6 μM, 48 h) significantly inhibited the growth of parasites more efficiently than the pure QT suspension in a dose- and time-dependent manner. Results of the anti-amastigote assay revealed that the infected macrophages (%) of QTNE were significantly more than those of the pure QT suspension at all concentrations (6.6, 26.4, and 52.8 μM; p < 0.05, p < 0.01 compared to the control). Moreover, the results of in vitro and ex vivo studies assisted in determining the mechanistic insights associated with the ALA of QTNE. The overall findings suggested that QTNE exhibited potential ALA by enhancing the intracellular ROS and nitric oxide levels, inducing distortion of membrane integrity and phosphatidylserine release (AV/PI), rupturing the parasite DNA (late apoptosis/necrosis process), and upregulating the immunomodulatory effects (IFN-γ and IL-10 levels). Additionally, QTNE showed superior biocompatibility against all of the treated healthy cells (PBMCs, PECs, and BMCs) as compared to the control. In conclusion, QTNE acts as a potential antileishmanial agent targeting both promastigote and intracellular amastigote forms of L. donovani, which thus opens a new avenue for the use of QTNE in VL therapy.

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Nano- and Microformulations to Advance Therapies for Visceral Leishmaniasis

Cited by 18 publications

References 104 publications

Mechanistic insight into the role of mevalonate kinase by a natural fatty acid-mediated killing of Leishmania donovani

Mechanistic insight into the role of mevalonate kinase by a natural fatty acid-mediated killing of Leishmania donovani

Micro and nanotechnologies: The little formulations that could

Therapeutic Potential of Quercetin-Loaded Nanoemulsion against Experimental Visceral Leishmaniasis: In Vitro/Ex Vivo Studies and Mechanistic Insights

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