scholarly journals Drug Conjugation Induced Modulation of Structural and Membrane Interaction Features of Cationic Cell-Permeable Peptides

2020 ◽  
Vol 21 (6) ◽  
pp. 2197
Author(s):  
Edit Pári ◽  
Kata Horváti ◽  
Szilvia Bősze ◽  
Beáta Biri-Kovács ◽  
Bálint Szeder ◽  
...  
Keyword(s):  
Drug Carrier ◽  
Biological Evaluation ◽  
Mycolic Acid ◽  
Cell Penetrating Peptides ◽  
Major Health Problem ◽  
Drug Molecules ◽  
Human Squamous Cell Carcinoma ◽  
Internalization Rate ◽  
Lipid Layers

Cell-penetrating peptides might have great potential for enhancing the therapeutic effect of drug molecules against such dangerous pathogens as Mycobacterium tuberculosis (Mtb), which causes a major health problem worldwide. A set of cationic cell-penetration peptides with various hydrophobicity were selected and synthesized as drug carrier of isoniazid (INH), a first-line antibacterial agent against tuberculosis. Molecular interactions between the peptides and their INH-conjugates with cell-membrane-forming lipid layers composed of DPPC and mycolic acid (a characteristic component of Mtb cell wall) were evaluated, using the Langmuir balance technique. Secondary structure of the INH conjugates was analyzed and compared to that of the native peptides by circular dichroism spectroscopic experiments performed in aqueous and membrane mimetic environment. A correlation was found between the conjugation induced conformational and membrane affinity changes of the INH–peptide conjugates. The degree and mode of interaction were also characterized by AFM imaging of penetrated lipid layers. In vitro biological evaluation was performed with Penetratin and Transportan conjugates. Results showed similar internalization rate into EBC-1 human squamous cell carcinoma, but markedly different subcellular localization and activity on intracellular Mtb.

scholarly journals Ternary Solid Dispersion Strategy for Solubility Enhancement of Poorly Soluble Drugs by Co-Milling Technique

2021 ◽  
Author(s):  
Marouene Bejaoui ◽  
Hanen Oueslati ◽  
Haykel Galai
Keyword(s):  
Solid Dispersion ◽  
Drug Carrier ◽  
Water Soluble ◽  
Pharmaceutical Ingredients ◽  
Drug Molecules ◽  
Water Soluble Drugs ◽  
Milling Method ◽  
Ternary Solid Dispersion

Amorphous ternary solid dispersion has become one of the strategies commonly used for improving the solubility and bioavailability of poorly water soluble drugs. Such multicomponent solid dispersion can be obtained by different techniques, this chapter provides an overview of ternary solid dispersion by co-milling method from the perspectives of physico-chemical characteristics in vitro and in vivo performance. A considerable improvement of solubility was obtained for many active pharmaceutical ingredients (e.g., Ibuprofen, Probucol, Gliclazid, Fenofibrate, Ibrutinib and Naproxen) and this was correlated to the synergy of multiple factors (hydrophilicity enhancement, particle size reduction, drug-carrier interactions, anti-plasticizing effect and complexation efficiency). This enhanced pharmacokinetic properties and bioavailability of these drug molecules (1.49 to 15-folds increase in plasma drug concentration). A particular focus was accorded to compare the ternary and binary system including Ibuprofen and highlighting the contribution of thermal and spectral characterization techniques. The addition of polyvinylpyrrolidone (PVP K30), a low molecular weight molecule, into the binary solid dispersion (Ibuprofen/β-cyclodextrin), leads to a 1.5–2 folds increase in the drug intrinsic dissolution rate only after 10 min. This resulted from physical stabilization of amorphous Ibuprofen by reducing its molecular mobility and inhibiting its recristallization even under stress conditions (75% RH and T = 40°C for six months).

Dextrins as Carriers for Drug Targeting: Reproducible Succinoylation as a Means to Introduce Pendant Groups

2001 ◽  
Vol 16 (5) ◽  
pp. 353-365 ◽  
Author(s):  
Dale Hreczuk-Hirst ◽  
Lisa German ◽  
Ruth Duncan
Keyword(s):  
Reaction Time ◽  
Drug Carrier ◽  
Biological Evaluation ◽  
Chemotherapeutic Agents ◽  
Reaction Conditions ◽  
Dialysis Solution ◽  
Polymeric Drug ◽  
Peritoneal Dialysis Solution

Dextrin (a-1,4 polyglucose) is in clinical use as a peritoneal dialysis solution and controlled drug delivery formulation. As a biodegradable polymer, dextrin has considerable potential as a polymeric drug carrier. Succinoylation, using dimethylaminopyridine (DMAP) as a catalyst, was used to conjugate chemotherapeutic agents, probes to follow biodistribution and probes to monitor intracellular fate. The aims of this study were to optimize the reaction conditions for the succinoylation (in respect of temperature and reaction time), to assess the suitability of succinoylated-dextrin as an intermediate for conjugation of drugs and probes selected to monitor pharmacokinetics (doxorubicin, tyrosinamide and biotin). The optimum temperature for succinoylation was 500C with a minimum of 8 h reaction time. Under these conditions succinoylation was reproducible with a coefficient of variation of < 10% and always gave a -50% yield. Different degrees of dextrin succinoylation (0.5-30 mol%) was achieved by variation of the reactants. Conjugation of doxorubicin to the succinoylated dextrin intermediate (15 or 34 mol%) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysulfosuccinimde (sulfo-NHS) reproducibly gave conjugates containing-9.0 wt% with < 1% of the total doxorubicin present as free drug. Tyrosinamide and biotin were bound to the succinoylated intermediate using carbodiimidazole (CDI). Dextrin-tyrosinamide conjugates were -1 mol% modified and the dextrin-biotin conjugates containing 6.8 wt% biotin. Succinoylation of dextrin is a non-polymer-disruptive method that can be used to reproducibly introduce pendant groups. The resultant conjugates are suitable for biological evaluation in in vitro and in vivo.

scholarly journals Biological Evaluation of Oil-in-Water Microemulsions as Carriers of Benzothiophene Analogues for Dermal Applications

Biomimetics ◽  
2021 ◽  
Vol 6 (1) ◽  
pp. 10
Author(s):  
Ioanna Theochari ◽  
Tanja Ilic ◽  
Ines Nicolic ◽  
Vladimir Dobricic ◽  
Alia Tenchiou ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Drug Carrier ◽  
Tween 80 ◽  
Biological Evaluation ◽  
Hair Follicles ◽  
Bioactive Molecules ◽  
Transdermal Administration ◽  
Thiazolyl Blue Tetrazolium Bromide ◽  
Oil In Water

During the last decade, many studies have been reported on the design and formulation of novel drug delivery systems proposed for dermal or transdermal administration. The efforts focus on the development of biocompatible nanodispersions that can be delivered to the skin and treat severe skin disorders, including cancer. In this context, oil-in-water (O/W) microemulsions have been developed to encapsulate and deliver lipophilic bioactive molecules for dermal application. An O/W biocompatible microemulsion composed of PBS buffer, Tween 80, and triacetin was assessed for its efficacy as a drug carrier of DPS-2, a lead compound, initially designed in-house to inhibit BRAFV600E oncogenic kinase. The system was evaluated through both in vitro and ex vivo approaches. The cytotoxic effect, in the presence and absence of DPS-2, was examined through the thiazolyl blue tetrazolium bromide (MTT) cell proliferation assay using various cell lines. Further investigation through Western blotting revealed that cells died of necrosis. Porcine ear skin was used as a skin model to evaluate the degree of permeation of DPS-2 through skin and assess its retention. Through the ex vivo experiments, it was clarified that encapsulated DPS-2 was distributed within the full thickness of the stratum corneum (SC) and had a high affinity to hair follicles.

scholarly journals Microfluidic in vitro brain endothelial monolayer model to evaluate cell-penetrating peptides

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Bohye Chung ◽  
Jaehoon Kim ◽  
Hui-Wen Liu ◽  
Jiyoung Nam ◽  
Hyunho Kim ◽  
...  
Keyword(s):  
Microfluidic Device ◽  
Drug Carrier ◽  
Cell Penetrating Peptides ◽  
Dimensional Model ◽  
Endothelial Monolayer ◽  
3 Dimensional ◽  
Cell Penetrating ◽  
Extracellular Matrix Scaffold ◽  
Monolayer Model

Abstract Blood vessels in central nervous system act as a great hurdle for drug delivery to the human brain. They only allow passage of water, some gases, lipid molecules, glucose and amino acid by selective transporter while restricting most of solutes and pathogens to protect brain. A lot of studies have tried to overcome this hurdle by discovering and optimizing brain deliverable drugs however the platforms used for preclinical stage are still limited. In this study, we constructed an in vitro 3-dimensional model for brain endothelial monolayer using hydrogel incorporated microfluidic device that provides an 3D extracellular matrix scaffold. We confirmed the stable endothelial barrier by staining a tight junction marker, VE-Cadherin, and strong block ability by comparing permeability with normal endothelial cells. Also, we succeed in verifying the strong permeability of angiopep-2 using our device that is known as a brain permeable peptide by utilizing receptor-mediated transcytosis. We propose our microfluidic device as an in vitro platform for evaluating various brain drugs or drug carrier candidates.

Synthesis, Characterization and in vitro Biological Evaluation of a New Schiff Base Derived from Drug and its Complexes with Transition Metal Ions

2018 ◽  
Vol 69 (7) ◽  
pp. 1678-1681
Author(s):  
Amina Mumtaz ◽  
Tariq Mahmud ◽  
M. R. J. Elsegood ◽  
G. W. Weaver
Keyword(s):  
Schiff Base ◽  
Transition Metal ◽  
Metal Ions ◽  
Metal Complexes ◽  
Transition Metal Complexes ◽  
Free Ligand ◽  
Transition Metal Ions ◽  
Biological Evaluation ◽  
Pyridoxal Hydrochloride

New series of copper (II), cobalt (II), zinc (II), nickel (II), manganese (II), iron (II) complexes of a novel Schiff base were prepared by the condensation of sulphadizine and pyridoxal hydrochloride. The ligand and metal complexes were characterized by utilizing different instrumental procedures like microanalysis, thermogravimetric examination and spectroscopy. The integrated ligand and transition metal complexes were screened against various bacteria and fungus. The studies demonstrated the enhanced activity of metal complexes against reported microbes when compared with free ligand.

Synthesis and Biological Evaluation of Amoxicillin Loaded Hybrid Material Composite Spheres Against Methicillin-Resistant Staphylococcus aureus

2020 ◽  
Vol 21 ◽  
Author(s):  
Muhammad Arfat Yameen ◽  
Amir Zeb ◽  
Raza E Mustafa ◽  
Sana Mushtaq ◽  
Nargis Aman ◽  
...  
Keyword(s):  
Mtt Assay ◽  
Hybrid Material ◽  
Ag Nanoparticles ◽  
Hybrid Composite ◽  
Synthesis Method ◽  
Biological Evaluation ◽  
Vitro Assay ◽  
Cytotoxicity Studies ◽  
Material Composite

Background: Incoherent use of antibiotics has led toward resistance in MRSA, which is becoming multidrugresistant with high rate of virulence in the community and hospital settings. Objective: Synergistic anti-MRSA activity was investigated in this study for hybrid material composite spheres of amoxicillin, Ag nanoparticles and chitosan which were prepared by one-step synthesis method and various characterizations were performed. Methods: Antimicrobial-susceptibility assay on MRSA was achieved by disc diffusion and agar dilution techniques while agar well diffusion was used for hybrid composite spheres. The in vitro and cytotoxicity studies was done by skin abrasion mouse model and MTT assay on RD cell respectively. Results: All isolates were resistant with the tested antibiotics except vancomycin. MIC against MRSA showed high resistance with amoxicillin from 4 to 128 mg L-1. The mean diameter of chitosan spheres and Ag nanoparticles was 02 mm and 277 nm respectively. Morphology of spheres was uneven, varied, porous and irregular in SEM and Ag nanoparticles presence and formation was also seen in micrograph. No substantial interface among drug, nanoparticles and polymer was found in XRD and IR showed characteristic peaks of all compound in the formulation. The in vitro assay showed augmented anti-MRSA activity with amoxicillin loaded hybrid composite spheres (22-29 mm). A significant reduction in microbial burden (~6.5 log10 CFU ml-1) was seen in vivo with loaded hybrid composite spheres formulation. The MTT assay indicated no potential cytotoxicity with hybrid composite spheres. Conclusion: Synergistic effect, amoxicillin, new hybrid formulation, anti-MRSA activity, composite spheres. nanoparticles.

Hybrid Design of Isonicotinic Acid Hydrazide Derivatives: Machine Learning Studies, Synthesis and Biological Evaluation of their Antituberculosis Activity

2020 ◽  
Vol 17 (3) ◽  
pp. 365-375
Author(s):  
Vasyl Kovalishyn ◽  
Diana Hodyna ◽  
Vitaliy O. Sinenko ◽  
Volodymyr Blagodatny ◽  
Ivan Semenyuta ◽  
...  
Keyword(s):  
Machine Learning ◽  
Isonicotinic Acid ◽  
Acid Hydrazide ◽  
Predictive Ability ◽  
Antitubercular Activity ◽  
Biological Evaluation ◽  
Starting Point ◽  
Binary Classifiers ◽  
Synthesis And Biological Evaluation

Background: Tuberculosis (TB) is an infection disease caused by Mycobacterium tuberculosis (Mtb) bacteria. One of the main causes of mortality from TB is the problem of Mtb resistance to known drugs. Objective: The goal of this work is to identify potent small molecule anti-TB agents by machine learning, synthesis and biological evaluation. Methods: The On-line Chemical Database and Modeling Environment (OCHEM) was used to build predictive machine learning models. Seven compounds were synthesized and tested in vitro for their antitubercular activity against H37Rv and resistant Mtb strains. Results: A set of predictive models was built with OCHEM based on a set of previously synthesized isoniazid (INH) derivatives containing a thiazole core and tested against Mtb. The predictive ability of the models was tested by a 5-fold cross-validation, and resulted in balanced accuracies (BA) of 61–78% for the binary classifiers. Test set validation showed that the models could be instrumental in predicting anti- TB activity with a reasonable accuracy (with BA = 67–79 %) within the applicability domain. Seven designed compounds were synthesized and demonstrated activity against both the H37Rv and multidrugresistant (MDR) Mtb strains resistant to rifampicin and isoniazid. According to the acute toxicity evaluation in Daphnia magna neonates, six compounds were classified as moderately toxic (LD50 in the range of 10−100 mg/L) and one as practically harmless (LD50 in the range of 100−1000 mg/L). Conclusion: The newly identified compounds may represent a starting point for further development of therapies against Mtb. The developed models are available online at OCHEM http://ochem.eu/article/11 1066 and can be used to virtually screen for potential compounds with anti-TB activity.

Design, Synthesis, Molecular Docking and Biological Evaluation of 1-(benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-ol Derivatives as Antiproliferative Agents

2019 ◽  
Vol 16 (10) ◽  
pp. 837-845
Author(s):  
Sandhya Jonnala ◽  
Bhaskar Nameta ◽  
Murthy Chavali ◽  
Rajashaker Bantu ◽  
Pallavi Choudante ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Inhibitory Activity ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Mouse Skin ◽  
Coupling Reaction ◽  
Binding Mode ◽  
Biological Evaluation ◽  
Design Synthesis

A class of 1-((benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-ol derivatives (4a-t) has been synthesized in good yields through a three component coupling reaction. The newly synthesized compounds were evaluated for their in vitro antiproliferative activity against five cell lines such as DU145 (human prostate cancer), MDA-MB-B231 (human breast cancer), SKOV3 (human ovarian cancer), B16-F10 (mouse skin melanoma) and CHO-K1 (Chinese hamster ovary cells), a noncancerous cell line. In vitro inhibitory activity indicates that compounds 4a, 4b, 4c, 4d, 4g, 4j, and 4o exhibited potent anti-proliferative behavior. Among them, compounds 4g, 4j and 4o found to be the most active members exhibiting remarkable growth inhibitory activity. Molecular docking facilitates to investigate the probable binding mode and key active site interactions in tubulins α and β proteins. The docking results are complementary to experimental results.

a Novel Combinational Nanodrug Delivery System Induces Synergistic Inhibition of Lung Adenocarcinoma Cells in vitro

2020 ◽  
Vol 17 ◽  
Author(s):  
Mingliang Fan ◽  
Jiping Li
Keyword(s):  
Lung Adenocarcinoma ◽  
Delivery System ◽  
The Body ◽  
Anticancer Efficacy ◽  
Nanodrug Delivery ◽  
Drug Molecules ◽  
Cellular Assays ◽  
Lung Adenocarcinoma Cell Line ◽  
M Phase

Background: The combination of two or more therapeutic drugs is an attractive approach to improve the treatment of experimental tumors. Leveraging nanocarriers for combinational drug delivery can allow a control over drug biological fate and promote co-localization in the same area of the body. However, there are certain concerns regarding the biodegradability and potential long-term toxicity arising from these synthetic nanoscale carriers. Objective: Our aim was to develop a combinational nanodrug delivery system formed by self-assembling of amphiphilic drug molecules，minimizing potential toxicities associated with using additional synthetic nanocarriers. Methods: A novel prodrug chlorambucil gemcitabine conjugate was synthesized, this prodrug was used for the encapsulation of an additional hydrophobic anticancer drug paclitaxel, taking the form of combinational nanodrugs. Particle size and zeta potential were evaluated, cytotoxicity assay and apoptosis/cell cycle analysis were also performed to validate the anticancer efficacy of the combinational nanodrugs. Results: The combinational nanodrugs were acquired by means of nanoprecipitation. In A549 lung adenocarcinoma cell line, cellular assays revealed that co-delivery of low dosage paclitaxel with chlorambucil gemcitabine conjugate can act synergistically to inhibit cell growth and induce accumulation of cells in the G2/M phase with a concomitant decrease in G0/G1 compartment. Conclusion: Chlorambucil gemcitabine conjugate and paclitaxel can co-assemble into composite nanoparticles by a nanoprecipitation process and the resulting combinational nanodrugs showed synergistic anticancer effect. This synthetic nanocarrier-free approach might broaden the nanodrug concept and have potential in cancer therapy.

Structure-Based Design, Synthesis, Biological Evaluation and Molecular Docking Study of 4-Hydroxy-N'-methylenebenzohydrazide Derivatives Acting as Tyrosinase Inhibitors with Potentiate Anti-Melanogenesis Activities

2020 ◽  
Vol 16 (7) ◽  
pp. 892-902 ◽  
Author(s):  
Aida Iraji ◽  
Mahsima Khoshneviszadeh ◽  
Pegah Bakhshizadeh ◽  
Najmeh Edraki ◽  
Mehdi Khoshneviszadeh
Keyword(s):  
Molecular Docking ◽  
Active Site ◽  
Competitive Inhibition ◽  
Docking Study ◽  
Biological Evaluation ◽  
Primary Response ◽  
Ratio Method ◽  
Molecular Docking Study ◽  
Metal Chelating

Background: Melanogenesis is a process of melanin synthesis, which is a primary response for the pigmentation of human skin. Tyrosinase is a key enzyme, which catalyzes a ratelimiting step of the melanin formation. Natural products have shown potent inhibitors, but some of these possess toxicity. Numerous synthetic inhibitors have been developed in recent years may lead to the potent anti– tyrosinase agents. Objective: A number of 4-hydroxy-N'-methylenebenzohydrazide analogues with related structure to chalcone and tyrosine were constructed with various substituents at the benzyl ring of the molecule and evaluate as a tyrosinase inhibitor. In addition, computational analysis and metal chelating potential have been evaluated. Methods: Design and synthesized compounds were evaluated for activity against mushroom tyrosinase. The metal chelating capacity of the potent compound was examined using the mole ratio method. Molecular docking of the synthesized compounds was carried out into the tyrosine active site. Results: Novel 4-hydroxy-N'-methylenebenzohydrazide derivatives were synthesized. The two compounds 4c and 4g showed an IC50 near the positive control, led to a drastic inhibition of tyrosinase. Confirming in vitro results were performed via the molecular docking analysis demonstrating hydrogen bound interactions of potent compounds with histatidine-Cu+2 residues with in the active site. Kinetic study of compound 4g showed competitive inhibition towards tyrosinase. Metal chelating assay indicates the mole fraction of 1:2 stoichiometry of the 4g-Cu2+ complex. Conclusion: The findings in the present study demonstrate that 4-Hydroxy-N'- methylenebenzohydrazide scaffold could be regarded as a bioactive core inhibitor of tyrosinase and can be used as an inspiration for further studies in this area.

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