Andrographolide engineered gold nanoparticle to overcome drug resistant visceral leishmaniasis.
08 Feb 2018-Artificial Cells Nanomedicine and Biotechnology (Artif Cells Nanomed Biotechnol)-Vol. 46, pp 751-762
TL;DR: This study aims to arrive at terpenoid andrographolide engineered gold nanoparticle (AGAunps) facile synthesis and its efficacy evaluations against wild and drug resistant VL strains for the first time.
Abstract: Visceral leishmaniasis (VL) is World Health Organization designated most serious leishmaniasis with an annual mortality rate of 50,000. Even after country specific eradication programs, the disease...
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TL;DR: GNP-based delivery of AmB can be a better, cheaper, and safer alternative than available AmB formulations, and improved antileishmanial efficacy and reduced cytotoxicity.
Abstract: Background Amphotericin B (AmB) as a liposomal formulation of AmBisome is the first line of treatment for the disease, visceral leishmaniasis, caused by the parasite Leishmania donovani. However, nephrotoxicity is very common due to poor water solubility and aggregation of AmB. This study aimed to develop a water-soluble covalent conjugate of gold nanoparticle (GNP) with AmB for improved antileishmanial efficacy and reduced cytotoxicity. Methods Citrate-reduced GNPs (~39 nm) were functionalized with lipoic acid (LA), and the product GNP-LA (GL ~46 nm) was covalently conjugated with AmB using carboxyl-to-amine coupling chemistry to produce GNP-LA-AmB (GL-AmB ~48 nm). The nanoparticles were characterized by dynamic light scattering, transmission electron microscopy (TEM), and spectroscopic (ultraviolet-visible and infrared) methods. Experiments on AmB uptake of macrophages, ergosterol depletion of drug-treated parasites, cytokine ELISA, fluorescence anisotropy, flow cytometry, and gene expression studies established efficacy of GL-AmB over standard AmB. Results Infrared spectroscopy confirmed the presence of a covalent amide bond in the conjugate. TEM images showed uniform size with smooth surfaces of GL-AmB nanoparticles. Efficiency of AmB conjugation was ~78%. Incubation in serum for 72 h showed <7% AmB release, indicating high stability of conjugate GL-AmB. GL-AmB with AmB equivalents showed ~5-fold enhanced antileishmanial activity compared with AmB against parasite-infected macrophages ex vivo. Macrophages treated with GL-AmB showed increased immunostimulatory Th1 (IL-12 and interferon-γ) response compared with standard AmB. In parallel, AmB uptake was ~5.5 and ~3.7-fold higher for GL-AmB-treated (P<0.001) macrophages within 1 and 2 h of treatment, respectively. The ergosterol content in GL-AmB-treated parasites was ~2-fold reduced compared with AmB-treated parasites. Moreover, GL-AmB was significantly less cytotoxic and hemolytic than AmB (P<0.01). Conclusion GNP-based delivery of AmB can be a better, cheaper, and safer alternative than available AmB formulations.
37 citations
Additional excerpts
...5-25) (1-108) (1-108) GNP (μg/mL) GL (μg/mL) AmB (μM) GL-AmB (μM) *** *** *** *** ***...
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Chinese Ministry of Education1, Shanghai University2, Nanjing University of Chinese Medicine3, Beijing University of Chinese Medicine4, Tianjin University of Traditional Chinese Medicine5, Chengdu University of Traditional Chinese Medicine6, Chinese Academy of Sciences7, China Pharmaceutical University8, Guangzhou University of Chinese Medicine9, Guizhou University10, Fujian University of Traditional Chinese Medicine11, Fudan University12, Yale University13, Peking University14, Zhejiang University15
TL;DR: In this article, the authors discuss the overlapping connectivity and relevance of the two fields, including nanoaggregates generated in herbal medicine decoctions, the application of nanotechnology in the delivery and treatment of natural active ingredients, and the influence of physiological regulatory capability of traditional herbal medicine on the in vivo fate of nanoparticles.
37 citations
TL;DR: This review reports on published studies related to microparticles (MPs) and nanoparticles (NPs) loaded with Andrographolide and improved bioavailability, target-tissue distribution, and efficacy of AG loaded in the described drug delivery systems have been reported.
34 citations
TL;DR: In this article, the main emphasis was given on the anticancer activity of AG, its proposed mechanisms of action, novel approaches used to improve its biopharmaceutical properties, and its development as an adjuvant therapy for cancer treatment in future.
26 citations
TL;DR: In this article, the role of physicochemical properties of a nanoscale delivery system is discussed and different ways of nano-formulation delivery ranging from liposome, niosomes, polymeric, metallic, solid-lipid NPs were updated along with the possible mechanisms of action against the parasite.
16 citations
References
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TL;DR: In this paper, a rapid method based on HPTLC and RP-HPLC with UV detection for quantitative determination of two major bioactive compounds in Andrographis paniculata, andrographolide and 14-deoxy-11, 12-didehydroandrographiolide, is described.
94 citations
TL;DR: Because of its appreciable efficacy in destroying intracellular parasites as well as non-hepatotoxic and non-nephrotoxic nature, harmine, in the vesicular forms, may be considered for clinical application in humans.
Abstract: Harmine, a beta-carboline amine alkaloid isolated from Peganum harmala, was tested for its antileishmanial properties both in vitro and in vivo. In vitro antileishmanial activity of harmine was encouraging and prompted us to confirm the activity in vivo in hamster models. Harmine was tested both in free form and in different vesicular forms viz. liposomes, niosomes and nanoparticles. The different vesicles were prepared by the published protocols. The percent intercalation of harmine in liposomes, niosomes and nanoparticles was found to be 65, 60 and 20, respectively, when determined at 325 nm (epsilon(M) =2.33 x 10 M(-1) cm(-1)). At an equivalent dose of 1.5 mg/kg body weight, injected subcutaneously (SC) for a total of six doses in 15 days, harmine was found to reduce spleen parasite load by approximately 40, 60, 70 and 80%, respectively in free, liposomal, niosomal and nanoparticular forms. An inverse relationship could be established between the efficacy in the lowering of spleen parasite load and the size of the vesicles. Specific biochemical tests related to normal liver and kidney functions revealed that the toxicity of the drug was reduced in the vesicular forms in the same order as their efficacy and the same was confirmed by the histopathological studies of splenic sections. Cell cycle analysis studies using flow cytometry suggested that although harmine interferes in the cell division stage, it does not induce apoptosis in Leishmania donovani promastigotes. The results using Confocal Microscopy supported that the cell death could be attributed to necrosis due to non-specific membrane damage. Even then, because of its appreciable efficacy in destroying intracellular parasites as well as non-hepatotoxic and non-nephrotoxic nature, harmine, in the vesicular forms, may be considered for clinical application in humans.
93 citations
TL;DR: It is demonstrated that different resistance patterns can be obtained in L. donovani depending upon the drug combinations used, and that promastigotes/amastigote resistant to one drug combination showed a marked cross-resistant profile to other anti-leishmanial drugs.
Abstract: Drug combinations for the treatment of leishmaniasis represent a promising and challenging chemotherapeutic strategy that has recently been implemented in different endemic areas. However, the vast majority of studies undertaken to date have ignored the potential risk that Leishmania parasites could develop resistance to the different drugs used in such combinations. As a result, this study was designed to elucidate the ability of Leishmania donovani to develop experimental resistance to anti-leishmanial drug combinations. The induction of resistance to amphotericin B/miltefosine, amphotericin B/paromomycin, amphotericin B/SbIII, miltefosine/paromomycin, and SbIII/paromomycin was determined using a step-wise adaptation process to increasing drug concentrations. Intracellular amastigotes resistant to these drug combinations were obtained from resistant L. donovani promastigote forms, and the thiol and ATP levels and the mitochondrial membrane potential of the resistant lines were analysed. Resistance to drug combinations was obtained after 10 weeks and remained in the intracellular amastigotes. Additionally, this resistance proved to be unstable. More importantly, we observed that promastigotes/amastigotes resistant to one drug combination showed a marked cross-resistant profile to other anti-leishmanial drugs. Additionally, the thiol levels increased in resistant lines that remained protected against the drug-induced loss of ATP and mitochondrial membrane potential. We have therefore demonstrated that different resistance patterns can be obtained in L. donovani depending upon the drug combinations used. Resistance to the combinations miltefosine/paromomycin and SbIII/paromomycin is easily obtained experimentally. These results have been validated in intracellular amastigotes, and have important relevance for ensuring the long-term efficacy of drug combinations.
93 citations
"Andrographolide engineered gold nan..." refers background in this paper
...donavani has developed resistance even against drug combinations like amphotericin-B with sodium stibogluconate [6], which further paralyzes VL management....
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TL;DR: Antileishmanial activity was found to be significant for the nanoparticle preparation with 4% PVA in about one-fourth of the dosage of the pure compound AG (IC50 160 μM), which have significant potential to target the infested macrophage cells and prove valuable in chemotherapy of neglected tropical diseases such as leishmaniasis.
Abstract: Andrographolide (AG) is a diterpenoid lactone isolated from the leaves of Andrographis paniculata. AG is a potent and low-toxicity antileishmanial agent. Chemotherapy applications of AG are, however, seriously constrained because of poor bioavailability, short plasma half-life, and inappropriate tissue localization. Nanoparticulation of AG was therefore envisaged as a possible solution. AG nanoparticles (AGnp) loaded in 50:50 poly(DL-lactide-co-glycolic acid) were prepared for delivery into the monocyte-macrophage cells infested with the amastigote form of leishmanial parasite for evaluation in the chemotherapy of leishmaniasis. Particle characteristics of AGnp were optimized by proportionate application of a stabilizer, polyvinyl alcohol (PVA). Physicochemical characterization of AGnp by photon correlation spectroscopy exhibited an average particle size of 173 nm and zeta potential of -34.8 mV. Atomic force microscopy visualization revealed spherical nanoparticles with a smooth surface. Antileishmanial activity was found to be significant for the nanoparticle preparation with 4% PVA (IC₅₀) 34 μM) in about one-fourth of the dosage of the pure compound AG (IC₅₀) 160 μM). AGnp therefore have significant potential to target the infested macrophage cells and prove valuable in chemotherapy of neglected tropical diseases such as leishmaniasis.
78 citations
"Andrographolide engineered gold nan..." refers background or methods or result in this paper
...The promastigotes were routinely cultured in the medium 199 supplemented with 10% heat inactivated foetal bovine serum, 2mM L- glutamine, 20mM HEPES, 100U/ml penicillin and 100 mg/ml streptomycin at 25 C [21]....
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...Our earlier experiments with nanoparticulated AG in PLGA showed promising leishmanicidal activity against axenic amastigotes and amastigote infested macrophages [21] which further supported the inception for this work....
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...Pharmacology of AG in leishmania is linked with its capacity to regulate reactive oxygen species and mitochondrial membrane potential [21]....
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TL;DR: The selectivity of the different classes of antiparasitic compounds for the protein targets considered in this work can be explored in fragment- and/or structure-based drug design towards the development of leads for new antileishmanial drugs.
Abstract: Neglected Tropical Diseases (NTDs), like leishmaniasis, are major causes of mortality in resource-limited countries. The mortality associated with these diseases is largely due to fragile healthcare systems, lack of access to medicines, and resistance by the parasites to the few available drugs. Many antiparasitic plant-derived isoprenoids have been reported, and many of them have good in vitro activity against various forms of Leishmania spp. In this work, potential Leishmania biochemical targets of antiparasitic isoprenoids were studied in silico. Antiparasitic monoterpenoids selectively docked to L. infantum nicotinamidase, L. major uridine diphosphate-glucose pyrophosphorylase and methionyl t-RNA synthetase. The two protein targets selectively targeted by germacranolide sesquiterpenoids were L. major methionyl t-RNA synthetase and dihydroorotate dehydrogenase. Diterpenoids generally favored docking to L. mexicana glycerol-3-phosphate dehydrogenase. Limonoids also showed some selectivity for L. mexicana glycerol-3-phosphate dehydrogenase and L. major dihydroorotate dehydrogenase while withanolides docked more selectively with L. major uridine diphosphate-glucose pyrophosphorylase. The selectivity of the different classes of antiparasitic compounds for the protein targets considered in this work can be explored in fragment- and/or structure-based drug design towards the development of leads for new antileishmanial drugs.
66 citations
"Andrographolide engineered gold nan..." refers background in this paper
...Terpenoid compounds are preferred in leishmania due to their specific affinity for the leishmanial parasite [19] and their ability to alter the parasite cell membrane fluidity at IC50 concentration range [43]....
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...Terpenoids are more promising members of this class due to their selectivity towards leishmania biochemical targets [19]....
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