Current status of nanoscale drug delivery and the future of nano-vaccine development for leishmaniasis - A review.

Visceral leishmaniasis (VL) is the most lethal of all leishmaniasis diseasesand the second most common parasiticdisease after malaria and,still, categorized as a neglected tropical disease (NTD). According to the latest WHO study, >20 Leishmania species spread 0.7–1.0 million new cases of leishmaniasis each year. VL is caused by the genus, Leishmania donovani (LD), which affects between 50,000 and 90,000 people worldwide each year. Lack of new drug development, increasing drug resistance, toxicity and high cost even with the first line of treatmentof Amphotericin B (AmB), demands new formulation for treatment of VLFurther the lack of a vaccine, allowedthe researchers to develop nanofomulation-based AmB for improved delivery. The limitation of AmB is its kidney and liver toxicity which forced the development of costly liposomal AmB (AmBisome) nanoformulation. Success of AmBisome have inspired and attracted a wide range of AmB nanoformulations ranging from polymeric, solid lipid, liposomal/micellar, metallic, macrophage receptor-targetednanoparticles (NP) and even with sophisticated carbon/quantum dot-based AmBnano delivery systems. Notably, NP-based AmB delivery has shown increased efficacy due to increased uptake, on-target delivery and synergistic impact of NP and AmB. In this review, we have discussed the different forms of leishmaniasis disease and their current treatment options with limitations. The discovery, mechanism of action of AmB, clinical status of AmB and improvement with AmBisome over fungizone (AmB-deoxycholate)for VL treatment was further discussed. At last, the development of various AmB nanoformulation was discussed along with its adavantages over traditional chemotherapy-based delivery. Graphical Abstract The nanoparticles with different size, shape and structure for drug delivery against Leishmania donovani.

Limitations of current chemotherapy and future of nanoformulation-based AmB delivery for visceral leishmaniasis—An updated review

Flavones such as 7,8-dihydroxyflavone (tropoflavin), 5,6,7-trihydroxyflavone (baicalein), 3′,4′,5,6-tetrahydroxyflavone (luteolin), 3,3′,4′,5,5′,7-hexahydroxyflavone (myricetin), 4′,5,7-trihydroxyflavone (apigenin), and 5,7-dihydroxyflavone (chrysin) are important both for their presence in natural products and for their pharmacological applications. However, due to their chemical characteristics and their metabolic processes, they have low solubility and low bioavailability. Knowledge about the physicochemical properties of nanocarriers and the possible mechanisms of covalent and non-covalent interaction between nanoparticles (NPs) and drugs is essential for the design of nanocarriers to improve the bioavailability of molecules with pharmacological potential, such as tropoflavin, baicalein, luteolin, myricetin, apigenin, and chrysin. The parameters of characterization of some NPs of these flavones, such as size, polydispersity index (PDI), zeta potential, encapsulation efficiency (EE), and % release/time, utilized in biomedical applications and the covalent and non-covalent interactions existing between the polymeric NPs and the drug were analyzed. Similarly, the presence of functional groups in the functionalized carbon nanotubes (CNTs), as well as the effect of pH on the % adsorption of flavonoids on functionalized multi-walled carbon nanotubes (MWCNT-COOH), were analyzed. Non-covalent interaction mechanisms between polymeric NPs and flavones, and covalent interaction mechanisms that could exist between the NPs and the amino and hydroxyl functional groups, are proposed.

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Some Nanocarrier’s Properties and Chemical Interaction Mechanisms with Flavones

The leishmaniases are a group of diseases caused by protozoan parasites—Leishmania sp. Leishmaniasis is classified among the 20 neglected diseases by WHO. Although the disease has been known for more than 120 years, the number of drugs used for the treatment is still limited to 5–6. The first-line drugs against leishmaniasis are pentavalent antimonials, which were introduced to the treatment 70 years ago—despite all their side effects. Molecular targets are becoming increasingly important for efficacy and selectivity in postgenomic drug research studies. In this chapter, we have discussed potential therapeutic targets of antileishmanial drug discovery such as pteridine reductase (PTR1), trypanothione reductase (TR), N-myristoyltransferase (NMT), trypanothione synthetase (TryS), IU-nucleoside hydrolase, and topoisomerases, enzymes and their inhibitors reported in the literature. 

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Toward New Antileishmanial Compounds: Molecular Targets for Leishmaniasis Treatment

Abstract 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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V Ravichandiran

Papers

7,8-dihydroxyflavone-functionalized gold nanoparticles target the arginase enzyme of Leishmania donovani.