TPGS Decorated Liposomes as Multifunctional Nano-Delivery Systems.

Liposomes are sphere-shaped vesicles that can capture therapeutics either in the outer phospholipid bilayer or inner aqueous core. Liposomes, especially when surface-modified with functional materials, have been used to achieve many benefits in drug delivery, including improving drug solubility, oral bioavailability, pharmacokinetics, and delivery to disease target sites such as cancers. Among the functional materials used to modify the surface of liposomes, the FDA-approved non-ionic surfactant D-alpha-tocopheryl polyethylene glycol succinate (TPGS) is increasingly being applied due to its biocompatibility, lack of toxicity, applicability to various administration routes and ability to enhance solubilization, stability, penetration and overall pharmacokinetics. TPGS decorated liposomes are emerging as a promising drug delivery system for various diseases and are expected to enter the market in the coming years. In this review article, we focus on the multifunctional properties of TPGS-coated liposomes and their beneficial therapeutic applications, including for oral drug delivery, vaccine delivery, ocular administration, and the treatment of various cancers. We also suggest future directions to optimise the manufacture and performance of TPGS liposomes and, thus, the delivery and effect of encapsulated diagnostics and therapeutics.

Functionalization of Nanoparticulate Drug Delivery Systems and Its Influence in Cancer Therapy.

Research into the application of nanocarriers in the delivery of cancer-fighting drugs has been a promising research area for decades. On the other hand, their cytotoxic effects on cells, low uptake efficiency, and therapeutic resistance have limited their therapeutic use. However, the urgency of pressing healthcare needs has resulted in the functionalization of nanoparticles' (NPs) physicochemical properties to improve clinical outcomes of new, old, and repurposed drugs. This article reviews recent research on methods for targeting functionalized nanoparticles to the tumor microenvironment (TME). Additionally, the use of relevant engineering techniques for surface functionalization of nanocarriers (liposomes, dendrimers, and mesoporous silica) and their critical roles in overcoming the current limitations in cancer therapy-targeting ligands used for targeted delivery, stimuli strategies, and multifunctional nanoparticles-were all reviewed. The limitations and future perspectives of functionalized nanoparticles were also finally discussed. Using relevant keywords, published scientific literature from all credible sources was retrieved. A quick search of the literature yielded almost 400 publications. The subject matter of this review was addressed adequately using an inclusion/exclusion criterion. The content of this review provides a reasonable basis for further studies to fully exploit the potential of these nanoparticles in cancer therapy.

Synthetic berberine derivatives as potential new drugs

Abstract The modern process of new drug discovery and development is an exciting, yet a challenging, endeavor. Although it can result in significant financial income and meet the medical needs of patients, it ultimately may result in failure. To achieve a fast and successful new product discovery and development process, natural products which are evolutionarily optimized as drug-like molecules have gained great attention as better potential sources of new chemical entities. Historically, plant species containing berberine are used in various traditional phytotherapy. However, despite the various therapeutic effects it exerts, berberine is not yet developed into a drug product. Addressing the barriers that hinder its successful development and the efforts made to overcome them is thus crucial. The toxicological and pharmacokinetic properties of berberine are the main barriers towards its development into a marketed drug product. It has low aqueous solubility, poor absorption, fast metabolism, and wide tissue distribution which lead to low bioavailability limiting its clinical application. Synthetic berberine derivatives with improved properties are suggested as better alternatives for further development and future therapeutic application. Hence, this paper summarizes the preclinical research studies conducted in the last decade to reveal the therapeutic potential of synthetic berberine derivatives for the treatment of various diseases and hence achieve successful berberine-based drug development in the future. To exploit the value of natural products as a source of leads for the development of effective drugs, collaboration among the different discovery and development scientists is essential.

Nanomaterials in the Management of Gram-Negative Bacterial Infections.

The exploration of multiplexed bacterial virulence factors is a major problem in the early stages of Escherichia coli infection therapy. Traditional methods for detecting Escherichia coli (E. coli), such as serological experiments, immunoassays, polymerase chain reaction, and isothermal microcalorimetry have some drawbacks. As a result, detecting E. coli in a timely, cost-effective, and sensitive manner is critical for various areas of human safety and health. Intelligent devices based on nanotechnology are paving the way for fast and early detection of E. coli at the point of care. Due to their specific optical, magnetic, and electrical capabilities, nanostructures can play an important role in bacterial sensors. Another one of the applications involved use of nanomaterials in fighting microbial infections, including E. coli mediated infections. Various types of nanomaterials, either used directly as an antibacterial agent such as metallic nanoparticles (NPs) (silver, gold, zinc, etc.), or as a nanocarrier to deliver and target the antibiotic to the E. coli and its infected area. Among different types, polymeric NPs, lipidic nanocarriers, metallic nanocarriers, nanomicelles, nanoemulsion/ nanosuspension, dendrimers, graphene, etc. proved to be effective vehicles to deliver the drug in a controlled fashion at the targeted site with lower off-site drug leakage and side effects.

Cationic chitosan-modified silica nanoparticles for oral delivery of protein vaccine.

Mesoporous silica nanoparticles coated with Chitosan are exploited here as a potential carrier for oral vaccine delivery. Bovine serum albumin (BSA) was used as a protein antigen model to reveal the carrier property. Chitosan-coated BSA-loaded silica NPs had particle size 345 ± 60 nm with a cationic surface charge of 18.28 ± 0.71 mV. The encapsulation efficiency, drug loading was 25.34 ± 0.76 and 20.21 ± 0.48%, respectively. Transmission electron microscopy investigation showed the spherical shape of NPs, also confirmed surface coating around modified nanoparticles (NPs), and nitrogen absorption/desorption isotherm confirmed mesostructured inside the NPs. Fourier transform infrared spectroscopy did not show any physiochemical interactions between excipients and formulations. The structural stability of antigen after release from NPs was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, and chitosan-coated silica NPs exhibited a slow-release pattern. The results of in vivo experiments presented that chitosan-mesoporous silica NPs could induce a robust immune response in mice, indicating that chitosan-mesoporous silica NPs might be used as a promising carrier for oral vaccine delivery.

Formulation, optimization, and characterization of whey protein isolate nanocrystals for celecoxib delivery.

AIM: Current study aimed to improve the solubility and release profile of the celecoxib for cancer application. However, the low water solubility of celecoxib limited its application for cancer chemotherapy. Hence, new drug delivery-based approaches are compulsory for the efficient delivery of hydrophobic celecoxib for chemotherapy. METHODS: The celecoxib-loaded nanocrystals were prepared by anti-solvent precipitation-ultrasonication technique, and the formulation was optimised through various process parameters. RESULTS: The optimised formulation had an average particle diameter of 171.09 ± 6.23 nm, with a PDI of 0.123 ± 0.009 and high ZP -27.3 ± 0.2 mV. The optimised formulation was stable, had higher entrapment efficiency 97.26 ± 1.12%. The conformational changes in the denatured protein solution were detected through fluorescence spectroscopy. The transmission electron microscopy investigation showed rod-shaped nanocrystals morphology, and no chemical interactions were observed in optimised formulation through FTIR. The DSC and PXRD analysis exhibited an amorphous state of the freeze-dried formulation drug. Also, optimised nanocrystals enhance drug solubility around 26.01-fold, 15.51-fold and 19.08-fold in purified water, pH 6.8 and pH 7.4, and accomplish sustained drug delivery, respectively. CONCLUSION: It can be concluded that biopolymer-coated celecoxib nanocrystals might be potential drug delivery of hydrophobic molecules for cancer therapy.

Therapeutic approach for global myocardial injury using bone marrow-derived mesenchymal stem cells by cardiac support device in rats.

Bone marrow-derived mesenchymal stem cells (BMSCs) have been considered a promising therapeutic approach to cardiovascular disease. This study intends to compare the effect of BMSCs through a standard active cardiac support device (ASD) and intravenous injection on global myocardial injury induced by isoproterenol. BMSCs were cultured in vitro, and the transplanted cells were labeled with a fluorescent dye CM-Dil. Isoproterenol (ISO) was injected into the rats; 2 weeks later, the labeled cells were transplanted into ISO-induced heart-jury rats through the tail vein or ASD device for 5 days. The rats were sacrificed on the first day, the third day, and the fifth day after transplantation to observe the distribution of cells in the myocardium by fluorescence microscopy. The hemodynamic indexes of the left ventricle were measured before sacrificing. H&E staining and Masson's trichrome staining were used to evaluate the cardiac histopathology. In the ASD groups, after 3 days of transplantation, there were a large number of BMSCs on the epicardial surface, and after 5 days of transplantation, BMSCs were widely distributed in the ventricular muscle. But in the intravenous injection group, there were no labeled-BMSCs distributed. In the ASD + BMSCs-three days treated group and ASD + BMSCs -five days-treated group, left ventricular systolic pressure (LVSP), the maximum rate of left ventricular pressure rise (+dP/dt), the maximum rate of left ventricular pressure decline (-dP/dt) increased compared with model group and intravenous injection group (P < 0.05). By giving BMSCs through ASD device, cells can rapidly and widely distribute in the myocardium and significantly improve heart function.

Enhanced cellular uptake and cytotoxicity of vorinostat through encapsulation in TPGS-modified liposomes.

Vorinostat (VOR) is known as one of the histone deacetylase inhibitors (HDACi) for cancer treatment, and the FDA approves it for cutaneous T cell lymphoma therapy. Poor solubility, permeability, and less anti-cancer activity are the main challenges for the effective delivery of VOR against various cancers. So, our team assumed that the surface-coated liposomes might improve the physicochemical properties of biopharmaceutics classification system class IV drugs such as VOR. The present study aimed to enhance the cytotoxicity and improve cellular uptake using TPGS-coated liposomes in breast cancer cells. Liposomes were fabricated by the film hydration following the probe ultra-sonication method. OR-LIPO and TPGS-VOR-LIPO showed an average particle size of 211.97 ± 3.42 nm with PDI 0.2168 ± 0.006 and 176.99 ± 2.06 nm with PDI 0.175 ± 0.018, respectively. TPGS-coated liposomes had better stability and revealed more than 80 % encapsulation efficiency than conventional liposomes. Transmission electron microscopy confirmed the TPGS coating around liposomes. Moreover, TPGS-coated liposomes enhanced the solubility and showed sustained release of VOR over 48 h. DSC and PXRD analysis also reveal an amorphous state of VOR within the liposomal formulation. MTT assay result indicates that the superior cytotoxic effect of surface-modified liposomes contrasts with the conventional and free VOR solution, respectively. Fluorescence microscopy and flow cytometry results also presented an enhanced cellular uptake of TPGS-coated liposomes against breast cancer cells, respectively. The current investigation's final results declared that TPGS-coated liposomes are promising drug carriers for the effective delivery of hydrophobic drugs for cancer therapy.

Nano-scaled materials may induce severe neurotoxicity upon chronic exposure to brain tissues: A critical appraisal and recent updates on predisposing factors, underlying mechanism, and future prospects.

Owing to their tremendous potential, the inference of nano-scaled materials has revolutionized many fields including the medicine and health, particularly for development of various types of targeted drug delivery devices for early prognosis and successful treatment of various diseases, including the brain disorders. Owing to their unique characteristic features, a variety of nanomaterials (particularly, ultra-fine particles (UFPs) have shown tremendous success in achieving the prognostic and therapeutic goals for early prognosis and treatment of various brain maladies such as Alzheimer's disease, Parkinson's disease, brain lymphomas, and other ailments. However, serious attention is needful due to innumerable after-effects of the nanomaterials. Despite their immense contribution in optimizing the prognostic and therapeutic modalities, biological interaction of nanomaterials with various body tissues may produce severe nanotoxicity of different organs including the heart, liver, kidney, lungs, immune system, gastro-intestinal system, skin as well as nervous system. However, in this review, we have primarily focused on nanomaterials-induced neurotoxicity of the brain. Following their translocation into different regions of the brain, nanomaterials may induce neurotoxicity through multiple mechanisms including the oxidative stress, DNA damage, lysosomal dysfunction, inflammatory cascade, apoptosis, genotoxicity, and ultimately necrosis of neuronal cells. Our findings indicated that rigorous toxicological evaluations must be carried out prior to clinical translation of nanomaterials-based formulations to avoid serious neurotoxic complications, which may further lead to develop various neuro-degenerative disorders.

Correction to "Thermosensitive Chitosan-Based Injectable Hydrogel as an Efficient Anticancer Drug Carrier".

[This corrects the article DOI: 10.1021/acsomega.0c02548.].

Advances in local and systemic drug delivery systems for post-surgical cancer treatment.

Surgery is considered to be the favored approach for the treatment of most solid tumor malignancies. The quality of life among cancer patients has significantly improved due to advancements in instrumentation and surgical techniques; however, the recurrence of tumors and metastasis after operation remains challenging and results in a decreased quality of life and an increase in the mortality rate. Therefore, there is a need to explore applicable approaches to eradicate the circulating tumor cells and any residual tumor at the surgical site to inhibit the recurrence of the tumor and reduce the threat of distant metastasis. Recently drug delivery systems have been used to deliver immunotherapy or chemotherapy agents, which could augment the efficacy of surgical resection. In this review, we have summarized the efficacy and the recent progress of controlled drug delivery systems based approaches for post-surgical cancer treatment. Clinical translation challenges and opportunities have also been discussed.

Thermosensitive Chitosan-Based Injectable Hydrogel as an Efficient Anticancer Drug Carrier.

A thermosensitive, physically cross-linked injectable hydrogel was formulated for the effective and sustained delivery of disulfiram (DSF) to the cancer cells as there is no hydrogel formulation available until now for the delivery of DSF. As we know, hydrogels have an advantage over other drug delivery systems because of their unique properties, so we proposed to formulate an injectable hydrogel system for the sustained delivery of an anticancer drug (DSF) to cancer cells. To investigate the surface morphology, a scanning electron microscope study was carried out, and for thermal stability of hydrogels, TGA (thermogravimetric analysis) and DSC (differential scanning calorimetry) were performed. The rheological behavior of hydrogels was evaluated with the increasing temperature and time. These developed hydrogels possessing excellent biocompatibility could be injected at room temperature following rapid gel formation at body temperature. The swelling index and in vitro drug release studies were performed at different pH (6.8 and 7.4) and temperatures (25 and 37 °C). The cell viability of the blank hydrogel, free DSF solution, and Ch/DSF (chitosan/DSF)-loaded hydrogel was studied by MTT assay on SMMC-7721 cells for 24 and 48 h, which exhibited higher cytotoxicity in a dose-dependent manner in contrast to the free DSF solution. Moreover, the cellular uptake of DSF-loaded hydrogels was observed stronger as compared with free DSF. Hence, chitosan-based hydrogels loaded with DSF possessing exceptional properties can be used as a novel injectable anticancer drug for the sustained delivery of DSF for long-term cancer therapy.

Green Synthesis of Silver Nanoparticles Using Parthenium Hysterophorus: Optimization, Characterization and In Vitro Therapeutic Evaluation.

Traditional synthetic techniques for silver nanoparticles synthesis involve toxic chemicals that are harmful to humans as well as the environment. The green chemistry method for nanoparticle synthesis is rapid, eco-friendly, and less toxic as compared to the traditional methods. In the present research, we synthesized silver nanoparticles employing a green chemistry approach from Parthenium hysterophorus leaf extract. The optimized parthenium silver nanoparticles (PrSNPs) had a mean particle size of 187.87 ± 4.89 nm with a narrow size distribution of 0.226 ± 0.009 and surface charge -34 ± 3.12 mV, respectively. The physicochemical characterization of optimized SNPs was done by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Moreover, the transmission electron microscopy (TEM) analysis indicates the spherical shape of NPs with an average diameter of 20-25 nm. PrSNPs were investigated for in vitro antibacterial, antifungal, anti-inflammatory, and antioxidant properties, and showed excellent profiles. The cytotoxic activity was analyzed against two cancer cell lines, i.e., B16F10 and HepG2 for 24 h and 48 h. PrSNPs proved to be an excellent anticancer agent. These PrSNPs were also employed for the treatment of wastewater by monitoring the E. coli count, and it turned out to be reduced by 58%; hence these NPs could be used for disinfecting water. Hence, we can propose that PrSNPs could be a suitable candidate as an antimicrobial, antioxidant, anti-inflammatory, and antitumor agent for the treatment of several ailments.

A New Oleanane Type Saponin from the Aerial Parts of Nigella sativa with Anti-Oxidant and Anti-Diabetic Potential.

Natural product studies explore potential and interesting new compounds to discover innovative drugs. Nigella sativa (N. sativa) (Ranunculaceae) is traditionally used to treat diabetes. Flavonoids and triterpenoid mostly show anti-diabetic activity. The current study aim to identify new compounds by a systematic study of the anti-oxidant and anti-diabetic activity of aerial parts of N. sativa concerning. Phytochemicals were isolated from the methanolic extract of aerial parts of the plant by column chromatography and identified by nuclear magnetic resonance spectroscopy and mass spectroscopy. A new triterpenoid saponin glycoside was isolated along with flavonoids. The anti-diabetic study was carried out by DPPH, ABTS, α -glucosidase, and protein tyrosine phosphatase 1B assays at doses of 12.5 to 250 µM. The isolated phytochemicals were identified as 3-O-(ß-d-xylopyranosyl-(1-3)-α-l-rhamnopyrnaosyl-(1-2)-α-l-arabinopyranosyl]-28-O-(α-l-rhamno-pyranosyl-(1-4)-ß-d-glucopyranosyl-(1-6)-ß-d-glucopyranosyl] hederagenin (1), flaccidoside III (2), catechol (3), quercetin-3-gentiobiosides (4), magnoflorine (5), nigelflavonoside B (6), nigelloside (7), quercetin sphorotrioside (8), kaempferol-3, 7-diglucoside (9), kaempferol 3-O-rutinoside (10), rutin (11), 3-O-[α-l-rhamnopyranosyl-(1→2)-α-l-arabinopyranpsylhederagenin (12), 3ß,23,28-trihydroxyolean-12-ene-3-O-α-l-arabinopyranoside(1→4)-a-rhamnopyranosyl,(1→4)-ß-d-gluco-pyranoside (13), 3-O-α-l-rhamnopyranosyl-(1→2)-α-l-arabinopyranpsyl]-28-O-ß-d-gluco-pyranosyl hederagenin (14), and α-hederin (15). These were isolated and are reported for the first time in this study. Compared 13 was identified as a new compound. Compound 2 was isolated for first time from the genus Nigella. Compound 6 was found to be the most active in the DPPH, and ABTS assays and compound 10 was found to be the most active in the α-glucosidase assay, with IC50 32.7 ± 0.1, 95.18 ± 0.9, 214.5 ± 0.0 µΜ, respectively. Compound 12, at a dose of 125 µΜ, showed anti-diabetic activity in a PTP1B assay with IC50 91.30 ± 2.5 µΜ. In conclusion, the anti-diabetic activity of N. sativa is due to its flavonoids and TTSGs. Therefore, our studies suggest that the aerial parts of N. sativa are also a valuable and alternate source of valuable phytochemicals that could be used to develop anti-oxidant and anti-diabetic medicines.

A Review of Medicinal Plants in Cardiovascular Disorders: Benefits and Risks.

Many cultivated and wild plants are used for the management of various diseases, specifically renal and hepatic diseases and those of the immune and cardiovascular systems. In China, medicinal plants from ancient to modern history have been used in patients with angina pectoris, congestive heart failure (CHF), systolic hypertension, arrhythmia, and venous insufficiency for centuries. The latest increase in the fame of natural products and alternative medicine has revived interest in conventional remedies that have been consumed in the management of CVD. The cardio-protective properties of the various herbs are possibly due to their anti-oxidative, antihypercholesterolemic, anti-ischemic activities, and inhibition of platelet aggregation that reduce the risk of CVD. Ethno-pharmacological and biological properties of these plants are explored, based upon published scientific literature. Although a majority of medicinal plants having a biological mechanism that linked with CVD management, to date, published literature pertaining to their promising scientific properties are still poorly understood. Compared with synthetic medicines, alternative medicines do not need scientific studies before their formal approval from the government sector and due to this purpose; their safety, as well as efficacy, still remain elusive. Taken together, we addressed all accessible evidence on alternative medicines commonly consumed in CVD management. Our comprehensive analysis of the scientific literature indicated that many TCMs are available and valuable herbal medication would be the best alternative for the management of CVD as a complementary therapy. Furthermore, practitioners should always discuss possible benefits-risks of alternative medicines with patients so that they are aware of the consumption of alternative medications.

Synthesis of Ligand Functionalized ErbB-3 Targeted Novel DNA Nano-Threads Loaded with the Low Dose of Doxorubicin for Efficient In Vitro Evaluation of the Resistant Anti-Cancer Activity.

PURPOSE: Doxorubicin (Dox) being a hydrophobic drug needs a unique carrier for the effective encapsulation with uniformity in the aqueous dispersion, cell culture media and the biological-fluids that may efficiently target its release at the tumor site. METHODS: Circular DNA-nanotechnology was employed to synthesize DNA Nano-threads (DNA-NTs) by polymerization of triangular DNA-tiles. It involved circularizing a linear single-stranded scaffold strand to make sturdier and rigid triangles. DNA-NTs were characterized by the AFM and Native-PAGE tests. Dox binding and loading to the Neuregulin1 (NRG1) functionalized DNA based nano-threads (NF-DBNs) was estimated by the UV-shift analysis. The biocompatibility of the blank NRG-1/DNA-NTs and enhanced cytotoxicity of the NF-DBNs was assessed by the MTT assay. Cell proliferation/apoptosis was analyzed through the Flow-cytometry experiment. Cell-surface binding and the cell-internalization of the NF-DBNs was captured by the double-photon confocal microscopy (DPCM). RESULTS: The AFM images revealed uniform DNA-NTs with the diameter 30 to 80 nm and length 400 to 800 nm. PAGE native gel was used for the further confirmation of the successful assembly of the strands to synthesize DNA-NTs that gave one sharp band with the decreased electrophoretic mobility down the gel. MTT assay showed that blank DNA-NTs were biocompatible to the cells with less cytotoxicity even at elevated concentrations with most of the cells (94%) remaining alive compared to the dose-dependent enhanced cytotoxicity of NF-DBNs further evidenced by the Flow-cytometry analysis. CONCLUSION: Uniform and stiffer DNA-NTs for the potential applications in targeted drug delivery was achieved through circular DNA scaffolding.

Food Protein-Based Nanodelivery Systems for Hydrophobic and Poorly Soluble Compounds.

The hydrophobicity of bioactive molecules poses a considerable problem in the pharmaceutical and the food industry. Using food-based protein nanocarriers is one promising way to deliver hydrophobic molecules. These types of protein possess many functional properties such as surface activity, water-binding capacity, emulsification, foaming, gelation, and antioxidant activity, as well as their incorporation in the food industry as ingredients. Besides, they express low toxicity, are less expensive compared to synthetic polymers, and are biodegradable. This review aims to give a brief overview of the recent studies done using food proteins as colloidal delivery systems for hydrophobic and poorly soluble compounds.

Synthetic NRG-1 functionalized DNA nanospindels towards HER2/neu targets for in vitro anti-cancer activity assessment against breast cancer MCF-7 cells.

DNA based nano-carriers synthesized from short circular scaffolds (circular DNA nanotechnology) attains stiffer topology for ligand functionalization (neuregulin-1/NRG-1 ligand) and biological applications (targeted drug delivery). Daunorubicin (DR) is a hydrophobic chemical that requires robust vectors to efficiently encapsulate and avoid its free dispersion in water, biological media and cell culture. Here we design DNA nanospindels (DNA-NS) to efficiently load DR and target the (highly expressed) HER2/neu receptors on the plasma membrane of drug-resistant MCF-7 (breast cancer) cells. DNA-NS were synthesized by polymerizing the DNA-triangles (utilizing 84-nt short circular scaffold strand) into larger DNA nano-ribbons characterized by the native-PAGE testing. AFM results revealed the spinning of DNA nanoribbons on its (own) axis because of the intrinsic curvature of the DNA double helix resulting in the formation of the firm and twisted DNA-NS with the diameter (50-70 nm) and length (0.5-4 µm). DA loading onto DNA-NS was confirmed by the UV shift analysis. The MTT results with the blank DNA-NS evidenced its biocompatibility (remained value of 93%) compared to the decreased viability of the MCF-7 cells after treatment with DNA-NS (DR loaded). These findings were further supported by the analysis of cell proliferation/apoptosis through flow cytometry showing 64% apoptosis after treating with the DR loaded DNA-NS. Hence, through the short circular DNA nanotechnology, we have achieved a stiffer, uniform, and biocompatible DNA-NS for applications in the targeted therapy.

3D QSAR pharmacophore-based virtual screening for the identification of potential inhibitors of tyrosinase.

Tyrosinase plays an important role in melanin biosynthesis and protects skin against ultraviolet radiations. Functional deficiency of tyrosinase results in serious dermatological diseases. Tyrosinase also participates in neuromelanin formation in the human brain, which leads to neurodegeneration resulting in Parkinson's disease. In fruits and vegetables, tyrosinase plays a critical role in senescence, causing undesired browning that results in faster deterioration and shorter shelf lines. The only commercially available tyrosinase is mushroom tyrosinase and it shows the highest homology to the mammalian tyrosinase. Although kojic acid is currently used as a tyrosinase inhibitor, they have serious side effects such as dermatitis, carcinogenesis and hepatotoxicity. Therefore, in order to develop a more active and safer tyrosinase inhibitor, 3D QSAR pharmacophore models were generated based on experimentally known inhibitors. The pharmacophore model, Hypo1, was developed with a large cost difference, high correlation coefficient and low RMS deviation. Hypo1 showed a good spatial arrangement; consisting of five-point features including two hydrogen bond acceptor, one hydrogen bond donor and two hydrophobic features. Hypo1 was further validated by cost analysis, test set and Fisher's randomisation method. Hypo1 was used as a 3D query for screening the in-house drug-like databases, and the hits were further selected by applying ADMET, Lipinski's rule of five and fit value criteria. To identify binding conformations, the obtained hits were subjected to molecular docking. Finally, molecular dynamics simulations revealed the appropriate binding modes of hit compounds. To conclude, we propose the final three hit compounds with new structural scaffolds as a virtual candidate as tyrosinase inhibitors.Communicated by Ramaswamy H. Sarma.

Recent advances in the delivery of disulfiram: a critical analysis of promising approaches to improve its pharmacokinetic profile and anticancer efficacy.

BACKGROUND: Disulfiram (DSF) has a long history of being used as a first-line promising therapy for treatment of alcoholism in human. Besides its prominence in the treatment of alcoholism, extensive investigations have been carried out to explore other biomedical and pharmacological effects of DSF. Amongst other biomedical implications, plenty researches have shown evidence of promising anticancer efficacy of this agent for treatment of wide range of cancers such as breast cancer, liver cancer and lung carcinoma. METHODS: Electronic databases, including Google scholar, PubMed and Web of science were searched with the keywords disulfiram, nanoparticles, cancer, drug delivery systems. RESULT: Despite its excellent anticancer efficacy, the pharmaceutical significance and clinical applicability of DSF are hampered due to poor stability, low solubility, short plasma half-life, rapid metabolism, and early clearance from systemic circulation. Various attempts have been made to eradicate these issues. Nanotechnology based interventions have gained remarkable recognition in improving pharmacokinetic and pharmacodynamic profile of DSF by improving its stability and avoiding its degradation. CONCLUSION: The aim of the present review is to critically analyse all recent developments in designing various nanotechnology-based delivery systems, to ponder their relevance in improving stability, pharmacokinetic and pharmacodynamic profile, and achieving target-specific delivery of this agent to cancer cells to effectively eradicate cancer and abolish its metastasis. Nanotechnology is a novel approach for overcoming such obstacles faced presently, the results obtained so far using different novel drug delivery systems seem to be very promising to increase the stability and half-life of DSF. Graphical abstract Nanocrrier mediated drug delivery systems for disulfiram.