Browsing by Author "Ganesh Yadagiri"

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Advanced Biomaterials in Neuroprotection: Innovations and Clinical Applications
(Springer Nature, 2025) Ramakrishna Kakarla; Matte Kasi Viswanadh; Dumala Naresh; Guntupalli Chakravarthi; Kojja Venkateswarlu; Gopichand Gutti; Ganesh Yadagiri; Sajusha Duguluri; Sachchida Nand Rai
Biomaterials are biodegradable, biocompatible, and bioinert and mimic the extracellular matrix of the cell. This chapter discusses the current challenges in neuroprotective agents and the advantages of various biomaterials and their applications as neuroprotective agents. Natural and synthetic biomaterials mimic the ECM of the brain and aid drug and cell delivery. Biomaterials are widely used as carriers for the delivery of drugs and other biological substances particularly into the brain. Doping of drugs with biomaterials enhanced their bioavailability, permeability, safety, efficacy, and reduced toxicity and exhibited neuroprotection against AD, PD, stroke, SCI, TBI, ALS, etc. This chapter further addresses biomaterials and their loaded drugs-mediated improvement in neuroprotection by modulating oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammation, and apoptosis. Furthermore, challenges in using biomaterials as a carrier for drug and cell delivery are also discussed in the present chapter. In conclusion, to improve the neuroprotective potential of biomaterials, continued multidisciplinary collaboration and translational research efforts are essential. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2025.
Carboxymethyl chitosan modified lipid nanoformulations as a highly efficacious and biocompatible oral anti-leishmanial drug carrier system
(Elsevier B.V., 2022) Aakriti Singh; Ganesh Yadagiri; Manorma Negi; Anurag Kumar Kushwaha; Om Prakash Singh; Shyam Sundar; Shyam Lal Mudavath
Herein, carboxymethyl chitosan (CMC) grafted lipid nanoformulations were facilely prepared by thin-film hydration method as a highly efficient biocompatible anti-leishmanial carrier encapsulating amphotericin B (AmB). Nanoformulations were characterized for their physicochemical characteristics wherein TEM analysis confirmed the spherical structure, whereas FTIR analysis revealed the conjugation of CMC onto nanoformulations and confirmed the free state of AmB. Furthermore, the wettability study confirmed the presence of CMC on the surface of nanoformulations attributed to the enhanced hydrophilicity. Surface hydrophilicity additionally contributes towards consistent mucin retention ability for up to 6 h, superior mucoadhesiveness, and hence enhanced bioavailability. The proposed nanoformulations with high encapsulation and drug loading properties displayed controlled drug release in the physiological microenvironment. In vitro, antileishmanial results showed an astounding 97% inhibition in amastigote growth. Additionally, in vivo studies showed that treatment with nanoformulations significantly reduced the liver parasitic burden (93.5%) without causing any toxicity when given orally. © 2022 Elsevier B.V.
Coalition of Biological Agent (Melatonin) with Chemotherapeutic Agent (Amphotericin B) for Combating Visceral Leishmaniasis via Oral Administration of Modified Solid Lipid Nanoparticles
(American Chemical Society, 2023) Shabi Parvez; Ganesh Yadagiri; Kanika Arora; Aaqib Javaid; Anurag Kumar Kushwaha; Om Prakash Singh; Shyam Sundar; Shyam Lal Mudavath
In this study, 2-hydroxypropyl-β-cyclodextrin (HPβCD) grafted solid lipid nanoparticle (SLN)-based bioconjugate was synthesized and used for administering a combination of melatonin (Mel) and amphotericin B (AmB) orally for effective visceral leishmaniasis (VL) treatment. The formulations (HPCD-Mel-AmB SLN) were synthesized by the emulsion solvent evaporation method. HPCD-Mel-AmB SLN showed a high loading capacity and a high entrapment efficiency of AmB (% DL = 9.0 ± 0.55 and % EE = 87.9 ± 0.57) and Mel (% DL = 7.5 ± 0.51 and % EE = 63 ± 6.24). The cumulative percent release of AmB and Mel was 66.10 and 73.06%, respectively, up to 72 h. Time-dependent cellular uptake was noticed for HPCD-Mel-AmB SLN for 4 h. Further, HPCD-Mel-AmB SLN did not show any toxic effects on J774A.1 macrophages and Swiss albino mice. HPCD-Mel-AmB SLN (10 mg/kg ×5 days, p.o.) has significantly diminished (98.89%) the intracellular parasite load in liver tissues of L. donovani-infected BALB/c mice, subsequently highlighting the role of melatonin toward an effective strategy in combating leishmanial infection. Therefore, these results indicated that administration of HPCD-Mel-AmB SLN improve the therapeutic index of the first-line drug in addition to the introduction of biological agent and would be a promising therapeutic candidate for effective VL therapy. In the present study, the objective is to test the efficacy of the chemotherapeutic approach in combination with a biological immunomodulatory agent against leishmanial infection using in vitro and in vivo studies. This information suggests that melatonin could be an efficacious and potent antileishmanial agent. © 2023 American Chemical Society. All rights reserved.
Evaluation of Safety and Antileishmanial Efficacy of Amine Functionalized Carbon-Based Composite Nanoparticle Appended With Amphotericin B: An in vitro and Preclinical Study
(Frontiers Media S.A., 2020) Mallikarjuna Rao Gedda; Prasoon Madhukar; Alok Kumar Vishwakarma; Vimal Verma; Anurag Kumar Kushwaha; Ganesh Yadagiri; Shyam Lal Mudavath; Om Prakash Singh; Onkar Nath Srivastava; Shyam Sundar
Visceral leishmaniasis (VL) has been a major health concern in the developing world, primarily affecting impoverished people. It is caused by a protozoan parasite Leishmania donovani and is characterized by immune dysfunction that can lead to deadly secondary infections. Several adverse side effects limit the existing treatment options; hence, the need of the hour is some drug option with high efficacy and no toxicity. To make targeted delivery of Amphotericin B (AmB), we have used amine-functionalized versions of carbon nanostructures, namely f-CNT and f-Graphene (f-Grap). The results with f-Grap-AmB, because of a much larger surface area, were expected to be better. However, the results obtained by us showed only marginal improvement (IC50 f-Grap-AmB; 0.0038 ± 0.00119 μg/mL). This is, in all likelihood, due to the agglomeration effect of f-Grap-AmB, which is invariably obtained with graphene. To resolve this issue, we have synthesized a graphene-CNT composite (graphene 70% and CNT 30% by weight). Because CNT is dispersed in between graphene sheets, the agglomeration effect is avoided, and our study suggests that the f-Composite-AmB (f-Comp-AmB) showed no toxicity against the murine J774A.1 macrophage cell line and did not induce any hepatic or renal toxicity in Swiss albino mice. The f-Comp-AmB also showed a remarkable elevation in the in vitro and in vivo antileishmanial efficacy in comparison to AmB and f-CNT-AmB or f-Grap-AmB in J774A.1 and Golden Syrian hamsters, respectively. Additionally, we have also observed that the percentage suppression of parasite replication in the spleen of the hamster was significantly higher in the f-Comp-AmB (97.79 ± 0.2375) treated group in comparison with the AmB (85.66 ± 1.164) treated group of hamsters. To conclude, f-Comp-AmB could be a safe and reliable therapeutic option over the other carbon-based nanoparticles (NPs), i.e., f-CNT-AmB, f-Grap-AmB, and conventional AmB. © Copyright © 2020 Gedda, Madhukar, Vishwakarma, Verma, Kushwaha, Yadagiri, Mudavath, Singh, Srivastava and Sundar.
Formulation, characterization and in vitro anti-leishmanial evaluation of amphotericin B loaded solid lipid nanoparticles coated with vitamin B12-stearic acid conjugate
(Elsevier Ltd, 2020) Aakriti Singh; Ganesh Yadagiri; Shabi Parvez; Om Prakash Singh; Anurag Verma; Shyam Sundar; Shyam Lal Mudavath
Despite the advancement of new anti-leishmanials, amphotericin B (AmB) prevails as one of the most potent agent in the treatment of visceral leishmaniasis (VL), a neglected tropical disease affecting mostly poverty ridden and underdeveloped regions of the globe. Nonetheless, many patients display intolerance to parenteral AmB, notably at higher dosages. Also, conventional AmB presents an apparently poor absorption. Therefore, to improve AmB bioavailability and overcome multiple barriers for oral delivery of AmB, we fabricated a promising vitamin B12-stearic acid (VBS) conjugate coated solid lipid nanoparticles (SLNs) encapsulated with AmB (VBS-AmB-SLNs) by a combination of double emulsion solvent evaporation and thermal sensitive hydrogel techniques. VBS-AmB-SLNs showed a particle size of 306.66 ± 3.35 nm with polydispersity index of 0.335 ± 0.08 while the encapsulation efficiency and drug loading was observed to be 97.99 ± 1.6% and 38.5 ± 5.6% respectively. In vitro drug release showed a biphasic release pattern and chemical stability of AmB was ensured against simulated gastrointestinal fluids. Cellular uptake studies confirmed complete internalization of the formulation. Anti-leishmanial evaluation against intramacrophage amastigotes showed an enhanced efficacy of 94% which was significantly (P < 0.01) higher than conventional AmB without showing any toxic effects on J774A.1 cells. VBS-AmB-SLNs could serve as a potential therapeutic strategy against VL. © 2020 Elsevier B.V.
Hijacking the intrinsic vitamin B12 pathway for the oral delivery of nanoparticles, resulting in enhanced in vivo anti-leishmanial activity
(Royal Society of Chemistry, 2022) Aakriti Singh; Ganesh Yadagiri; Aaqib Javaid; Krishna Kumar Sharma; Anurag Verma; Om Prakash Singh; Shyam Sundar; Shyam Lal Mudavath
Surface-functionalized vitamin B12 (VB12) biocompatible nanoparticles exploit the well-characterized uptake pathway of VB12, shielding it from enzymatic degradation and inadequate absorption. In this perspective, subsequent to escalated mucus interaction and diffusion analysis, the nanoparticles were investigated by immunostaining with the anti-CD320 antibody, and their internalization mechanisms were examined by selectively blocking specific uptake processes. It was observed that their internalization occurred via an energy-dependent clathrin-mediated mechanism, simultaneously highlighting their remarkable ability to bypass the P-glycoprotein efflux. In particular, the synthesized nanoparticles were evaluated for their cytocompatibility by analyzing cellular proliferation, membrane viscoelasticity, and fluidity by fluorescence recovery after photobleaching and oxidative-stress detection, making them well-suited for successful translation to a clinical setup. Our previous in vitro antileishmanial results were paramount for their further in vivo and toxicity analysis, demonstrating their targeted therapeutic efficiency. The augmented surface hydrophilicity, which is attributed to VB12, and monomerization of amphotericin B in the lipid core strengthened the oral bioavailability and stability of the nanoparticles, as evidenced by the fluorescence resonance energy transfer analysis. © 2022 The Royal Society of Chemistry.
Improvising anti-leishmanial activity of amphotericin B and paromomycin using co-delivery in D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) tailored nano-lipid carrier system
(Elsevier Ireland Ltd, 2020) Shabi Parvez; Ganesh Yadagiri; Aakriti Singh; Archana Karole; Om Prakash Singh; Shyam Sundar; Shyam Lal Mudavath
In the current study, we have focused on the design, development and in-vitro evaluation of D-α-tocopheryl polyethylene glycol 1000 succinate modified amphotericin B (AmB) and paromomycin (PM) loaded solid lipid nanoparticles (TPGS-SLNPs) by emulsion-solvent evaporation method. The optimized TPGS-SLNPs had a mean particle size of 199.4 ± 18.9 nm with a polydispersity index of 0.22 ± 0.14 and entrapment efficiency for AmB and PM was found to be 94 ± 1.5 % and 89 ± 0.50 % respectively. The prepared lipid nanoparticles were characterized by Powdered X-ray diffraction study, Fourier transform infrared spectroscopy, Nuclear magnetic resonance spectroscopy to confirm the absence of any interaction between lipids and drugs. The developed formulation showed a sustained drug release over a period of 48 h and were stable at different temperatures. Finally, TPGS-SLNPs (1 μg/mL) was found to significantly (P < 0.001) mitigate the intra-cellular amastigote growth compared to free AmB. The results obtained suggest TPGS-SLNPs could be an efficient carrier for delivering poorly water-soluble drugs and efficiently enhance its therapeutic potential. © 2020 Elsevier B.V.
Modified solid lipid nanoparticles encapsulated with Amphotericin B and Paromomycin: an effective oral combination against experimental murine visceral leishmaniasis
(Nature Research, 2020) Shabi Parvez; Ganesh Yadagiri; Mallikarjuna Rao Gedda; Aakriti Singh; Om Prakash Singh; Anurag Verma; Shyam Sundar; Shyam Lal Mudavath
The development of an effective oral therapeutics is an immediate need for the control and elimination of visceral leishmaniasis (VL). We exemplify the preparation and optimization of 2-hydroxypropyl-β-cyclodextrin (HPCD) modified solid lipid nanoparticles (SLNs) based oral combinational cargo system of Amphotericin B (AmB) and Paromomycin (PM) against murine VL. The emulsion solvent evaporation method was employed to prepare HPCD modified dual drug-loaded solid lipid nanoparticles (m-DDSLNs). The optimized formulations have a mean particle size of 141 ± 3.2 nm, a polydispersity index of 0.248 ± 0.11 and entrapment efficiency for AmB and PM was found to be 96% and 90% respectively. The morphology of m-DDSLNs was confirmed by scanning electron microscopy and transmission electron microscopy. The developed formulations revealed a sustained drug release profile upto 57% (AmB) and 21.5% (PM) within 72 h and were stable at both 4 °C and 25 °C during short term stability studies performed for 2 months. Confocal laser scanning microscopy confirmed complete cellular internalization of SLNs within 24 h of incubation. In vitro cytotoxicity study against J774A.1 macrophage cells confirmed the safety and biocompatibility of the developed formulations. Further, m-DDSLNs did not induce any hepatic/renal toxicities in Swiss albino mice. The in vitro simulated study was performed to check the stability in simulated gastric fluids and simulated intestinal fluids and the release was found almost negligible. The in vitro anti-leishmanial activity of m-DDSLNs (1 µg/ml) has shown a maximum percentage of inhibition (96.22%) on intra-cellular amastigote growth of L. donovani. m-DDSLNs (20 mg/kg × 5 days, p.o.) has significantly (P < 0.01) reduced the liver parasite burden as compared to miltefosine (3 mg/kg × 5 days, p.o.) in L. donovani-infected BALB/c mice. This work suggests that the superiority of as-prepared m-DDSLNs as a promising approach towards the oral delivery of anti-leishmanial drugs. © 2020, The Author(s).
Recuperating Biopharmaceutical Aspects of Amphotericin B and Paromomycin Using a Chitosan Functionalized Nanocarrier via Oral Route for Enhanced Anti-leishmanial Activity
(Frontiers Media S.A., 2020) Shabi Parvez; Ganesh Yadagiri; Archana Karole; Om Prakash Singh; Anurag Verma; Shyam Sundar; Shyam Lal Mudavath
The design and development of new pharmaceutical formulations for the existing anti-leishmanial is a new strategic alternate to improve efficacy and safety rather than new drug discovery. Herein hybrid solid lipid nanoparticles (SLN) have been engineered to direct the oral delivery of two anti-leishmanial drugs amphotericin B (AmB) and paromomycin (PM). The combinatorial nanocarriers consist of conventional SLN, antileishmanial drugs (AmB and PM) which have been functionalized with chitosan (Cs) grafted onto the external surface. The Cs-SLN have the mean particle size of 373.9 ± 1.41 nm, polydispersity index (PDI) of 0.342 ± 0.02 and the entrapment efficiency for AmB and PM was found to be 95.20 ± 3.19% and 89.45 ± 6.86 %, respectively. Characterization of SLN was performed by scanning electron microscopy and transmission electron microscopy. Complete internalization of the formulation was observed in Caco-2 cells. Cs-SLN has shown a controlled and slow drug release profile over a period of 72 h and was stable at gastrointestinal fluids, confirmed by simulated gastro-intestinal fluids study. Cs coating enhanced the mucoadhesive property of Cs-SLN. The in-vitro anti-leishmanial activity of Cs-SLN (1 μg/ml) has shown a maximum percentage of inhibition (92.35%) on intra-cellular amastigote growth of L. donovani. © Copyright © 2020 Parvez, Yadagiri, Karole, Singh, Verma, Sundar and Mudavath.
Sensible graphene oxide differentiates macrophages and: Leishmania: a bio-nano interplay in attenuating intracellular parasite
(Royal Society of Chemistry, 2020) Aakriti Singh; Sandeep Sharma; Ganesh Yadagiri; Shabi Parvez; Ritika Gupta; Nitin Kumar Singhal; Nikhil Koratkar; Om Prakash Singh; Shyam Sundar; Vijayakumar Shanmugam; Shyam Lal Mudavath
Leishmania is an obligate intracellular protozoan parasite, which resides in human macrophage vacuoles that are referred to as parasitophorus vacuoles. Amphotericin B (AmB) is the first-line drug with 99% cure rates; however, overdose-induced toxic side effects are a major limitation. To improve the efficacy at lower dose and subsequently to avoid toxicity and to further investigate the role of charge dynamics on the efficacy, a graphene oxide (GO)-based composite of AmB was developed with native negatively charged GO and amine-conjugated positively charged AGO. The AGO composite resulted in enhanced uptake as confirmed by confocal and FACS analysis. Thus, AGO caused a strong inhibition of amastigotes, with IC50 values 5-fold lower than free AmB. The parasitophorus vacuoles harbour a hydrolytic and acidic environment, which is favourable for the parasites, as they don't attenuate this condition. AGO-AmB was able to modify the intracellular pH of the Leishmania donovani-infected macrophages, generating unfavourable conditions for the amastigote, and thus improving its efficacy. © The Royal Society of Chemistry.