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1.
Pharmaceutics ; 15(1)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36678895

RESUMO

Peptide monomers can either self-assemble with themselves enacting a solo-component assembly or they can co-assemble by interacting with other suitable partners to mediate peptide co-assembly. Peptide co-assemblies represent an innovative class of naive, multifunctional, bio-inspired supramolecular constructs that result in the production of nanostructures with widespread functional, structural, and chemical multiplicity. Herein, the co-assembly of novel chimeric peptides (conjugates of T7 (HAIYPRH)/t-Lyp-1 (CGNKRTR) peptides and aurein 1.2 (GLFDIIKKIAESF)) has been explored as a means to produce glioma theranostics exhibiting combinatorial chemo-phototherapy. Briefly, we have reported here the design and solid phase synthesis of a naive generation of twin-functional peptide drugs incorporating the blood-brain barrier (BBB) and glioma dual-targeting functionalities along with anti-glioma activity (G-Anti G and B-Anti G). Additionally, we have addressed their multicomponent co-assembly and explored their potential application as glioma drug delivery vehicles. Our naive peptide drug-based nanoparticles (NPs) successfully demonstrated a heightened glioma-specific delivery and anti-glioma activity. Multicomponent indocyanine green (ICG)-loaded peptide co-assembled NPs (PINPs: with a hydrodynamic size of 348 nm and a zeta-potential of 5 mV) showed enhanced anti-glioma responses in several cellular assays involving C6 cells. These included a mass demolition with no wound closure (i.e., a 100% cell destruction) and around 63% collaborative chemo-phototoxicity (with both a photothermal and photodynamic effect) after near infrared (NIR) 808 laser irradiation. The dual targeting ability of peptide bioconjugates towards both the BBB and glioma cells, presents new opportunities for designing tailored and better peptide-based nanostructures or nanophototheranostics for glioma.

2.
Ecotoxicol Environ Saf ; 243: 113985, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36027712

RESUMO

The present study aimed to assess the in-vitro toxicity of a popular azodye, Eriochrome Black T (EBT) which may be an environmental hazard causing water pollution if released by textile industries as waste effluents to nearby water ponds. We explored the toxic potential of EBT at 200, 400 and 800 µg/ml concentrations, which were selected based on quantification of EBT present in the pond water near carpet industries. We investigated the permeability of EBT across the organ barriers and found it to be 6.48 ± 0.44% at the highest concentration. EBT also showed up to 26.46 ± 0.533% hemolytic potential on human RBCs. MTT assay revealed toxicity of up to 64.9 ± 10.12%. A dose-dependent increase in intracellular ROS levels and Caspase 3/7 activity was observed and confocal microscopy also demonstrated a similar trend of cellular apoptosis indicating ROS mediated induction of apoptosis as a mechanism of EBT induced cytotoxicity. After establishing the toxicity of EBT, an innovative nano-photocatalytic approach for dye remediation was applied by using as synthesized Mf-NGr-CNTs-SnO2 heterostructures. This catalyst showed dye degradation potential of up to 82% in 2 h in the presence of sun light. The degraded dye products were tested to have up to 30% reduced cellular toxicity as compared to the parent compound. This work successfully establishes the toxicity of EBT along with devising an innovative approach towards dye degradation where the catalyst is adhered on melamine foam and not being mixed in the effluents directly, thereby, reducing the possibility of catalyst being leached out into the river water.


Assuntos
Compostos Azo , Indústria Têxtil , Compostos Azo/química , Compostos Azo/toxicidade , Corantes/química , Humanos , Espécies Reativas de Oxigênio , Têxteis , Água
3.
Bioconjug Chem ; 33(2): 397-410, 2022 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-35120290

RESUMO

The phenomenon of proteins/peptide assembly into amyloid fibrils is associated with various neurodegenerative and age-related human disorders. Inhibition of the aggregation behavior of amyloidogenic peptides/proteins or disruption of the pre-formed aggregates is a viable therapeutic option to control the progression of various protein aggregation-related disorders such as Alzheimer's disease (AD). In the current work, we investigated both the amyloid inhibition and disaggregation proclivity of levodopa-functionalized gold nanoroses (GNRs) against various peptide-based amyloid models, including the amyloid beta peptide [Aß (1-42) and Aß (1-40)] and the dipeptide phenylalanine-phenylalanine (FF). Our results depicted the anti-aggregation behavior of the GNR toward FF and both forms of Aß-derived fibrils. The peptides demonstrated a variation in their fiber-like morphology and a decline in thioflavin T fluorescence after being co-incubated with the GNR. We further demonstrated the neuroprotective effects of the GNR in neuroblastoma cells against FF and Aß (1-42) fiber-induced toxicity, exemplified both in terms of regaining cellular viability and reducing production of reactive oxygen species. Overall, these findings support the potency of the GNR as a promising platform for combating AD.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Ouro/uso terapêutico , Humanos , Levodopa/uso terapêutico , Fragmentos de Peptídeos/metabolismo , Fenilalanina/farmacologia
4.
J Photochem Photobiol B ; 228: 112407, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35189576

RESUMO

The successful application of nanomedicine against glioma is basically hooked on to the fabrication of specific and efficient glioma targeted multifunctional theranostics. Herein, through an easy synthetic methodology, we fabricated a type of novel multifunctional theranostic nanoplatform comprising of anisotropic gold nanoroses (AuNs) co-loaded with doxorubicin (DOX) and the near-infrared (NIR) active/responsive dye, indocyanine green (ICG). The tailored nanotheranostics upon being exposed to NIR laser helped in achieving combinatorial chemo-phototherapy along with optical cell imaging. BBB/glioma-targeting ability was realized by amalgamating the AuNs with a naive peptide drug with BBB-glioma targeting and anti-glioma twin functionality. Efficacy studies carried out in C6 cells and spheroids demonstrated heightened synergistic glioma chemo-PDT-PTT effect (~85% ablation in C6 cells and ~88% in C6 spheroids) by the AuNDIPs as compared to the individual therapeutic entities. Here, the AuNs derived nanophototheranostics with in force targeting and on-demand drug release nature will further aid in abolishing chemotherapy associated adverse events by adopting a combinatorial approach for synergistic glioma eradication.


Assuntos
Glioma , Nanopartículas , Linhagem Celular Tumoral , Glioma/diagnóstico por imagem , Glioma/tratamento farmacológico , Ouro , Humanos , Verde de Indocianina/farmacologia , Nanopartículas/uso terapêutico , Peptídeos/farmacologia , Fototerapia , Nanomedicina Teranóstica/métodos
5.
Bioconjug Chem ; 32(9): 2014-2031, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34461019

RESUMO

Combined chemo-phototherapy for boosting the efficacy of individual modalities by synergism for antiglioma treatments is in its embryonic stage and far away from effective clinical translation. Herein, moving a step closer, we recommend a facile stratagem to fabricate smart biocompatible and biodegradable multifunctional nanoplatforms comprising inherently fluorescent poly(levodopamine) nanoparticles (FLs) co-loaded with doxorubicin (DOX) and indocyanine green (ICG). The designed near-infrared (NIR) phototheranostic agents upon NIR laser irradiation helped precipitate combined chemo-phototherapy [both photothermal therapy (PTT) and photodynamic therapy (PDT)] and optical imaging under one roof. Excellent glioma-targeting ability was allocated to the nanoplatforms by conjugating them with a novel chimeric therapeutic peptide with glioma homing and antiglioma dual functionality. Further, DOX/ICG/peptide co-loaded nanoplatforms (FLDIPs) exhibited triggered drug release in response to multiple stimuli. Studies performed in 2D C6 glioma cells and 3D spheroids exhibited superior combined chemo-PDT/PTT effects (∼94% killing in cells and ∼87% in spheroids) of the designed FL based nanoplatforms compared to individual therapeutic components. Herein, the FL based multifunctional nanoplatforms with active targeting ability and stimuli responsive drug release behavior will further help in nullifying chemotherapy based adverse effects and mitigate chemo-resistance by adopting a combinatorial approach.


Assuntos
Barreira Hematoencefálica , Glioblastoma , Doxorrubicina , Humanos
6.
Adv Ther (Weinh) ; 4(2): 2000172, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33173808

RESUMO

The deadly pandemic, coronavirus disease 2019 (COVID-19), caused due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has paralyzed the world. Although significant methodological advances have been made in the field of viral detection/diagnosis with 251 in vitro diagnostic tests receiving emergency use approval by the US-FDA, little progress has been made in identifying curative or preventive therapies. This review discusses the current trends and potential future approaches for developing COVID-19 therapeutics, including repurposed drugs, vaccine candidates, immune-modulators, convalescent plasma therapy, and antiviral nanoparticles/nanovaccines/combinatorial nanotherapeutics to surmount the pandemic viral strain. Many potent therapeutic candidates emerging via drug-repurposing could significantly reduce the cost and duration of anti-COVID-19 drug development. Gene/protein-based vaccine candidates that could elicit both humoral and cell-based immunity would be on the frontlines to prevent the disease. Many emerging nanotechnology-based interventions will be critical in the fight against the deadly virus by facilitating early detection and enabling target oriented multidrug therapeutics. The therapeutic candidates discussed in this article include remdesivir, dexamethasone, hydroxychloroquine, favilavir, lopinavir/ritonavir, antibody therapeutics like gimsilumab and TJM2, anti-viral nanoparticles, and nanoparticle-based DNA and mRNA vaccines.

7.
Int J Biol Macromol ; 163: 2374-2391, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32961180

RESUMO

Cataract, the major cause of blindness worldwide occurs due to the misfolding and aggregation of the protein crystallin, which constitute a major portion of the lens protein. Other than the whole protein crystallin, the peptide sequences generated from crystallin as a result of covalent protein damage have also been shown to possess and foster protein aggregation, which can be established as crystallin aggregation models. Thus, the disaggregation or inhibition of these protein aggregates could be a viable approach to combat cataract and preserve lens proteostasis. Herein, we tried to explore the disruption as well as inhibition of the intact α-crystallin protein and α-crystallin derived model peptide aggregates by l-3,4-dihydroxyphenylalanine (levodopa) coated gold (Au) nano/micro-roses as modulators. Thioflavin T fluorescence enhancement assay, and electron microscopic analysis were being employed to probe the anti-aggregation behavior of the Au nano/micro-roses towards the aggregating α-crystallin peptides/protein. Further, computational studies were performed to reveal the nature of molecular interactions between the levodopa molecule and the α-crystallin derived model peptides. Interestingly, both levodopa coated Au nano/micro-roses were found to be capable of inhibiting as well as preventing the aggregation of the intact α-crystallin protein and other model peptides derived from it.


Assuntos
Anisotropia , Nanopartículas Metálicas/química , Peptídeos/química , alfa-Cristalinas/química , Ouro/química , Levodopa/farmacologia , Peptídeos/antagonistas & inibidores , Agregação Patológica de Proteínas/genética , alfa-Cristalinas/genética
8.
Int J Pharm ; 573: 118850, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31759993

RESUMO

Cpl-1, an endolysin derived from Cp-1 phage has been found to be effective in a number of in-vitro and in-vivo pneumococcal infection models. However its lower bioavailability under in-vivo conditions limits its applicability as therapeutic agent. In this study, Cpl-1 loaded chitosan nanoparticles were set up in order to develop a novel therapeutic delivery system to counter antibiotic resistant S. pneumoniae infections. Interactions of chitosan and Cpl-1 were studied by in-silico docking analysis. Chitosan nanoparticles and Cpl-1 loaded chitosan nanoparticles were prepared by using ionic gelation method and the process was optimized by varying chitosan:TPP ratio, pH, stirring time, stirring rate and Cpl-1 concentration. Chitosan nanoparticles and Cpl-1 loaded chitosan nanoparticles were characterized to ascertain successful formation of nanoparticles and entrapment of Cpl-1 into nanoparticles. Chitosan nanoparticles and Cpl-1 loaded nanoparticles were also evaluated for nanoparticle yield, entrapment efficiency, in-vitro release, stability, structural integrity of Cpl-1, in-vitro bioassay, swelling studies, in-vitro biodegradation and heamolysis studies. Mucoadhesion behavior of chitosan nanoparticles and Cpl-1 loaded nanoparticles was explored using mucous glycoprotein assay and ex-vivo mucoadhesion assay, both preparations exhibited their mucoadhesive nature. Cellular cytotoxicity and immune stimulation studies revealed biocompatible nature of nanoparticles. The results of this study confirm that chitosan nanoparticles are a promising biocompatible candidate for Cpl-1 delivery with a significant potential to increase bioavailability of enzyme that in turn can increase its in-vivo half life to treat S. pneumoniae infections.


Assuntos
Portadores de Fármacos/química , Composição de Medicamentos/métodos , Endopeptidases/administração & dosagem , Nanopartículas/química , Pneumonia Pneumocócica/tratamento farmacológico , Proteínas Virais/administração & dosagem , Células A549 , Administração Intranasal , Animais , Bacteriófagos/enzimologia , Disponibilidade Biológica , Quitosana/química , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Liberação Controlada de Fármacos , Endopeptidases/química , Endopeptidases/isolamento & purificação , Endopeptidases/farmacocinética , Estudos de Viabilidade , Meia-Vida , Humanos , Masculino , Teste de Materiais , Camundongos , Simulação de Acoplamento Molecular , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/microbiologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacocinética , Streptococcus pneumoniae/isolamento & purificação , Streptococcus pneumoniae/virologia , Proteínas Virais/química , Proteínas Virais/isolamento & purificação , Proteínas Virais/farmacocinética
9.
Expert Opin Drug Deliv ; 16(2): 113-128, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30572726

RESUMO

INTRODUCTION: Effective therapy of various neurological disorders is hindered on account of the failure of various therapeutics crossing blood-brain-barrier (BBB). Nanotheranostics has emerged as a cutting-edge unconventional theranostic nanomedicine, capable of realizing accurate diagnosis together with effective and targeted delivery of therapeutics across BBB to the unhealthy regions of the brain for potential clinical success. AREAS COVERED: We have tried to review the current status of nanotheranostic based approaches followed to manage neurological disorders. The focus has been majorly laid on to explore various theranostic nanoparticles and their application potential towards image-guided neurotherapies. Additionally, the usefulness of exceptional diagnostic, imaging techniques including magnetic resonance imaging and fluorescence imaging are being discussed by highlighting their promising opportunities in the detection, diagnosis, and treatment of the neurological disorders. EXPERT OPINION: Inimitable diagnostic and therapeutic potential of nanotheranostics have accomplished the aim of personalized therapies by governing the therapeutic efficacy of the system along with facilitating patient pre-selection grounded on non-invasive imaging, thereby predicting the responses of patients to nanomedicine treatments. While these accomplishments are encouraging, they are still the minority and demands for a continuous effort to improve sensitivity and precision in screening/diagnosis along with improving therapeutic efficacy in various neural disorders.


Assuntos
Sistemas de Liberação de Medicamentos , Doenças do Sistema Nervoso/tratamento farmacológico , Nanomedicina Teranóstica/métodos , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Humanos , Imageamento por Ressonância Magnética , Nanomedicina/métodos , Nanopartículas/uso terapêutico
10.
Pathog Dis ; 76(9)2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30576479

RESUMO

Plasmodium falciparum (Pf) proteins exported to infected erythrocytes are key effectors of malaria pathogenesis. These include the PfEMP1 (Pf erythrocyte membrane protein 1) protein family that affects malaria-related mortality through cytoadhesion and parasite immune evasion. Parasites also induce membranous structures called Maurer's clefts (MC) in infected erythrocytes to compensate the lack of host protein synthetic and export machinery. PfEMP1 export is mediated by a myriad of proteins including Pf skeleton binding protein 1 (PfSBP1) and PF70, a hypothetical 16 family member. Here, we aim to understand the function of the only other exported PEXEL-positive hyp16 member 'PfJ23'. Our in vitro and in silico data suggest this protein to be mostly α-helical while displaying different oligomeric forms under reducing and non-reducing conditions. We show coherent expression, partial co-localization and direct interaction of purified PfSBP1 with recombinant and native PfJ23. Recombinant and parasite-expressed PfJ23 also bind to the cytoplasmic tail of PfEMP1, and they seem to partly co-localize during parasite development. Both novel binding partners interact simultaneously with PfJ23 in vitro to form a complex. Our results suggest a probable role for PfJ23 in export of PEXEL-negative proteins like PfSBP1 and PfEMP1, furthering our understanding of malaria biology.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas de Membrana/metabolismo , Plasmodium falciparum/metabolismo , Multimerização Proteica , Proteínas de Protozoários/metabolismo , Fatores de Virulência/metabolismo , Sítios de Ligação , Ligação Proteica , Conformação Proteica , Mapeamento de Interação de Proteínas , Transporte Proteico , Fatores de Virulência/química , Fatores de Virulência/genética
11.
Pharm Res ; 35(2): 35, 2018 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-29362936

RESUMO

PURPOSE: Nanoparticles (NPs) exhibiting responsiveness towards pH variations in organs, tissue microenvironments and cellular compartments can significantly add on to the drug delivery potential. Here, we have developed NPs from an amphipathic dipeptide, Arginine-α, ß-dehydrophenylalanine (RΔF), and tried to explore their pH responsive drug delivery potential in various cancer cells. METHODS: RΔF-NPs were architectured by harnessing the process of molecular self-assembly followed by the assessment of effect of pH on NPs morphology using zetasizer, SEM and CD. FTIR and PXRD analysis of the dipeptide and doxorubicin (Dox) were carried out for compatibility assessment followed by encapsulation of Dox in RΔF-NPs. RΔF-Dox-NPs were evaluated for pH dependent release as well as for in-vitro cellular internalization and efficacy in cancer cells. RESULTS: RΔF self-assembled to form monodispersed particles at pH 7. SEM analysis revealed a loss of overall particle morphology along with particle aggregation at highly acidic and basic pH respectively. The NPs demonstrated a slow and sustained release behaviour at pH 7 (97.64 ± 4.71% after 36 h) in comparison to pH 2 (90.27 ± 1.45% after 8 h) and pH 10 (96.39 ± 3.87% after 12 h). In-vitro efficacy studies carried-out in various cancer cells revealed that RΔF-Dox-NPs exhibited higher efficacy with 1.65, 1.95 and 13.34 fold lower IC50 values in comparison to Dox in C6, HCT-116 and AGS cell lines. CONCLUSIONS: RΔF-Dox-NPs with higher drug release at acidic pH, enhanced internalization in cancer cells along with higher cytotoxic potential can act as effective pH responsive drug delivery systems.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Dipeptídeos/química , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Nanopartículas/química , Animais , Antibióticos Antineoplásicos/farmacocinética , Arginina/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Fenilalanina/análogos & derivados , Fenilalanina/química , Ratos
12.
ACS Chem Neurosci ; 8(10): 2105-2117, 2017 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-28768412

RESUMO

The window of neurological maladies encompasses 600 known neurological disorders. In the past few years, an inordinate upsurge in the incidences of neuronal ailments with increased mortality rate has been witnessed globally. Despite noteworthy research in the discovery and development of neural therapeutics, brain drug delivery still encounters limited success due to meager perviousness of most of the drug molecules through the blood-brain barrier (BBB), a tight layer of endothelial cells that selectively impedes routing of the molecules across itself. In this Review, we have tried to present a comprehensive idea on the recent developments in nanoparticle based BBB delivery systems, with a focus on the advancements in receptor targeted polymeric nanoparticles pertaining to BBB delivery. We have also attempted to bridge the gap between conventional brain delivery strategies and nanoparticle based BBB delivery for in-depth understanding. Various strategies are being explored for simplifying delivery of molecules across the BBB; however, they have their own limitations such as invasiveness and need for hospitalization and surgery. Introduction of nanotechnology can impressively benefit brain drug delivery. Though many nanoparticles are being explored, there are still several issues that need to be analyzed scrupulously before a real and efficient BBB traversing nanoformulation is realized.


Assuntos
Transporte Biológico/fisiologia , Barreira Hematoencefálica/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Nanopartículas , Animais , Barreira Hematoencefálica/metabolismo , Humanos , Nanopartículas/química , Nanotecnologia/métodos , Polímeros/química
13.
Amino Acids ; 49(5): 975-993, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28283907

RESUMO

Surging reports of peptide-based nanosystems and their growing potency in terms of biological utility demand for the search of newer and simpler peptide-based systems that could serve as smart templates for the development of self-assembled nanostructures. Use of simple amino acids as monomeric building blocks for synthesizing ensembles of nanostructures have gained momentum in this direction with some reports focusing on the development of nanosystems from single or modified single amino acids. In this work, we have demonstrated self-assembly and nanoparticle formation ability of a single amino acid derivative, N-alpha-(9-fluorenylmethyloxycarbonyl)-N(in)-tert-butyloxycarbonyl-L-tryptophan [Fmoc-Trp(Boc)-OH]. The nanoparticles formed by the amino acid were found to be stable to various environmental perturbations like temperature, salts and showed responsiveness to pH change. These were capable of loading and releasing different bioactive molecules and were biocompatible. These systems demonstrated high cellular uptake and doxorubicin-loaded nanoparticles were found to be more efficient in killing glioma cells as compared to the drug alone. Thus, their simple amino acid-based origin along with the ability to ferry bioactive molecules to various cells, endows them the suitability for future applications in the field of drug delivery.


Assuntos
Aminoácidos/química , Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Portadores de Fármacos , Fluorenos/química , Nanopartículas/química , Neuroglia/efeitos dos fármacos , Triptofano/análogos & derivados , Animais , Antibióticos Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Corantes Fluorescentes/metabolismo , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Cinética , Nanopartículas/ultraestrutura , Neuroglia/patologia , Ratos , Rodaminas/metabolismo , Temperatura
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