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1.
Mikrochim Acta ; 191(1): 16, 2023 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-38086991

RESUMO

The current study designed and applied a novel self-ratiometric fluorescent nanosensor composed of green-synthesized silver nanoparticles (Ag-NPs) to determine vanillin in adult and infant foods and human plasma. A straightforward microwave-assisted approach is proposed for synthesizing Ag-NPs in less than 1 min using a reducing agent, tailed pepper seed extract. The synthesized Ag-NPs had a strong fluorescence with an intense emission band at 360 nm and a shoulder peak at 430 nm when excited at 265 nm. Upon interaction with vanillin, the fluorescence peak of Ag-NPs at 360 nm decreases in a concentration-dependent manner while being shifted to a longer wavelength, 385 nm. Meanwhile, the shoulder fluorescence peak at 430 nm is only slightly affected by vanillin addition. Thus, a new Ag-NP self-ratiometric probe was designed and validated for vanillin determination using the peak at 385 nm and the shoulder peak at 430 as two built-in reference peaks. The optimized system accurately measured vanillin with a detection limit of 9.0 ng/mL and a linear range of 0.05-8.0 µg/mL without needing pre-derivatization or high-cost instrumentation. The method successfully measured vanillin in adult and infant milk formula, biscuits, and human plasma samples with high percentage recoveries (95.3-104.6%) and excellent precision (relative SD; ≤3.85%).


Assuntos
Nanopartículas Metálicas , Humanos , Prata , Extratos Vegetais , Fluorescência
2.
Luminescence ; 2023 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-38088021

RESUMO

Vanillin is a flavouring agent that is prohibited for use in infant food products with ages lower than 6 months. Excessive vanillin usage could lead to eating disorders, nausea, headache, and vomiting. Therefore, it is essential to control the contents of vanillin in food samples, especially in infant formula. Here, we developed a highly sensitive nanosensor for vanillin based on using green synthesized highly fluorescent (QY = 29.5%) N-doped carbon quantum dots (N-CQDs) as a turn-off fluorescent nanoprobe. The N-doped CQDs synthesis was adopted using citrus bulb squeeze extract and the commonly used fertilizer, urea, as substrates. After mixing with vanillin, the fluorescence of the N-CQDs was largely quenched in a vanillin concentration-dependent manner. The sensing conditions were optimized by quality-by-design using a two-level full factorial design (22 FFD). The N-doped CQDs could detect vanillin in the range 0.1-12.0 µg/ml with a limit of detection of 0.013 µg/ml. Next, a smartphone imaging-based assay combined with a UV chamber was adopted and applied for vanillin determination. This simple detection technique showed sensitivity similar to that of the conventional fluorimetric method. Both conventional and smartphone-based methods were successfully applied for the determination of vanillin in infant milk formula and biscuits and could detect real vanillin concentrations in the analyzed samples with high % recoveries (94.5% to 105.5%). At last, the biocompatibility of the newly synthesized N-CQDs was tested, and it was found to be an excellent candidate for cancer cell imaging.

3.
Biomolecules ; 13(10)2023 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-37892156

RESUMO

We evaluated the therapeutic potentials of Khudari fruit pulp, a functional food and cultivar of Phoenix dactylifera, against neurological disorders. Our results demonstrate a good amount of phytochemicals (total phenolic content: 17.77 ± 8.21 µg GA/mg extract) with a high antioxidant potential of aqueous extract (DPPH assay IC50 = 235.84 ± 11.65 µg/mL) and FRAP value: 331.81 ± 4.56 µmol. Furthermore, the aqueous extract showed the marked inhibition of cell-free acetylcholinesterase (electric eel) with an IC50 value of 48.25 ± 2.04 µg/mL, and an enzyme inhibition kinetics study revealed that it exhibits mixed inhibition. Thereafter, we listed the 18 best-matched phytochemical compounds present in aqueous extract through LC/MS analysis. The computational study revealed that five out of eighteen predicted compounds can cross the BBB and exert considerable aqueous solubility. where 2-{5-[(1E)-3-methylbuta-1,3-dien-1-yl]-1H-indol-3-yl}ethanol (MDIE) indicates an acceptable LD50. value. A molecular docking study exhibited that the compounds occupied the key residues of acetylcholinesterase with ΔG range between -6.91 and -9.49 kcal/mol, where MDIE has ∆G: -8.67 kcal/mol, which was better than that of tacrine, ∆G: -8.25 kcal/mol. Molecular dynamics analyses of 100 ns supported the stability of the protein-ligand complexes analyzed through RMSD, RMSF, Rg, and SASA parameters. TRP_84 and GLY_442 are the most critical hydrophobic contacts for the complex, although GLU_199 is important for H-bonds. Prime/MM-GBSA showed that the protein-ligand complex formed a stable confirmation. These findings suggest that the aqueous extract of Khudari fruit pulp has significant antioxidant and acetylcholinesterase inhibition potentials, and its compound, MDIE, forms stably with confirmation with the target protein, though this fruit of Khudari dates can be a better functional food for the treatment of Alzheimer's disease. Further investigations are needed to fully understand the therapeutic role of this plant-based compound via in vivo study.


Assuntos
Colinesterases , Phoeniceae , Antioxidantes/farmacologia , Antioxidantes/química , Acetilcolinesterase/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Phoeniceae/química , Phoeniceae/metabolismo , Cromatografia Líquida , Simulação de Acoplamento Molecular , Ligantes , Espectrometria de Massas em Tandem , Compostos Fitoquímicos
4.
ACS Omega ; 8(37): 33955-33965, 2023 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-37744808

RESUMO

This study aims to enhance the dissolution rate of a poorly water-soluble drug physcion by producing its nanoparticles (NPs) using an antisolvent precipitation with a syringe pump (APSP) method and to assess its antioxidant and cytotoxic potential. The NPs were prepared using a simple and cost-effective APSP method and subsequently characterized by different analytical techniques including dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and X-ray powder diffractometry (XRD). They were also subjected to solubility and dissolution studies, and different parameters such as dissolution efficiency (DE), mean dissolution time (MDT), and difference (f1) and similarity factors (f2) were determined. Furthermore, physcion and its NPs were investigated for antioxidant and cytotoxic effects using various in vitro assays. SEM and DLS analysis indicated that the average size of physcion NPs was 110 and 195 ± 5.6 nm, respectively. The average ζ-potential and polydispersibility index (PDI) of the prepared NPs were -22.5 mV and 0.18, respectively, showing excellent dispersibility. XRD confirmed the amorphous nature of physcion NPs. The solubility and dissolution rates of NPs were significantly higher than those of the original powder. The antioxidant potential studied by the (DPPH), FRAP, and H2O2 assays was greater for physcion NPs than that for the raw powder. The IC50 values of physcion NPs against the aforementioned models were 57.56, 22.30, and 22.68 µg/mL, respectively. Likewise, the cytotoxic potential investigated through the MTT assay showed that physcion NPs were more cytotoxic to cancer cell lines A549 (IC50 4.12 µg/mL), HepG2 (IC50 2.84 µg/mL), and MDA-MB-231 (IC50 2.97 µg/mL), while it had less effect on HPAEpiC (IC50 8.68 µg/mL) and HRPTEpiC (IC50 10.71 µg/mL) normal human epithelial cells. These findings have proved that the APSP method successfully produced physcion NPs with enhanced solubility, dissolution rate, and antioxidant and cytotoxic activities.

5.
Nanomedicine (Lond) ; 18(22): 1567-1584, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37753727

RESUMO

Dengue is an arbovirus infection which is transmitted by Aedes mosquitoes. Its prompt detection and effective treatment is a global health challenge. Various nanoparticle-based vaccines have been formulated to present immunogen (antigens) to instigate an immune response or prevent virus spread, but no specific treatment has been devised. This review explores the role of nanomedicine-based therapeutic agents against dengue virus, taking into consideration the applicable dengue virus assays that are sensitive, specific, have a short turnaround time and are inexpensive. Various kinds of metallic, polymeric and lipid nanoparticles with safe and effective profiles present an alternative strategy that could provide a better remedy for eradicating the dengue virus.


Assuntos
Aedes , Vírus da Dengue , Dengue , Animais , Dengue/tratamento farmacológico , Dengue/prevenção & controle , Vírus da Dengue/fisiologia , Nanomedicina
6.
ACS Omega ; 8(33): 30221-30230, 2023 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-37636925

RESUMO

Biogenic synthesis of silver nanoparticles (AgNPs) using plant extracts is gaining attention as a substitute to the conventional physical and chemical synthesis methods. This study reports a facile, cost-effective, and ecofriendly synthesis of AgNPs using leaf extract of Alnus nitida (A. nitida) and their antioxidant and antiproliferative activities. The biosynthesized AgNPs were characterized using various analytical techniques including UV-visible spectroscopy, energy-dispersive spectrometry, scanning electron microscopy (SEM), Fourier transform infrared (FTIR), X-ray diffraction (XRD), and dynamic light scattering. The antioxidant and cytotoxic potential of the extract and AgNPs was evaluated using different in vitro models. The UV-vis analysis revealed a surface plasmon resonance peak of 400 nm corresponding to the synthesis of AgNPs. SEM analysis confirmed the formation of heterogeneously dispersed particles of nano size, while the XRD and FTIR spectra confirmed the crystallinity and existence of different functional groups that helped in capping and stability of AgNPs. The antioxidant activity of AgNPs and extract, studied by 1,1-diphenyl 2-picryl hydrazyl (DPPH), fluorescence recovery after photobleaching (FRAP), 2, 2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS), and H2O2 scavenging assays, showed a dose-dependent effect. The AgNPs at 1000 µg/mL significantly scavenged DPPH, FRAP, ABTS, and H2O2 by 66.45, 74.65, 78.81, and 72.56% with an average IC50 value of 33.31, 18.50, 16.46, and 15.65 µg/mL, respectively. The cytotoxic potential investigated by MTT assay revealed promising antiproliferative effects against different cancer cell lines. The IC50 values of AgNPs on MDA-MB-231, A549, and Hep-G2 cells were 14.88, 3.6, and 5.38 µg/mL, respectively. The results showed that AgNPs were more effective against lung and hepatocellular carcinoma. The selectivity index showed that AgNPs remained highly selective in retarding the growth of A549 and Hep-G2 cells as compared to normal cell lines HPAEpiC and HRPTEpiC. Overall, this study showed that biosynthesized AgNPs were associated with considerable antioxidant and cytotoxic effects. Our work suggests that A. nitida-mediated AgNPs should be evaluated further in order to develop safe and effective formulations for the treatment of different degenerative diseases.

7.
Saudi Pharm J ; 31(7): 1167-1180, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37273269

RESUMO

Solid-lipid nanoparticles (SLNs) are an innovative group of nanosystems used to deliver medicine to their respective targets with better efficiency and bioavailability in contrast to classical formulations. SLNs are less noxious, have fewer adverse effects, have more biocompatibility, and have easy biodegradability. Lipophilic, hydrophilic and hydrophobic drugs can be loaded into SLNs, to enhance their physical and chemical stability in critical environments. Certain antifungal agents used in different treatments are poorly soluble medications, biologicals, proteins etc. incorporated in SLNs to enhance their therapeutic outcome, increase their bioavailability and target specificity. SLNs-based antifungal agents are currently helpful against vicious drug-resistant fungal infections. This review covers the importance of SLNs in drug delivery of classical antifungal drugs, historical background, preparation, physicochemical characteristic, structure and sizes of SLNs, composition, drug entrapment efficacy, clinical evaluations and uses, challenges, antifungal drug resistance, strategies to overcome limitations, novel antifungal agents currently in clinical trials with special emphasis on fungal infections.

8.
Gels ; 9(4)2023 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-37102938

RESUMO

Breast cancer is the second most common cancer in women worldwide. Long-term treatment with conventional chemotherapy may result in severe systemic side effects. Therefore, the localized delivery of chemotherapy helps to overcome such a problem. In this article, self-assembling hydrogels were constructed via inclusion complexation between host ß-cyclodextrin polymers (8armPEG20k-CD and pß-CD) and the guest polymers 8-armed poly(ethylene glycol) capped either with cholesterol (8armPEG20k-chol) or adamantane (8armPEG20k-Ad) and were loaded with 5-fluorouracil (5-FU) and methotrexate (MTX). The prepared hydrogels were characterized by SEM and rheological behaviors. The in vitro release of 5-FU and MTX was studied. The cytotoxicity of our modified systems was investigated against breast tumor cells (MCF-7) using an MTT assay. Additionally, the histopathological changes in breast tissues were monitored before and after their intratumor injection. The results of rheological characterization indicated the viscoelastic behavior in all cases except for 8armPEG-Ad. In vitro release results showed a variable range of release profiles from 6 to 21 days, depending on the hydrogel composition. MTT findings indicated the inhibition ability of our systems against the viability of cancer cells depending on the kind and concentration of the hydrogel and the incubation period. Moreover, the results of histopathology showed the improvement of cancer manifestation (swelling and inflammation) after intratumor injection of loaded hydrogel systems. In conclusion, the obtained results indicated the applicability of the modified hydrogels as injectable vehicles for both loading and controlled release of anticancer therapies.

9.
Front Pharmacol ; 14: 1025013, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36825154

RESUMO

The purpose of this study was to assess the parameters of doxorubicin (DOX) loaded lipid polymer hybrid nanoparticles (LPHNs) formulation development, and then the bioavailability of DOX were determined in the rabbit model, in order to evaluate the intrinsic outcome of dosage form improvement after the oral administration. LPHNs were prepared by combine approach, using both magnetic stirring and probe sonication followed by its characterization in terms of size-distribution (Zeta Size), entrapment efficiency (EE), loading capacity, and the kinetics of DOX. LPHNPs were further characterized by using scanning electron microscopy (SEM), powder X-Ray diffractometry (P-XRD), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), in vitro and in vivo studies. The molecular modeling was determined through the density functional theory (DFT) simulations and interactions. DOX loaded and unloaded LPHNs were administered orally to the rabbits for bioavailability and pharmacokinetic parameters determinations. The plasma concentration of DOX was determined through high performance liquid chromatography (HPLC). The average size of DOX-loaded LPHNs was 121.90 ± 3.0 nm. The drug loading of DOX was 0.391% ± 0.01 of aqueous dispersion, where its encapsulation efficiency was 95.5% ± 1.39. After oral administration of the DOX-LPHNs, the area under the plasma drug concentration-time curve (AUC) improved about 2-folds comparatively (p < 0.05). DFT simulations were used to understand the interactions of polymers with different sites of DOX molecule. The larger negative binding energies (-9.33 to -18.53 kcal/mol) of the different complexes evince that the polymers have stronger affinity to bind with the DOX molecule while the negative values shows that the process is spontaneous, and the synthesis of DOX-LPHNs is energetically favorable. It was concluded that DOX-LPHNs provides a promising new formulation that can enhance the oral bioavailability, which have optimized compatibilities and improve the pharmacokinetic of DOX after oral administration.

10.
Front Pharmacol ; 13: 1046599, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36419621

RESUMO

Depression is a condition characterized by low mood and an aversion to activity, that causes behavioral problems, poor quality of life and limits daily life activities. It is considered as the fourth leading cause of disability worldwide. Selective Serotonin Reuptake Inhibitors (SSRIs) Monoamine Oxidase (MAO) inhibitors, Tricyclic Antidepressants (TCAs), and atypical antidepressants are some of the conventional medications used to treat depression. However, only about half of patients with major depressive disorder (MDD) respond effectively to first-line antidepressant therapy. Additionally, there are a number of drawbacks to standard antidepressants, such as anti-cholinergic side effects, drug-drug interactions, and food-drug interactions, which prompts researchers to look at alternative approaches to the treatment of depression. Medicinal plants and their metabolites are extensively tested for their efficacy against depression. Electronic databases such as Google scholar, Science Direct, SciFinder and PubMed were used to search relevant literature on the role of polyphenols in depression. Plants-derived Polyphenols represent a major class of compounds extensively distributed in plants. Number of polyphenols have demonstrated antidepressant activity, among which berberine, piperine, curcumin, naringenin, ascorbic acid and ginsenosides are extensively evaluated. The medicinal plants and their derived compounds mediated synthesized green nanoparticles have also exhibited considerable efficacy in the management of depression. The therapeutic effects of these phytochemicals is mediated via differentiation and inhibition of neuronal cell apoptosis, promotion of neuronal cell survival and modulation of key neurotransmitters. The aim of this study is to review compressively the chemical, pharmacological and neurological evidence showing the potential of polyphenols in depression.

11.
Int J Pharm ; 624: 121882, 2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-35671853

RESUMO

Non-aqueous nanoemulsion (NANE) of Alpinia galanga extract (AGE) was prepared using Palmester 3595 (MCT oil) as oil phase, Cremophor RH 40-Transcutol P® as surfactant-co-surfactant (Smix), and glycerin as non-aqueous polar continuous phase. The composition was optimized by applying three-level, four factor Box-Behnken design (BBD). The mean droplet size and zeta potential of the optimized AGE NANE was found to be 60.81 ± 18.88 nm and -7.99 ± 4.14 mV, respectively. The ex vivo permeation studies of AGE NANE and AGE per se on porcine skin reported flux of 125.58 ± 8.36 µg/cm2 h-1 and 12.02 ± 1.64 µg/cm2 h-1, respectively. Therefore, the enhancement ratio has shown 10-folds increase in the flux for AGE NANE when compared to extract per se. Later, confocal laser scanning microcopy confirmed that AGE NANE were able to penetrate into skin's stratum by trans-follicular transport mechanism. The stability studies of AGE NANE confirmed its stability at 30 ± 2 °C/75 ± 5 % RH and 5 ± 3 °C. The efficacy of AGE NANE was evaluated in vivo on imiquimod (IMQ) induced mouse model. The mice treated with low and high doses of AGE NANE (groups VI and VII) showed significant (p < 0.05) amelioration of psoriasis. Results of histopathology indicated reduction in psoriasis area severity index in AGE NANE treated mice (group VI and group VII).


Assuntos
Alpinia , Nanopartículas , Psoríase , Administração Cutânea , Animais , Emulsões , Camundongos , Psoríase/tratamento farmacológico , Absorção Cutânea , Tensoativos , Suínos
12.
Antibiotics (Basel) ; 11(4)2022 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-35453184

RESUMO

Leishmaniasis, remains a serious health problem in many developing countries with thousands of new cases recorded annually. Novel therapies are required as existing treatment regimens are limited by their high cost, high toxicity, increased parasite resistance, patient's intolerance, and invasive means of long-duration administration. With several studies reporting the anti-leishmaniasis promise of medicinal plants, interest in plants and herbal drugs is attracting much attention worldwide. In this pilot study, we analysed extracts of Linum usitatissimum seeds (LU) to identify essential phytochemicals and test their activity against cutaneous leishmaniasis both in-vitro and in-vivo. We performed phytochemical screening of LU seeds extract as well as its in-vitro leishmanicidal and anti-amastigote assays. Water-in-oil cream containing 10% LU crude extract (10 mg/mL) was then prepared. The stability of the cream was evaluated for 28 days at 8 °C, 25 °C and 40 °C. In-vivo efficacy and safety of the cream was performed in 26 patients with cutaneous leishmaniasis who agreed to participate voluntarily in the study. The active treatment period lasted for 3 weeks, while the follow-up period was extended to 4 months. During the active study period, images of skin lesions were taken before and after treatment. Analyses of LU seeds extract confirmed the presence of terpenoids, flavonoids, tannins, alkaloids, and polyphenols. In-vitro studies showed significant activity against promastigote and intracellular amastigote forms of Leishmaniamajor. The cream was pharmaceutically stable, although some minor changes were noticed in relation to its physical characteristics. In-vivo assessment of the cream showed a 69.23% cure rate with no side effects, allergy, or irritation. We conclude that our newly developed water in oil cream containing 10% LU seeds extract could be an effective and safe topical anti-leishmanial medication for patients with CL.

13.
Pharmaceutics ; 14(4)2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35456651

RESUMO

An inclusion complexation, between polymerized ß-cyclodextrin and cholesterol end-capping branched polyethylene glycol, was utilized for constructing a self-assembled hydrogel. The physicochemical properties, the in vitro release profiles of 5-Fluorouracil/methotrexate (anticancer drugs), and the surface morphology of the resulting hydrogel were studied. Moreover, in vivo studies were carried out on female rats bearing breast cancer. The results revealed that the prepared systems were white in color, rubbery, and homogenous. The in vitro release studies showed an efficient ability of the modified system for drug loading and release in a sustained release manner for 14 days. The surface morphology was spongy porous. Moreover, the tumors' healing was indicated from the analysis of tumor volume, plasma tumor markers, and histopathological analysis, compared to the controlled rats. The pharmacokinetic parameters appeared significant differences (p < 0.05) in the Cmax and Tmax of the medicated hydrogel samples, as compared with sole or combined saline-injected samples. The whole AUC of each drug in the medicated hydrogel samples was five-fold more than the mixture administrated in PBS. In conclusion, the proposed work delivered a hydrogel system that has a convenient ability for localized sustained release of breast cancer management.

14.
Pharmaceuticals (Basel) ; 15(3)2022 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-35337169

RESUMO

Injectable hydrogels (IHs) are smart biomaterials and are the most widely investigated and versatile technologies, which can be either implanted or inserted into living bodies with minimal invasion. Their unique features, tunable structure and stimuli-responsive biodegradation properties make these IHs promising in many biomedical applications, including tissue engineering, regenerative medicines, implants, drug/protein/gene delivery, cancer treatment, aesthetic corrections and spinal fusions. In this review, we comprehensively analyze the current development of several important types of IHs, including all those that have received FDA approval, are under clinical trials or are available commercially on the market. We also analyze the structural chemistry, synthesis, bonding, chemical/physical crosslinking and responsive release in association with current prospective research. Finally, we also review IHs' associated future prospects, hurdles, limitations and challenges in their development, fabrication, synthesis, in situ applications and regulatory affairs.

15.
ACS Omega ; 7(9): 7696-7705, 2022 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-35284709

RESUMO

The current study investigates the potential for topical delivery of a fluticasone propionate (FP) and levocetirizine dihydrochloride (CTZ)-loaded microemulsion (ME) for the management of atopic dermatitis. Various microemulsion components were chosen based on their solubility and emulsification capabilities, and the ternary phase diagram was constructed. A total of 12 microemulsion formulations were screened for various attributes like vesicle size, polydispersity index, ζ-potential, percent transmittance, density, and pH. The average globule size and ζ-potential of FP and levocetirizine-containing ME were 52.12 nm and -2.98 ζ-potential, respectively. Transmission electron microscopy confirmed the spherical nature of the globules. The developed system not only controlled the release of both drugs but also enhanced the efficacy of the drugs on a rodent model. Histopathological studies confirmed the safety of the developed system. The present findings provide evidence for a scalable and simpler approach for the management of atopic dermatitis.

16.
AAPS PharmSciTech ; 23(1): 45, 2022 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-34981280

RESUMO

Topical formulation of non-steroidal anti-inflammatory drugs (NSAIDs) exhibits many advantages over the oral administration route, such as avoiding the direct effect on GIT and avoiding the poor oral bioavailability of such drugs. Our study aims to develop a new self-assembling construct based on the hydrophobic interaction between adamantane terminated poly (ethylene glycol) polymers and polymerized ß-cyclodextrin. The viscous constructs were developed from direct mixing of host and guest polymer solutions, indicating spontaneous formation without cross-linkers. The modified system was evaluated by different analyses, including X-ray diffractometry, electron microscopy, isothermal titration calorimetry, and rheological analysis. Moreover, such a system's ability for drug loading and release was investigated via the in vitro release of ketorolac tromethamine (KT) as a model of NSAIDs. Finally, the prepared formulas were applied on a rat paw edema model to prove the enhanced anti-inflammatory activities. The obtained results indicated that the modified constructs have a rubbery porous structure with an amorphous nature. Also, from rheological results, the modified system exhibited a viscous behavior with higher loss modulus (G″) compared with storage (G'). The inclusion complexation between cyclodextrin and adamantane moieties was proved by the recorded high binding constants with a 1:1 stoichiometric ratio. Furthermore, the results showed the successful KT incorporation into the modified system and quantitatively released through a semi-permeable membrane in a sustained fashion (over 24 h). Finally, the in vivo results of the medicated constructs showed a significant inhibition of the induced inflammation and swelling, indicating that the modified construct has a great utility for safe non-irritating topical delivery applications.


Assuntos
Adamantano , Ciclodextrinas , Animais , Hidrogéis , Cetorolaco de Trometamina , Polietilenoglicóis , Ratos
17.
Pharmaceuticals (Basel) ; 14(8)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34451883

RESUMO

In this study, gliclazide-loaded cubosomal particles were prepared for improving the oral bioavailability and antidiabetic activity of gliclazide. Four formulations of gliclazide-loaded cubosomal nanoparticles dispersions were prepared by the emulsification method using four different concentrations of glyceryl monooleate (GMO) and poloxamer 407 (P407) as the stabilizer. The prepared formulations were in vitro and in vivo evaluated. In vitro, the prepared gliclazide-loaded cubosomal dispersions exhibited disaggregated regular poly-angular particles with a nanometer-sized particle range from 220.60 ± 1.39 to 234.00 ± 2.90 nm and entrapped 73.84 ± 3.03 to 88.81 ± 0.94 of gliclazide. In vitro gliclazide release from cubosomal nanoparticles revealed an initially higher drug release during the first 2 h in acidic pH medium; subsequently, a comparatively higher drug release in alkaline medium relative to gliclazide suspension was observed. An in vivo absorption study in rats revealed a two-fold increase in the bioavailability of gliclazide cubosomal formulation relative to plain gliclazide suspension. Moreover, the study of in vivo hypoglycemic activity indicated that a higher percentage reduction in glucose level was observed after the administration of gliclazide cubosomal nanoparticles to rats. In conclusion, gliclazide-loaded cubosomal nanoparticles could be a promising delivery system for improving the oral absorption and antidiabetic activity of gliclazide.

18.
Theranostics ; 9(25): 7537-7555, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695785

RESUMO

Rationale: Hedgehog (Hh) pathway plays an essential role in liver fibrosis by promoting the proliferation of hepatic stellate cells (HSCs) by enhancing their metabolism via yes-associated protein 1 (YAP1). Despite the presence of several inhibitors, Hh signaling cannot be controlled exclusively due to their poor efficacy and the lack of a suitable delivery system to the injury site. Therefore, it is rationale to develop new potent Hh inhibitors and suitable delivery carriers. Methods: Based on the structure and activity of Hh inhibitor GDC-0449, we replaced its sulfonamide group with two methylpyridine-2yl at amide nitrogen to synthesize MDB5. We compared the Hh pathway inhibition and anti-fibrotic effect of MDB5 with GDC-0449 in vitro. Next, we developed MDB5 loaded micelles using our methoxy poly(ethylene glycol)-blockpoly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol (PEG-PCC-g-DC) copolymer and characterized for physicochemical properties. We evaluated the therapeutic efficacy of MDB5 loaded micelles in common bile duct ligation (CBDL) induced liver fibrosis, mouse model. We also determined the intrahepatic distribution of fluorescently labeled micelles after MDB5 treatment. Results: Our results show that MDB5 was more potent in inhibiting Hh pathway components and HSC proliferation in vitro. We successfully developed MDB5 loaded micelles with particle size of 40 ± 10 nm and drug loading up to 10% w/w. MDB5 loaded micelles at the dose of 10 mg/kg were well tolerated by mice, without visible sign of toxicity. The serum enzyme activities elevated by CBDL was significantly decreased by MDB5 loaded micelles compared to GDC-0449 loaded micelles. MDB5 loaded micelles further decreased collagen deposition, HSC activation, and Hh activity and its target genes in the liver. MDB5 loaded micelles also prevented liver sinusoidal endothelial capillarization (LSEC) and therefore restored perfusion between blood and liver cells. Conclusions: Our study provides evidence that MDB5 was more potent in inhibiting Hh pathway in HSC-T6 cells and showed better hepatoprotection in CBDL mice compared to GDC-0449.


Assuntos
Derivados de Benzeno/farmacologia , Proteínas Hedgehog/antagonistas & inibidores , Cirrose Hepática/tratamento farmacológico , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Anilidas/farmacologia , Animais , Linhagem Celular , Modelos Animais de Doenças , Dodecanol/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Micelas , Poliésteres/química , Polietilenoglicóis/química , Ratos
19.
Pharm Res ; 35(1): 17, 2018 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-29305793

RESUMO

PURPOSE: The aim of this study was to determine whether co-administration of hedgehog (Hh) pathway inhibitor cyclopamine (CYP) and microtubule stabilizer docetaxel (DTX) as polymer-drug conjugates, methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylenecarbonate-graft-dodecanol-graft-cyclopamine) (P-CYP) and methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol-graft-docetaxel) (P-DTX) could synergistically inhibit orthotopic pancreatic tumor growth in NSG mice. METHODS: P-DTX and P-CYP were synthesized from mPEG-b-PCC through carbodiimide coupling reaction and characterized by 1H-NMR. The micelles were prepared by film hydration and particle size was measured by dynamic light scattering (DLS). Cytotoxicity, apoptosis and cell cycle analysis of P-DTX and P-CYP were evaluated in MIA PaCa-2 cells. In vivo efficacy of P-DTX and P-CYP were evaluated in NSG mice bearing MIA PaCa-2 cells derived orthotopic pancreatic tumor. RESULTS: P-CYP and P-DTX self-assembled into micelles of <90 nm and their combination therapy efficiently inhibited the proliferation of MIA PaCa-2 cells, induced apoptosis and cell cycle arrest at M-phase more efficiently than P-CYP and P-DTX monotherapies. Furthermore, the combination therapy of P-CYP and P-DTX significantly reduced Hh component expression compared to P-CYP alone as determined by Western blot analysis. Lastly, the combination therapy induced greater inhibition of orthotopic pancreatic tumor growth in NSG mice compared to their monotherapies. CONCLUSION: Combination of polymer conjugated anticancer drug (P-DTX) with polymer conjugated Hh inhibitor (P-CYP) enhanced pancreatic cancer cell killing, apoptosis as well as in vivo tumor growth inhibition with no obvious toxicities.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Polímeros/química , Taxoides/farmacologia , Alcaloides de Veratrum/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel , Portadores de Fármacos , Liberação Controlada de Fármacos , Ouriços/metabolismo , Humanos , Camundongos , Micelas , Microtúbulos/metabolismo , Metástase Neoplásica , Neoplasias Pancreáticas/patologia , Espectroscopia de Prótons por Ressonância Magnética , Taxoides/administração & dosagem , Taxoides/química , Alcaloides de Veratrum/administração & dosagem , Alcaloides de Veratrum/química
20.
Mol Pharm ; 14(9): 3121-3133, 2017 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-28719220

RESUMO

Gemcitabine (GEM), a first-line chemotherapy for pancreatic cancer undergoes rapid metabolism and develops chemoresistance after repeated administration. We previously demonstrated that the combination of GEM and miR-205 provides an effective therapeutic strategy to sensitize GEM-resistant pancreatic cancer cells. Since epidermal growth factor receptor (EGFR) is overexpressed in pancreatic cancer cells, in this study, we aimed to deliver mixed micelles containing GEM and miR-205 decorated with EGFR-targeting cetuximab (C225) monoclonal antibody for targeted therapy. Cetuximab C225 was conjugated to malemido-poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol (C225-PEG-PCD) to prepare mixed micelles with mPEG-b-PCC-g-GEM-g-DC-g-TEPA for targeted codelivery of GEM and miR-205. This mixed micelle formulation showed a significant enhancement in EGFR-mediated cellular uptake in GEM-resistant MIA PaCa-2R cells. Further, an enhanced tumor accumulation of C225-micelles conjugated with near-infrared fluorescent Cy7.5 dye and Dy677-labeled miR-205 in orthotopic pancreatic tumor bearing NSG mice was evident after systemic administration. In addition, inhibition of tumor growth was also observed with increased apoptosis and reduced EMT after treatment with C225-micelles containing GEM and miR-205. Therefore, we believe that the targeted delivery of GEM and miR-205 in combination could be a novel strategy for treating advanced pancreatic cancer.


Assuntos
Cetuximab/uso terapêutico , Desoxicitidina/análogos & derivados , Receptores ErbB/metabolismo , Micelas , MicroRNAs/fisiologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Polímeros/química , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Cetuximab/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Humanos , MicroRNAs/genética , Polietilenoglicóis/química , Gencitabina
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