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1.
Int J Pharm ; 578: 119088, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32001291

RESUMO

Docetaxel (DTX), a widely prescribed anticancer agent, is now associated with increased instances of multidrug resistance. Also, being a problematic BCS class IV drug, it poses challenges for the formulators. Henceforth, it was envisioned to synthesize an analogue of DTX with a biocompatible lipid, i.e., palmitic acid. The in-silico studies (molecular docking and simulation) inferred lesser binding of docetaxel palmitate (DTX-PL) with P-gp vis-à-vis DTX and paclitaxel, indicating it to be a poor substrate for P-gp efflux. Solid lipid nanoparticles (SLNs) of the conjugate were prepared using various lipids, viz. palmitic acid, stearic acid, cetyl palmitate and glyceryl monostearate. The characterization studies for the nanocarrier were performed for the surface charge, drug payload, micromeritics, release pattern of drug and surface morphology. From the cytotoxicity assays on resistant MCF-7 cells, it was established that the new analogue offered substantially decreased IC50 to that of DTX. Further, apoptosis assay also corroborated the results obtained in IC50 determination wherein, SA-SLNs showed the highest apoptotic index than free DTX. The conjugate not only enhanced the solubility but also offered lower plasma protein binding and improved pharmacokinetic and pharmacodynamic effect for DTX loaded SA-SLNs in apt animal models, and lower affinity to P-gp efflux. The studies provide preliminary evidence and a ray of hope for a better candidate in its nano version for safer and effective cancer chemotherapy.

2.
Int J Pharm ; 576: 118977, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-31870953

RESUMO

Silver Sulphadiazine (SSD) is an effective antibacterial agent considered as the gold standard for burn wound treatment. The present study aimed to investigate EO-based organogel (SSD-EOOG) as an effective carrier system for SSD delivery in burn wound management employing Quality by Design (QbD) paradigm. The organogel-based formulations were prepared employing QbD-oriented approach and further evaluated for in vivo efficacy and stability. The developed formulations were characterized for particle size, drug content, morphology, in vitro drug release, skin safety studies, ex vivo permeation, skin retention, textural analysis and pharmacodynamic studies in murine burn wound model. I-optimal mixture design was employed for optimization and evaluating different critical quality attributes (CQAs). The optimized formulation exhibited particle size of 256.5 nm with enhanced permeation (72.33 ± 1.73%) and retention (541.20 ± 22.16 µg/cm2) across skin barrier as compared to SSD-MKT. The pharmacodynamic results proved superior therapeutic efficacy of SSD-EOOG in topical burn wounds inflicted with MRSA bacterium. The results indicated wound contraction rate (78.23 ± 5.65%) and faster re-epithelialization in SSD-EOOG treated group. The present study concluded that egg oil based organogel promoted therapeutic efficacy of SSD for burn wound treatment.

3.
Chemosphere ; 238: 124689, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31524624

RESUMO

Pharmaceutical effluents released from industries are accountable to deteriorate the aquatic and soil environment through indirect toxic effects. Microbes are adequately been used to biodegrade pharmaceutical industry wastewater and present study was envisaged to determine biodegradation of pharmaceutical effluent by Micrococcus yunnanensis. The strain showed 42.82% COD (Chemical oxygen demand) reduction before optimization. After applying Taguchi's L8 array as an optimization technique, the biodegradation rate was enhanced by 82.95% at optimum conditions (dextrose- 0.15%, peptone 0.1%, inoculum size 4% (wv-1), rpm 200, pH 8 at 25 °C) within 6 h. The confirmation of pharmaceuticals degradation was done by 1H NMR (Nuclear magnetic resonance) studies followed by elucidation of transformation pathways of probable drugs in the effluent through Q-Tof-MS (Quadrupole Time of Flight- Mass Spectrometry). The cytotoxicity evaluation of treated and untreated wastewater was analyzed on Human Embryonic Kidney (HEK 293) cells using Alamar Blue assay, which showed significant variance.


Assuntos
Biodegradação Ambiental , Resíduos Industriais/análise , Micrococcus/metabolismo , Preparações Farmacêuticas/análise , Águas Residuárias/química , Poluentes Químicos da Água/análise , Análise da Demanda Biológica de Oxigênio , Linhagem Celular , Indústria Farmacêutica , Células HEK293 , Humanos
4.
BMC Complement Altern Med ; 19(1): 334, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31771651

RESUMO

BACKGROUND: Psoriasis, a recurrent, chronic inflammatory disorder of skin, is a common problem in middle age and elderly people. Thymoquinone (TQ), a lipid soluble benzoquinone is the major active ingredient of volatile oil of Nigella sativa (NS), possesses good anti-psoriatic activity. However, its hydrophobicity, poor aqueous solubility, and photosensitive nature obstructs its development. Therefore, in the present research work, ethosomal vesicles (EVs) loaded with TQ were assessed for its anti-psoriatic potential employing mouse-tail model. METHODS: TQ-loaded EVs were prepared by cold method, and characterized for various essential attributes, viz. particle size, morphology, percent drug entrapment, flexibility, rheological and textural analysis, and skin absorption. The optimized formulation was finally evaluated for anti-psoriatic activity on Swiss albino mice employing mouse-tail model for psoriasis. RESULTS: The spherical shaped vesicles were in the nanosize range, and had high flexibility. The EVs incorporated hydrogel was rheologically acceptable and resulted in substantial TQ retention in the skin layers. The % anti-psoriatic drug activity was observed to be substantially better in the case of TQ-loaded ethosomal gel vis-à-vis plain TQ, NS extract, and marketed formulation. CONCLUSIONS: The promising outcomes of the current studies ratify the superiority of TQ-loaded phospholipid-based vesicular systems for the management of psoriasis over other studied test formulations. This study, thus open promising avenues for topical application of TQ in the form of EV hydrogel.


Assuntos
Benzoquinonas , Portadores de Fármacos , Nanomedicina/métodos , Fosfolipídeos , Psoríase , Animais , Benzoquinonas/administração & dosagem , Benzoquinonas/química , Benzoquinonas/farmacocinética , Modelos Animais de Doenças , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Camundongos , Nigella sativa/química , Fosfolipídeos/química , Fosfolipídeos/farmacocinética , Fosfolipídeos/farmacologia , Psoríase/metabolismo , Psoríase/patologia , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Absorção Cutânea/efeitos dos fármacos
5.
J Pharm Sci ; 108(12): 3879-3889, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31568776

RESUMO

The cost, side effects, and patient compliance-related issues of topically effective imiquimod have prevented its widespread acceptance. The present work intends to evaluate the feasibility of overcoming the shortcomings of poorly soluble and skin-penetrating immunomodulator by using biocompatible keratolytic agent with drug-loaded hybrid vesicles. Salicylic acid was complexed with phospholipid through simple mixing and incorporated into carbopol 940 gel containing drug-loaded vesicles, prepared by thin-film hydration method. The morphology, physicochemical properties, rheological behavior, release profile, and dermatokinetics of developed gel were compared with control gel (developed gel without keratolytic agent). In ex vivo drug release studies across the rat skin, there was significant increase in the steady-state permeation flux (Jss) and skin retention of drug from developed gel in comparison with control. There was favorable change in almost every evaluated dermatokinetic parameter. The innocuous nature of control gel had not changed on addition of skin structure-altering agent. The developed gel was found to be stable at room temperature and humidity for 1 year.

6.
AAPS PharmSciTech ; 20(6): 220, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201588

RESUMO

In this study, poly-(lactic-co-glycolic) acid (PLGA) was conjugated with aspartic acid and was characterized by nuclear magnetic resonance and Fourier transform infrared spectroscopy. Docetaxel-loaded polymeric micelles were prepared, and piperine was tagged. The neuroblastoma cytotoxicity studies revealed a substantially higher cytotoxic potential of the developed system to that of plain docetaxel, which was further corroborated by cellular uptake employing confocal laser scanning microscopy. The hemocompatible system was able to enhance the pharmacokinetic profile in terms of 6.5-fold increment in bioavailability followed by a 3.5 times increase in the retention time in comparison with the plain drug. The single-point brain bioavailability of docetaxel was amplified by 3.3-folds, signifying a better uptake and distribution to brain employing these carriers. The findings are unique as the physically adsorbed piperine was released before the DTX, increasing the propensity of curbing the CYP3A4 enzyme, which plays a vital role in the degradation of docetaxel. Meanwhile, piperine might have compromised the P-gp efflux mechanism, which can be ascribed to the enhanced retention of the drug at the target site. The elevated target site concentrations and extended residence by a biocompatible nanocarrier supplemented with co-delivery of piperine inherit immense promises to deliver this BCS class IV drug more safely and effectively.


Assuntos
Alcaloides/química , Antineoplásicos Fitogênicos/administração & dosagem , Benzodioxóis/química , Docetaxel/administração & dosagem , Micelas , Piperidinas/química , Alcamidas Poli-Insaturadas/química , Animais , Antineoplásicos Fitogênicos/farmacocinética , Disponibilidade Biológica , Encéfalo/metabolismo , Linhagem Celular Tumoral , Docetaxel/farmacocinética , Humanos , Ratos , Ratos Wistar , Espectroscopia de Infravermelho com Transformada de Fourier
7.
Artigo em Inglês | MEDLINE | ID: mdl-31082718

RESUMO

A simple, rapid, accurate, reproducible and sensitive reverse phase HPLC method for the estimation of fusidic acid (FA) by means of Analytical Quality by Design (AQbD) was the aim of the present study. Initially, the vital pre-requisites for AQbD like analytical method target profile and critical analytical attributes (CAAs) like theoretical plates, tailing factor and percent assay were defined. An octadecyl silyl silica C18 column with a packing size of 5 µm was employed and the detection was performed at 235 nm using UV-detector. The separation was performed with isocratic elution employing mixture of methanol: acetonitrile (5: 95, v/v) and an aqueous phase with pH of 2.8 containing 0.1% orthophosphoric acid in the ratio of 60: 40 (v/v). Ishikawa fish-bone diagram provided the basis of the variation in CAAs with various inputs. Taguchi Design was selected as the initial screening design to select critical method parameters (CMPs) affecting method development and Central Composite Design (CCD) was further applied for systematic optimization of chromatographic method by evaluating CAAs. Crucial parameters viz. limit of detection, limit of quantification, specificity, linearity and sensitivity were employed to validate the method in accordance with the ICH guidelines. Stress degradation studies were performed and the developed method was able to successfully differentiate the degraded products from the parent drug, that too in a topical gel. In conclusion, the findings of the present study validated the utility of AQbD in the systematic design of a liquid chromatographic method with fine sensitivity for FA estimation in medicinal products.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida de Alta Pressão/normas , Cromatografia de Fase Reversa/métodos , Cromatografia de Fase Reversa/normas , Ácido Fusídico , Ácido Fusídico/análise , Ácido Fusídico/química , Ácido Fusídico/farmacocinética , Cinética , Limite de Detecção , Modelos Lineares , Modelos Químicos , Reprodutibilidade dos Testes , Projetos de Pesquisa
8.
Ecotoxicol Environ Saf ; 180: 430-438, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31112842

RESUMO

The potential of Dunaliella salina isolated from Sambhar Salt Lake (Rajasthan, India) for biosorption of hexavalent chromium Cr(VI) in aqueous solution has been examined under optimized culture conditions. The influence of various process parameters, such as pH (6-11), incubation time (48-120 h), metal concentration (5-25 mgL-1), inoculum dose (2-10% vv-1), and their combination effects during Cr(VI) sorbtion were analyzed by means of Response Surface Methodology (RSM) based on a 3-level Box-Behnken experiment design. Microalgae showed highest chromium biosorption with 66.4% efficiency at optimum pH (8.6) and 10% (vv-1) inoculum size within 120 h. The experimental data obtained were analyzed by analysis of variance (ANOVA) along with lower value of coefficient of variation (34%), indicated the well fitness of quadratic equation as proposed by response surface model. Involvement of the surface morphology of the microalgae biomass and elemental distribution was studied through Scanning Electron Microscope (SEM), Energy Dispersive X-ray Spectroscopic (EDS), Fourier-transform infrared spectroscopy (FTIR) and X-ray Diffraction (XRD) analysis. The findings unequivocally corroborates that the novel microalgae inherits immense potential in alleviating the levels of toxic heavy metal, such as Cr(VI) from the hydrosphere at wide range of pH and metal concentrations. The present study provides a workable solution for bioremediation of hazardous heavy metals, in general, and Cr(VI) in specific from the industrial wastes like tannery effluents.


Assuntos
Clorófitas/crescimento & desenvolvimento , Cromo/análise , Lagos/química , Poluentes Químicos da Água/análise , Adsorção , Biodegradação Ambiental , Clorófitas/química , Concentração de Íons de Hidrogênio , Índia , Resíduos Industriais/análise , Modelos Teóricos
9.
Toxicol In Vitro ; 59: 126-134, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30986424

RESUMO

The present study aimed to explore the potential of hydroxylated carbon nanotubes (CNTnols) conjugated with aspartic acid for the delivery of docetaxel (DTX) to breast cancer cells. The conjugate was well-characterized by FT-IR, NMR, XRD and FE-SEM. The nanoconjugate offered a hydrodynamic diameter of 86.31 ±â€¯1.02 nm, with a PDI of 0.113 and zeta potential of -41.6 ±â€¯0.17 mV. The designed nanosystem offered a controlled & pH dependent release vouching release of drug in the cancerous cytosol, not in blood, assuring delivery of the pay-load to the site of action. The carriers offered substantial hemocompatibility and lower plasma protein binding, ensuring more drug available at the site of action. The in-vitro cell viability studies in MDA MB-231 cells inferred approx. 2.8 times enhancement in the cytotoxicity potential of the conjugate vis-à-vis plain drug. Pharmacokinetic studies also corroborated the superiority of the designed nanoconjugate in terms of enhanced bioavailable fractions, reduced clearance and longer bioresidence to that of plain docetaxel. The present studies, successfully provide a workable nanomedicine, loaded with a BCS class-IV drug, for improved efficacy and safety in breast cancer.


Assuntos
Antineoplásicos/administração & dosagem , Ácido Aspártico/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Docetaxel/administração & dosagem , Portadores de Fármacos/administração & dosagem , Nanotubos de Carbono , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Ácido Aspártico/química , Ácido Aspártico/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/química , Docetaxel/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Humanos , Nanotubos de Carbono/química , Ratos Wistar
10.
Drug Dev Ind Pharm ; 45(5): 826-838, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30764674

RESUMO

OBJECTIVE: The aim of this study was to formulate nanostructured lipid carriers (NLCs) of dithranol-loaded in gel for ease of application and to evaluate its anti-psoriatic efficacy vis-a-vis conventional ointment formulation. SIGNIFICANCE: This study will provide an insight about the use of nanocarriers, esp. NLCs loaded with dithranol for the effective treatment of psoriasis. METHODS: Dithranol-loaded NLCs were prepared by hot melt homogenization method and characterized for particle size and percentage entrapment efficiency. The optimized NLCs were loaded into gel and evaluated for drug release, spreadability, rheological behavior, and staining. Anti-psoriatic efficacy of the NLC gel was evaluated in imiquimod (IMQ) induced psoriatic plaque model in comparison with prepared conventional ointment formulation (1.15% w/w dithranol). RESULTS: NLCs were prepared with particle size below 300 nm, polydispersity index (PDI) below 0.3 and percentage entrapment efficiency of ∼100%. The prepared NLC gel was then compared with the ointment for drug release, staining property, and efficacy. Topical application of dithranol-loaded NLC gel on IMQ-induced psoriatic plaque model reduced the symptoms of psoriasis assessed by both Psoriasis area severity index (PASI) scoring and enzyme-linked immunosorbent assay. There was a significant reduction in disease severity and cytokines like Interleukins-17, 22, 23 and Tumor necrosis factor-α by the developed system in comparison to the negative control. CONCLUSIONS: To conclude dithranol-loaded NLCs in gel base was efficacious in management of psoriasis at the same drug concentration and also offer less cloth staining to that of the ointment product.


Assuntos
Antralina/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Portadores de Fármacos/química , Psoríase/tratamento farmacológico , Administração Cutânea , Animais , Antralina/farmacocinética , Fármacos Dermatológicos/farmacocinética , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Géis , Humanos , Imiquimode/administração & dosagem , Imiquimode/imunologia , Lipídeos/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Pomadas , Tamanho da Partícula , Psoríase/diagnóstico , Psoríase/imunologia , Psoríase/patologia , Índice de Gravidade de Doença , Pele/efeitos dos fármacos , Pele/patologia , Resultado do Tratamento
11.
AAPS PharmSciTech ; 20(3): 100, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30721373

RESUMO

Beta-carotene (BC), a red-colored pigment found in plants and animals, is one of the most extensively investigated carotenoids due to its provitamin-A, antioxidant, and anticancer properties. The anticancer activity of BC through oral administration is severely affected due to its low bioavailability and oxidative degradation. The present study aimed to formulate and characterize solid lipid nanoparticles (SLNs) of BC for enhanced bioavailability and therapeutic efficacy. Beta-carotene-loaded solid lipid nanoparticles (BC-SLNs) were prepared employing different combinations of glyceryl monostearate and gelucire. The characterization studies were performed for particle size, morphology, release behavior, and stability. BC-SLNs were also studied for in vitro cytotoxicity in human breast cancer cell lines (MCF-7) and pharmacokinetic studies in Wistar rats. The cytotoxicity studies confirmed that encapsulation of BC within the lipid bilayers of nanoparticles did not affect its anticancer efficacy. An improved anticancer activity was observed in BC-SLNs as compared to the free BC. BC-SLNs enhanced the bioavailability of BC on oral administration by sustaining its release from the lipid core and prolongation of circulation time in the body. Similarly, area under the curve (AUCtotal) enhanced 1.92-times more when BC was incorporated into SLNs as compared to free BC. In conclusion, solid lipid nanoparticles could be an effective and promising strategy to improve the biopharmaceutical properties of carotenoids for anticancer effects.


Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , beta Caroteno/administração & dosagem , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Disponibilidade Biológica , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Portadores de Fármacos/química , Glicerídeos/administração & dosagem , Glicerídeos/química , Glicerídeos/metabolismo , Humanos , Lipídeos , Células MCF-7 , Masculino , Nanopartículas/química , Nanopartículas/metabolismo , Tamanho da Partícula , Ratos , Ratos Wistar , beta Caroteno/química , beta Caroteno/metabolismo
12.
AAPS PharmSciTech ; 20(2): 74, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30631981

RESUMO

The present study aimed to orally deliver methylthioadenosine (MTA) to the brain employing solid lipid nanoparticles (SLNs) for the management of neurological conditions like multiple sclerosis. The stearic acid-based SLNs were below 100 nm with almost neutral zeta potential and offered higher drug entrapment and drug loading. Cuprizone-induced demyelination model in mice was employed to mimic the multiple sclerosis-like conditions. It was observed that the MTA-loaded SLNs were able to maintain the normal metabolism, locomotor activity, motor coordination, balancing, and grip strength of the rodents in substantially superior ways vis-à-vis plain MTA. Histopathological studies of the corpus callosum and its subsequent staining with myelin staining dye luxol fast blue proved the potential of MTA-loaded SLNs in the remyelination of neurons. The pharmacokinetic studies provided the evidences for improved bioavailability and enhanced bioresidence supporting the pharmacodynamic findings. The studies proved that SLN-encapsulated MTA can be substantially delivered to the brain and can effectively remyelinate the neurons. It can reverse the multiple sclerosis-like symptoms in a safer and effective manner, that too by oral route.


Assuntos
Encéfalo/efeitos dos fármacos , Desoxiadenosinas/administração & dosagem , Sistemas de Liberação de Medicamentos , Atividade Motora/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Nanopartículas/administração & dosagem , Ácidos Esteáricos/administração & dosagem , Tionucleosídeos/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Encéfalo/patologia , Desoxiadenosinas/farmacocinética , Camundongos , Ratos , Ratos Wistar , Tionucleosídeos/farmacocinética
13.
Mater Sci Eng C Mater Biol Appl ; 89: 274-282, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29752099

RESUMO

Our aim was to develop multiwalled carbon nanotubes (MWCNTs)-based nanoconstructs for the codelivery of N-desmethyl tamoxifen (N-TAM) and a mild P-gp efflux inhibitor, i.e., quercetin (QT) to treat multiple drug resistant (MDR) cancer cells. The hypothesis banks on three-tier attack on the MDR mechanisms viz. drug derivatization, MWCNT permeation and P-gp inhibition. Tamoxifen was converted to N-TAM and was conjugated to carboxylated MWCNTs mediated by a biodegradable linker, i.e., tetraethylene glycol (TEG). QT was adsorbed on the conjugate to fetch the final product, i.e., N-TAM-TEG-MWCNT-QT. Spectroscopic analysis confirmed successful conjugation of N-TAM and physical adsorption of QT. The in-vitro release of N-TAM from the N-TAM-TEG-MWCNT conjugate was minimal to that of pure drug under physiological conditions, but markedly enhanced under the acidic pH of cancer cells. The developed nanometeric formulation was found to be haemo-compatible. Reduced IC50values and better cellular uptake in drug resistant MDA-MB-231 cells were observed, followed by enhanced drug availability in the systemic circulation of rodents vis-à-vis naïve drug. The smart nanosystem conferred the desired temporal drug delivery, enhanced drug efficacy, biocompatibility and conducive pharmacokinetics, which are the crucial desired attributes to tackle the increasing concern of MDR in cancer chemotherapy.


Assuntos
Portadores de Fármacos/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Nanotubos de Carbono/química , Quercetina/química , Tamoxifeno/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Meia-Vida , Hemólise/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Polietilenoglicóis/química , Quercetina/metabolismo , Quercetina/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier , Tamoxifeno/metabolismo , Tamoxifeno/farmacologia
14.
ACS Chem Neurosci ; 9(5): 1152-1158, 2018 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-29357233

RESUMO

Multiple sclerosis (MS) is a neurodegenerative disease in which myelin sheath damage occurs due to internal and external factors. MS especially affects the young population. Dimethyl fumarate (DMF) is a promising agent for MS treatment, although it is associated with concerns such as poor brain permeation, multiple dosing, and gastrointestinal flushing. The present study attempts to evaluate the preclinical performance of specially designed DMF-based lipoidal nanoparticles in a cuprizone-induced demyelination model in rodents. The studies proved the efficacy of lipid-based nanoparticles containing DMF in a once-a-day dosage regimen over that of thrice-a-day plain DMF administration on crucial parameters like motor coordination, grip strength, mortality, body weight, and locomotor activity. However, neither blank lipid nor blank neuroprotective (vitamins A, D, and E) loaded nanoparticles were able to elicit any desirable behavioral response. Histopathological studies showed that the designed once-a-day DMF nanomedicines were well tolerated and rejuvenated the myelin sheath vis-à-vis the plain DMF thrice-a-day regimen. These findings provide proof of concept for a biocompatible nanomedicine for MS with tremendous promise for effective brain delivery and patient compliance on the grounds of a reduction in the dosage frequency.


Assuntos
Encéfalo/efeitos dos fármacos , Fumarato de Dimetilo/farmacologia , Imunossupressores/farmacologia , Esclerose Múltipla/tratamento farmacológico , Animais , Modelos Animais de Doenças , Lipídeos , Camundongos , Bainha de Mielina/efeitos dos fármacos , Nanopartículas/metabolismo
15.
Artif Cells Nanomed Biotechnol ; 46(8): 1763-1772, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29069915

RESUMO

The objective of the present study was to deliver docetaxel to cancerous cells with enhanced efficacy and safety profile, using aspartic acid linked fullerenols. This aspartic acid derivatized fullerenol conjugate linked with docetaxel was characterized by UV, FT-IR and NMR spectroscopy. Studies for particle size, PDI, zeta potential and FE-SEM were also performed. The conjugate was evaluated for release kinetics, cancer cell cytotoxicity, cellular uptake using confocal laser microscopy and also for pharmacokinetic profile. Cytotoxic studies proved that there was almost 4.3 folds decrease in IC50 with significantly enhanced cellular uptake of the nanometric conjugates. It was observed that the bioavailability was enhanced by 5.8 folds when compared to that of pure DTX. The developed nanoconstructs were erythrocyte compatible and offered decreased protein binding. The findings are encouraging and offer a novel carrier with enhanced efficacy and safety of a drug, belonging to BCS class IV.


Assuntos
Docetaxel , Portadores de Fármacos , Fulerenos , Docetaxel/química , Docetaxel/farmacocinética , Docetaxel/farmacologia , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Eritrócitos/metabolismo , Fulerenos/química , Fulerenos/farmacocinética , Fulerenos/farmacologia , Humanos
16.
AAPS PharmSciTech ; 19(3): 1084-1092, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29159749

RESUMO

Derivatization of fullerenes to polyhydroxylated fullerenes, i.e., fullerenols (FLU), dramatically decreases their toxicity and has been reported to enhance the solubility as well as cellular permeability. In this paper, we report synthesis of FLU as nanocarrier and subsequent chemical conjugation of Methotrexate (MTX) to FLU with a serum-stable and intracellularly hydrolysable ester bond between FLU and MTX. The conjugate was characterized for physiochemical attributes, micromeritics, drug-loading, and drug-release and evaluated for cancer cell-toxicity, cellular-uptake, hemocompatibility, protein binding, and pharmacokinetics. The developed hemocompatible FL-MTX offered lower protein binding vis-à-vis naïve drug and substantially higher drug loading. The conjugate offered pH-dependent release of 38.20 ± 1.19% at systemic pH and 85.67 ± 3.39% at the cancer cell pH. FLU-MTX-treated cells showed significant reduction in IC50 value vis-à-vis the cells treated with pure MTX. Analogously, the results from confocal scanning laser microscopy also confirmed the easy access of the dye-tagged FLU-MTX conjugate to the cell interiors. In pharmacokinetics, the AUC of MTX was enhanced by approx. 6.15 times and plasma half-life was enhanced by 2.45 times, after parenteral administration of single equivalent dose in rodents. FLU-MTX offered enhanced availability of drug to the biological system, meanwhile improved the cancer-cell cytotoxicity, sustained the effective plasma drug concentrations, and offered substantial compatibility to erythrocytes.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Fulerenos/química , Metotrexato/administração & dosagem , Nanoconjugados/química , Animais , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/farmacologia , Citotoxinas/administração & dosagem , Citotoxinas/química , Citotoxinas/farmacocinética , Citotoxinas/farmacologia , Liberação Controlada de Fármacos , Meia-Vida , Humanos , Metotrexato/química , Metotrexato/farmacocinética , Metotrexato/farmacologia , Ratos , Solubilidade , Água/química
17.
Mol Pharm ; 15(6): 2084-2097, 2018 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-29195048

RESUMO

Successful delivery of a chemotherapeutic agent like bendamustine still remains a challenge in clinical conditions like chronic lymphatic leukemia (CLL), non-Hodgkin lymphoma (NHL), and multiple myeloma. We have conjugated bendamustine to polyamidoamine (PAMAM) dendrimers after conjugating with N-(hydroxyethyl)maleimide (spacer) via an ester bond. The particle size of PAMAM-bendamustine conjugate was 49.8 ± 2.5 nm. In vitro drug release resulted in sustained release with improved solution stability of drug up to 72 h. In a 24 h cytotoxicity study by MTT assay against human monoblastic leukemia cells (THP-1), the IC50 value for PAMAM-bendamustine was 32.1 ± 4.8 µM compared to 50.42 ± 3.4 µM and 2303 ± 106.5 µM for bendamustine and PAMAM dendrimer, respectively. Significantly higher cell uptake and apoptosis were observed in THP-1 cells by PAMAM-bendamustine conjugate which was confirmed by flow cytometry and confocal laser scanning microscopy. Preliminary in vivo studies undertaken included pharmacokinetics studies, organ distribution studies, and tumor inhibition studies. In healthy Wistar rat model (1CBM IV push model), the pharmacokinetic studies revealed that bioavailability and t1/2 increased significantly, i.e., almost 8.5-fold (193.8 ± 1.116 vs 22.8 ± 0.158 µg mL-1/h) and 5.1-fold (0.75 ± 0.005 vs 3.85 ± 0.015 h), respectively, for PAMAM-bendamustine conjugate compared to pure bendamustine ( p < 0.05), however, clearance and volume of distribution were found to be decreased compared to those of free drug. The study suggests that PAMAM-bendamustine conjugate was not only stable for the longer period but also least toxic and highly taken up by THP-1 cells to exert an anticancer effect at the reduced dose. Tumor inhibition and biodistribution studies in tumor-bearing BALB/c mice revealed that PAMAM-bendamustine conjugate was more effective than the pure drug and showed higher accumulation in the tumor.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Apoptose/efeitos dos fármacos , Cloridrato de Bendamustina/administração & dosagem , Nanoconjugados/química , Animais , Antineoplásicos Alquilantes/farmacocinética , Cloridrato de Bendamustina/farmacocinética , Carcinoma de Ehrlich/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Dendrímeros/química , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Poliaminas/química , Ratos , Ratos Wistar , Distribuição Tecidual , Resultado do Tratamento
19.
Crit Rev Ther Drug Carrier Syst ; 34(4): 355-386, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29199589

RESUMO

Topical drug delivery offers many advantages over oral delivery, such as avoidance of first-pass metabolism, targeting of the active ingredients for a local effect, and patient compliance. However, the achievement of dermal and transdermal delivery needs to conciliate difficulties in permeation across skin barrier at different levels (skin surface, epidermis, dermis, and hypodermis). Nanostructured lipid carriers (NLCs) are recently invented second-generation lipidic carriers. The present article intends to provide an insight of composition, production, and application of these carriers in topical delivery for local and systemic effects. We also discuss key considerations for standardization and critical scale-up issues. In the last decade, the volume of work on NLCs is reflected in various research reports including patents on the development of NLCs, which gives a deeper insight of this emerging field of innovation. These carriers have significance because of their uniqueness to facilitate the interactions at interfaces with the barrier membranes. NLCs are truly a "nanosafe" carrier due to their biodegradable composition and have immense promise to overcome the challenges of dermal and transdermal delivery.


Assuntos
Portadores de Fármacos/administração & dosagem , Lipídeos/administração & dosagem , Nanoestruturas/administração & dosagem , Administração Cutânea , Animais , Disponibilidade Biológica , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Humanos , Lipídeos/química , Lipídeos/farmacocinética , Nanoestruturas/química , Pele/metabolismo
20.
Nanomedicine (Lond) ; 12(23): 2607-2621, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29094640

RESUMO

AIM: Dimethyl fumarate is a frequent prescription for the management of numerous neurological disorders. Despite immense promises, DMF is associated with various problems such as multiple dosing (2-3 oral doses daily) and lower brain permeability. Our aim was to enhance the oral bioavailability and increase the brain concentrations of dimethyl fumarate. METHODS: Solid lipid nanoparticles were systematically formulated by optimizing the composition based on the desired attributes viz. particle size, entrapment efficiency and amount of drug released in 6 h. Results & conclusion: The developed system offered nanometric particle size with entrapment efficiency > 90%. Enhanced Caco-2 cells cellular uptake by optimized solid lipid nanoparticless with superior pharmacokinetic and higher brain biodistribution were observed.


Assuntos
Encéfalo/metabolismo , Fumarato de Dimetilo/administração & dosagem , Lipídeos/química , Nanopartículas/química , Ácidos Esteáricos/química , Administração Oral , Animais , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Células CACO-2 , Química Farmacêutica , Fumarato de Dimetilo/química , Fumarato de Dimetilo/farmacocinética , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Feminino , Humanos , Masculino , Tamanho da Partícula , Permeabilidade , Ratos Wistar , Solubilidade , Propriedades de Superfície , Distribuição Tecidual/efeitos dos fármacos
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