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The present study aimed at investigating the antidepressant and antioxidant actions of near-infrared (NIR) laser at a wavelength of 830 nm and power of 100 mW which applied transcranially on an animal model of depression induced by repeated doses of reserpine (0.2 mg/kg). Thirty male Wistar adult rats were divided into three groups: rat model of depression; rat model of depression irradiated with laser for 14 days after induction of depression; and the control group that was given the drug vehicle and sham-exposed to the laser. Forced swimming test (FST) was used to verify the induction of animal model of depression and to screen the effect of antidepressant effect of low-level laser at the end of the experiment. Monoamine level, oxidative stress markers, and activities of acetylcholinesterase (AchE) and monoamine oxidase (MAO) were determined in the cortex and hippocampus of the rat brain. Reserpine resulted in depletion of monoamines and elevation in the oxidative stress markers and change in the enzymatic activities measured in both brain areas. Laser irradiation has an inhibitory action on the monoamine oxidase (MAO) in the cortex and hippocampus leading to elevation of the monoamine levels and attenuation of the oxidative stress in the studied areas. FST has emphasized the antidepressant effect of the utilized laser irradiation parameters on the behavioral level. The present findings provide evidence for the antidepressant and antioxidant actions of NIR low-power laser in the rat model of depression. Accordingly, low-laser irradiation may be presented as a potential candidate modality for depression treatment.

The physiological barriers and clearance mechanism of the eye challenge the therapeutic delivery for treating various ocular disorders effectively. Here, we show the use of a cationic peptide (i.e., Nap-FFKK) as the molecular hydrogelator for generating supramolecular hydrogels spontaneously in a pH value of 5-7 which allows it to function as a promising ocular drug vehicle. The cationic peptide-based hydrogel hardly exhibited the cytotoxicity against human corneal epithelial cell (i.e., HCEC) from the in vitro cytotoxicity assay. Moreover, the single topical instillation of the hydrogel resulted in high ocular tolerance and biocompatibility. In vivo corneal distribution of the cationic peptide-based hydrogel showed that it dramatically increased the retention and the adhesion on the surface of cornea, compared to the anionic peptide-based analogue, owing to the ionic interactions with mucin on the ocular surface. In addition, we also synthesized environment-sensitive fluorophore-conjugated analogues (i.e., NBD-FFKK and NBD-FFD) to visualize the uptake of hydrogels in HCEC cells, revealing that the cationic peptide-based hydrogel displayed the better in vitro cellular uptake than the anionic peptide-based hydrogel. More importantly, the resulting cationic Nap-FFKK supramolecular hydrogel displayed a superior ocular bioavailability over that of anionic Nap-FFD supramolecular hydrogel, as indicated by in vivo pharmacokinetics study. This work, as a systematic investigation of ionic peptide-based molecular hydrogels in the ocular application, illustrates a new and powerful supramolecular approach for antagonizing clinically difficult ocular drug delivery. STATEMENT OF SIGNIFICANCE: Here we show the use of a cationic peptide as the molecular hydrogelator for generating supramolecular hydrogels, which allows it to function as a promising ocular drug vehicle for antagonizing the therapeutic delivery difficulties associated with the physiological barriers and clearance mechanism of the eye. The in vitro and in vivo studies of the hydrogel both show high ocular tolerance and biocompatibility. Moreover, the in vivo corneal distribution of the hydrogel exhibits the increased retention and adhesion on the surface of cornea. This work, as an investigation of cationic peptide-based molecular hydrogels in the ocular application, illustrates a powerful supramolecular approach for overcoming clinically difficult ocular drug delivery.

The use of venom fractions from the Iranian cobra could be useful adjunct treatments of malaria with chloroquine. A metabolomic investigation with 1HNMR spectroscopy was conducted on an effective fraction tested earlier using Plasmodium berghei as an experimental murine model. We sought to ascertain both safety and anti-parasitic effects of experimental therapies. After purification of the venom fractions, 25 mice were infected, then treated for 4 days with 0.2 ml of 5 mg/kg, 2.5 mg/kg and 1 mg/kg of the effective fraction, chloroquine, and a drug vehicle. An ED50 was obtained using Giemsa staining and real-time PCR analysis. The toxicity tests inspecting both liver and kidney tissues were performed. A clear inhibitory effect on parasitaemia was observed (with 75% inhibition with 5 mg/kg and 50% reduction when 2.5 mg/kg dosage used). ED50 obtained 2.5 mg/kg. The metabolomics were identified as differentiation of aminoacyl-t-RNA biosynthesis, valine, leucine, isoleucine biosynthesis and degradation pathways were observed. Upon therapeutic effects of cobra venom fraction, further optimization of dose-dependent response of pharmacokinetics would be worthwhile for further exploration in adjunct experimental venom therapies.

Malaria, as one of the most common human infectious diseases, remains the greatest global health concern, since approximately 3.5 billion people around the world, especially those in subtropical areas, are at the risk of being infected by malaria. Due to the emergence and spread of drug resistance to the current antimalarials, malaria-related mortality and incidence rates have recently increased. To overcome the aforementioned obstacles, nano-vehicles based on biodegradable, natural, and non-toxic polymers have been developed. Accordingly, these systems are considered as a potential drug vehicle, which due to their unique properties such as the excellent safety profile, good biocompatibility, tunable structure, diversity, and the presence of functional groups within the polymer structure, could facilitate covalent attachment of targeting moieties and antimalarials to the polymeric nano-vehicles. In this review, we highlighted some recent developments of liposomes as unique nanoscale drug delivery vehicles and several polymeric nanovehicles, including hydrogels, dendrimers, self-assembled micelles, and polymer-drug conjugates for the effective delivery of antimalarials.

Graphical abstract, Highlights • DMSO impacts on C. elegans feeding behaviour in short-term and in a reversible manner. • DMSO affects the cellular integrity of C. elegans. • nlg-1 mutant is refractory to DMSO induced pumping inhibition. • Judicious consideration of the effect of the DMSO in bioassays in C. elegans., Caenorhabditis elegans provides a multi-cellular model organism for toxicology and drug discovery. These studies usually require solvents such as dimethyl sulfoxide (DMSO), ethanol or acetone as a vehicle. This raises the need to carefully consider whether the chemical vehicles used in these screens are anodyne towards C. elegans. Here, we use pharyngeal pumping as a bioassay to assess this. Pharyngeal pumping is a visually scoreable behaviour that is controlled by environmental cues activating sensory and integrative neural signalling to coordinate pharyngeal activity. As such it serves as a rich bioassay to screen for chemical modulation. We found that while pumping was insensitive to high concentrations of the widely used drug solvents ethanol and acetone, it was perturbed by concentrations of DMSO above 0.5 % v/v encompassing concentrations used as drug vehicle. This was manifested as an inhibition of pharyngeal pump rate followed by a slow recovery in the continued presence of the solvent. The inhibition was not observed in a neuroligin mutant, nlg-1, consistent with DMSO acting at the level of sensory processing that modulates pumping. We found that bus-17 mutants, which have enhanced cuticle penetration to drugs are more sensitive to DMSO. The effect of DMSO is accompanied by a progressive morphological disruption in which internal membrane-like structures of varying size accumulate. These internal structures are seen in all three genotypes investigated in this study and likely arise independent of the effects on pharyngeal pumping. Overall, these results highlight sensory signalling and strain dependent vehicle sensitivity. Although we define concentrations at which this can be mitigated, it highlights the need to consider time-dependent vehicle effects when evaluating control responses in C. elegans chemical biology.

The aim of the present work is fabrication of dual cross linked sodium alginate (SA)/montmorillonite (MMT) microbeads as a potential drug vehicle for extended release of curcumin (CUR). The microbeads were prepared using in situ ion-exchange followed by simple ionotropic gelation technique. The developed beads were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray diffraction (X-RD) and scanning electron microscopy (SEM). The effect of MMT on encapsulation efficiency of CUR and intercalation kinetics was investigated. Dynamic swelling study and in vitro release study were investigated in simulated intestinal fluid (pH 7.4) and simulated gastric fluid (pH 1.2) at 37 °C. Results suggested that both the swelling and in vitro release studies were influenced by the pH of test media, which might be suitable for intestinal drug delivery. The release mechanism was analyzed by fitting the release data into Korsmeyer-Peppas equation., Graphical abstract Image 1, Highlights • The microbeads prepared using sodium alginate (SA)/montmorillonite (MMT) were found to be potentially good carriers of curcumin (CUR) for extended release of CUR. • The bioavailability of CUR is increased by the usage of MMT in the microbeads, hence making it possible to enhance the anti-tumour activity. • The incorporation of multivalent ions like Mg2+, Ba2+ and Al3+ into calcium alginate matrix modified the swelling property and release rate of bio-active molecules. • The porous nature of the microbeads was based on the size and interaction of the ions namely Mg2+, Ba2+ and Al3+ with alginate.

Albumin is an appealing carrier in nanomedicine because of its unique features. First, it is the most abundant protein in plasma, endowing high biocompatibility, biodegradability, nonimmunogenicity, and safety for its clinical application. Second, albumin chemical structure and conformation allows interaction with many different drugs, potentially protecting them from elimination and metabolism in vivo, thus improving their pharmacokinetic properties. Finally, albumin can interact with receptors overexpressed in many diseased tissues and cells, providing a unique feature for active targeting of the disease site without the addition of specific ligands to the nanocarrier. For this reason, albumin, characterized by an extended serum half-life of around 19 days, has the potential of promoting half-life extension and targeted delivery of drugs. Therefore, this article focuses on the importance of albumin as a nanodrug delivery carrier for hydrophobic drugs, taking advantage of the passive as well as active targeting potential of this nanocarrier. Particular attention is paid to the breakthrough NAB-Technology, with emphasis on the advantages of Nab-Paclitaxel (Abraxane), compared to the solvent-based formulations of Paclitaxel, i.e., CrEL-paclitaxel (Taxol) in a clinical setting. Finally, the role of albumin in carrying anticancer compounds is depicted, with a particular focus on the albumin-based formulations that are currently undergoing clinical trials. The article sheds light on the power of an endogenous substance, such as albumin, as a drug delivery system, signifies the importance of the drug vehicle in drug performance in the biological systems, and highlights the possible future trends in the use of this drug delivery system.

Phototherapy holds promise in cancer treatment for its prominent antitumor efficacy and low systematic toxicity compared with traditional chemotherapy. However, the higher risk of tumor metastasis caused by the severe hypoxic state during phototherapy is a threat in practical use. Here, in order to tackle this challenge, we developed a delivery system via loading the photosensitizer indocyanine green (ICG) into the low molecular weight heparin (LMWH) modified liposomes (LMWH-ICG-Lip) to realize the synergistic effects between photosensitizer and drug vehicle, achieving better phototherapeutic efficacy and meanwhile alleviating the potential risk of tumor metastasis caused by phototherapy. In this system, besides elongating the photosensitizers' circulation time and enhancing their accumulating efficacy to tumor tissues, LMWH itself also exhibited anti-metastasis efficacy via inhibiting adhesion of platelets to tumor cells and decreasing migration and invasion capability of tumor cells. In vivo efficacy evaluation was conducted on orthotopic 4T1 breast cancer model, and the system of LMWH-ICG-Lip could alleviate metastasis potential of residual tumor cells after irradiation, and elicit optimistic antitumor and anti-metastasis efficacy for phototherapy.

Advanced drug vehicle exploitation and the sophisticated synergy mechanism revelation are two great difficulties in combination therapy. Compared with most readily available polymer micelles, some undiscovered complex chemical design principles limit the expanding research of polymer vesicles. Here, polycaprolactone (PCL)-g-Dextran vesicle that dextran brush steric hindrance guide PCL lamellae-aligned growth was synthesized. The effect of the glycometabolism multi-drug vesicle combination treatment and synergism mechanism were investigated on senescence-accelerated mouse prone 8 (SAMP8) mice. The main insulin sensitizer drug could improve the memory ability of mice to a small extent, and the main insulin secretion promoter drug had little beneficial effect. Moreover, the triple anti-insulin resistant drugs of insulin (INS), repaglinide (REP) and metformin hydrochloride (MET) activated the glycometabolism-related bio-signals, and the energy cycle was normalized successfully. The insulin intracellular uptake and utilization efficiency could be the reason for the gap. The upregulation of the brain-derived neurotrophic factor (BDNF) protein confirmed that the crosstalk between the mitochondria and synapse contributes to the nerve repair. This study provided an excellent drug combination vesicle to treat Alzheimer's disease (AD). The discovery of the combination mechanism leads to an improvement in the AD clinical treatment.

Post-mortem studies suggest that schizophrenia is associated with abnormal expression of specific GABAA receptor (GABAAR) α subunits, including α5GABAAR. Positron emission tomography (PET) measures of GABAAR availability in schizophrenia, however, have not revealed consistent alterations in vivo. Animal studies using the GABAAR agonist [3H]-muscimol provide evidence that antipsychotic drugs influence GABAAR availability, in a region-specific manner, suggesting a potential confounding effect of these drugs. No such data, however, are available for more recently developed subunit-selective GABAAR radioligands. To address this, we therefore combined a rat model of clinically relevant antipsychotic drug exposure with quantitative receptor autoradiography. Haloperidol (0.5 and 2 mg/kg/day) or drug vehicle were administered continuously to adult male Sprague-Dawley rats via osmotic mini-pumps for 28 days. Quantitative receptor autoradiography was then performed post-mortem using the GABAAR subunit-selective radioligand [3H]-Ro15-4513 and the non-subunit selective radioligand [3H]-flumazenil. Chronic haloperidol exposure increased [3H]-Ro15-4513 binding in the CA1 sub-field of the rat dorsal hippocampus (pd = +1.3), which was not dose-dependent. [3H]-flumazenil binding also increased in most rat brain regions (pAR radioligands and is the first to demonstrate a potential effect of haloperidol on the binding of a α1/5GABAAR-selective radioligand. Although caution should be exerted when extrapolating results from animals to patients, our data support a view that exposure to antipsychotics may be a confounding factor in PET studies of GABAAR in the context of schizophrenia.

Human serum albumin (HSA) has the characteristics of biocompatibility and long circulation, which is widely used as the carrier of insoluble anticancer drugs, but it also has some disadvantages such as weak tumor targeting and uncontrollable drug release. Herein, HSA was modified to improve its biological performance by introducing polyhistidine (pHis), matrix metalloproteinase-2 (MMP-2) digestion, and Arg-Gly-Asp (RGD) peptide at the separated end of HSA through gene fusion technology. The resulting protein expressed by Pichia pastoris could self-assemble into 3RGD-HSA-MMP-18His nanoparticles (RHMH18 NPs) accompanied by loading hydrophobic drug paclitaxel (PTX) into the polyhistidine micelle core. RHMH18 NPs exhibited active tumor targeting in high efficiency owing to the RGD-mediated specific binding toward ανβ3-integrin upregulated on tumor vasculature endothelium, resulting in the enrichment of therapeutic substances in tumor sites. Once reaching the tumor microenvironment, RHMH18 NPs was cut off by MMP-2 to remove the HSA-3RGD moiety, leaving the small and positively charged histidine micelle, which could penetrate the deep part of tumor tissue more effectively. Finally, the histidine micelle escaped from lysosome successfully and released drug in response to pH. The in vivo experiments' results demonstrated that the three-stage propulsion RHMH18 NPs presented superior tumor inhibition activity with minimal side effects, providing potential strategies of protein based drug delivery systems for tumor therapy.

Industry is increasingly turning to biobased and environmentally benign materials for use in high-value applications. Kraft lignin’s low cost and inherent properties, such as its easily tunable amp...

This article covers the design and evaluation of a novel drug vehicle: a thermosensitive, injectable, high-oil-content (50% w/w) emulgel providing a controlled release of lipophilic pharmaceuticals. Different vegetable (castor, canola, olive, peanut, grapeseed, linseed), mineral (paraffin) and semisynthetic (isopropyl myristate, oleic acid) oils were screened for ibuprofen (IBU) solubility and for their capacity for high-shear emulsification in a 17% (w/w) aqueous solution of poloxamer 407. Chosen emulgels were subject to a rheological evaluation, a syringeability test (TA.XT texture analyser; 2 mL syringe; 18 G, 20 G and 22 G needles) and a drug release study (48 h; cellulose membrane; 0.05 mol/L phosphate buffer at pH 7.4). Castor oil turned out to be an optimal component for IBU incorporation. Blank and drug-loaded castor oil emulgels were susceptible to administration via a syringe and needle, with the absolute injection force not exceeding 3 kg (29.4 N). The drug release test revealed dose-dependent, quasi-linear kinetics, with up to 44 h of controlled, steady, linear release. The results indicate the significant potential of high-oil-content, oil-in-water thermosensitive emulgel formulations as vehicles for the controlled release of lipophilic APIs.

Tuberculosis (TB) is an infectious disease that causes a great number of deaths in the world (1.5 million people per year). This disease is currently treated by administering high doses of various oral anti-TB drugs for prolonged periods (up to 2 years). While this regimen is normally effective when taken as prescribed, many people with TB experience difficulties in complying with their medication schedule. Furthermore, the oral administration of standard anti-TB drugs causes severe side effects and widespread resistances. Recently, we proposed an original platform for pulmonary TB treatment consisting of mannitol microspheres (Ma MS) containing iron (III) trimesate metal–organic framework (MOF) MIL-100 nanoparticles (NPs). In the present work, we loaded this system with the first-line anti-TB drug isoniazid (INH) and evaluated both the viability and safety of the drug vehicle components, as well as the cell internalization of the formulation in alveolar A549 cells. Results show that INH-loaded MOF (INH@MIL-100) NPs were efficiently microencapsulated in Ma MS, which displayed suitable aerodynamic characteristics for pulmonary administration and non-toxicity. MIL-100 and INH@MIL-100 NPs were efficiently internalized by A549 cells, mainly localized in the cytoplasm. In conclusion, the proposed micro-nanosystem is a good candidate for the pulmonary administration of anti-TB drugs.

Three-dimensional food printing (3DFP) uses additive manufacturing concepts to fabricate customized designed products with food ingredients in powder, liquid, dough, or paste presentations. In some cases, it uses additives, such as hydrocolloids, starch, enzymes, and antibrowning agents. Chocolate, cheese, sugar, and starch-based materials are among the most used ingredients for 3DFP, and there is a broad and growing interest in meat-, fruit-, vegetable-, insect-, and seaweed-based alternative raw materials. Here, we reviewed the most recent published information related to 3DFP for novel uses, including personalized nutrition and health-oriented applications, such as the use of 3D-printed food as a drug vehicle, and four-dimensional food printing (4DFP). We also reviewed the use of this technology in aesthetic food improvement, which is the most popular use of 3DFP recently. Finally, we provided a prospective and perspective view of this technology. We also reflected on its multidisciplinary character and identified aspects in which social and regulatory affairs must be addressed to fulfill the promises of 3DFP in human health improvement.

Background Phytochemical agents such as thymoquinone (TQ) have osteogenic property. This study aimed to investigate the synergic impact of TQ and hydroxyapatite on mesenchymal stem cell differentiation. Alginate was also used as drug vehicle. Methods HA scaffolds were fabricated by casting into polyurethane foam and sintering at 800 °C, and then, 1250 °C and impregnated by TQ containing alginate. The adipose-derived stem cells were aliquoted into 4 groups: control, osteogenic induced-, TQ and osteogenic induced- and TQ-treated cultures. Adipose derived-mesenchymal stem cells were mixed with alginate and loaded into the scaffolds Results The results showed that impregnation of HA scaffold with alginate decelerated the degradation rate and reinforced the mechanical strength. TQ loading in alginate/HA had no significant influence on physical and mechanical properties. Real-time RT-PCR showed significant elevation in collagen, osteopontin, and osteocalcin expression at early phase of differentiation. TQ also led to an increase in alkaline phosphatase activity. At long term, TQ administration had no impact on calcium deposition and proliferation rate as well as bone-marker expression. Conclusion TQ accelerates the differentiation of the stem cells into the osteoblasts, without changing the physical and mechanical properties of the scaffolds. TQ also showed a synergic influence on differentiation potential of mesenchymal stem cells.

Dimethyl sulfoxide (DMSO) is an amphipathic molecule widely used as a solvent for water-insoluble substances, cryopreserving, and cell-biological therapies. It has known properties as an inducer of cellular differentiation, a free radical scavenger, and a radioprotectant. In addition, DMSO is used for its various therapeutic and pharmaceutical properties, such as anti-inflammatory, local and systemic analgesic, antibacterial, antifungal, antiviral, and membrane penetration enhancement agents. DMSO treatment can be given orally, intravenously, or topically for a wide range of indications. The administration of DMSO exhibits favorable outcomes in human eye diseases with low to none observed ocular or systemic ocular toxicity. Nevertheless, DMSO is an essential and nonpatentable potential therapeutic agent that remains underexplored and ignored by pharmaceutical developers and ophthalmologists. This current review takes data from experimental and clinical studies that have been published to substantiate the potential therapeutic efficacy of DMSO and stimulate the research of its application in clinical ophthalmology. Given that DMSO is inexpensive, safe, and easily formulated into therapeutic medicinal products and conventional ophthalmological drugs, this compound should be further explored and studied in the treatment of a variety of acute and chronic ocular disorders.

IR825 is a kind of near-infrared (NIR) small molecule cyanine dye and has distinct near-infrared absorbance and excellent thermal conversion performance. Due to poor stability and insufficient therapy efficacy, various nano-systems have been developed as delivery vehicles for NIR dyes to improve their application in tumor treatment. Herein, we developed an intelligent polymer drug vehicle (Mal-PAH-PEG-DMMA/ poly (ethylene imine) – poly(e-caprolactone) block polymers, MPPD/PEI-PCL) based on pH-responsive charge-reversal to deliver docetaxel (DTX) and photosensitizer (IR825) for chemo-photothermal combination therapy (MPPD@IR825/DTX NPs). MPPD@IR825/DTX NPs could undergo charge conversion in a slightly acidic microenvironment (pH 6.8), resulted in strong electrostatic repulsion to withdraw the shell of the polymer nanoparticles (MPPD), enhanced cellular uptake and increased drug release. MPPD@IR825/DTX NPs demonstrated nanoscale in size with good mono-dispersity and stability, triggered DTX release in response to acid environment and NIR stimulation, in the same time providing excellent photothermal conversion efficiency. In vitro and In vivo experiments confirmed that charge-reversal polymeric nanoparticles improved antitumor efficiency in 4T1 tumor cell modal than non-charge-reversal polymeric nanoparticles. Furthermore, in comparison with chemotherapy or photothermal therapy in a single treatment mode, chemo-photothermal combination therapy of MPPD@IR825/DTX NPs with laser irradiation showed highly efficient tumor ablation. In addition, the polymeric nanoparticles exhibited good biocompatibility and safety. Therefore, the design of charge-reversal polymeric nanoparticles (MPPD@IR825/DTX NPs) provides a new strategy and promising application for targeting and synergistic chemo-photothermal combination therapy.

Glaucoma is the second leading cause of blindness after cataracts and is usually irreversible...

Atypical antipsychotic drugs (AA) can cause rapid onset weight gain, insulin resistance, dyslipidemia and NAFLD. Although AA metabolic effects are often associated with obesity, acute AA treatment can cause whole body and hepatic insulin resistance in the absence of weight gain pre-clinically, indicating mechanisms distinct from chronic obesogenic effects of AA. Our aim was to identify pathways involved in AA-associated side effects by correlating differentially expressed traits common to acute AA-exposed mice and drug-exposed human cells using a multi-omic approach. C57BL/6J mice fed chow were treated daily with low, clinically relevant doses of risperidone (RIS; 1 mg/kg BW), olanzapine (OLAN; 5 mg/kg BW) or drug vehicle (VEH; 0.1% acetic acid) for 28 days. Drug treatment had no effect on body weight gain vs. VEH (P>0.05); however, hepatic steatosis was readily observed. Proteomic signatures were generated from hearts and livers of each treatment group, and differentially expressed (DE) proteins (P Disclosure M. May: None. M. Beauchemin: None. C. Vary: None. C. Bouchard: None. K. L. Houseknecht: None. Funding National Institutes of Health (DK095143)

Transdermal drug delivery systems (TDDS) are one of the fascinating unconventional drug delivery systems offering plentiful advantages of which patient compliance is of paramount importance. However, as a matter of fact, the transdermal delivery of drug molecules is absolutely a tedious job which is precisely influenced by a number of factors including penetration barrier properties of the skin, drug characteristics formulation allied issues, etc. Over the years, innumerable tremendous efforts have been made in transporting the drugs through the skin into the systemic circulation by noteworthy tactics. This paper discusses such revolutionary formulation based techniques that have been endeavored in achieving the enhanced skin permeation of drugs, controlled release, and safety.

This work aims at (1) assessing the potential of repurposing simvastatin (SV) to support the most common therapies against melanoma and (2) developing an innovative topical adhesive film, composed by chitosan-coated nanostructured lipid carriers (Ch-NLC) used as drug vehicle. A factorial design approach was employed as the basis for the formulation development. Optimized Ch-NLC displayed a particle size of 108 ± 1 nm, a polydispersity index of 0.226, a zeta potential of 17.0 ± 0.6 mV, as well as an entrapment efficiency of 99.86 ± 0.08%, and SV loading of 14.99 ± 0.01%. The performance of SV-Ch-NLC films was assessed in terms of release, permeation, and adhesion, as critical quality attributes. Cutaneous tolerability and in vitro cytotoxicity studies were performed to warrant film safety and drug effectiveness, respectively. The topical films provided a sustained release kinetic profile of SV and were classified as nonirritant systems. The encapsulation of SV increased cytotoxicity in melanoma cells. The key role of squalene as nanostructuring agent of the lipid nanoparticle matrix and as permeation enhancer was highlighted, suggesting its key action for potentiating skin permeation and uptake into melanoma cells. Topical SV-Ch-NLC films are thus able to provide an in situ extended drug delivery and useful as coadjuvant treatment of melanoma skin lesions.

Background Low density lipoprotein (LDL) has been regarded as a promising antitumor drug vehicle. However some problems, such as rare source, difficulty of large-scale production, and potential safety concerns, hinder its clinical application. Purpose The objective of this study is to develop a biomimetic LDL nanocarrier by replacing the native apolipoprotein B-100 (apoB-100) with an artificial amphipathic peptide and demonstrate its antitumor efficacy. Methods The amphipathic hybrid peptide (termed as FPL) consisting of a lipid binding motif of apoB-100 (LBMapoB)-polyethylene glycol (PEG)-folic acid (FA) was synthesized and characterized by 1H NMR and circular dichroism. FPL decorated lipoprotein-mimic nanoparticles (termed as FPLM NPs) were prepared by a modified solvent emulsification method. Paclitaxel (PTX) was incorporated into NPs and its content was quantified by HPLC analysis. The morphology of NPs was observed by transmission electron microscopy (TEM), and the particle size and zeta potential of NPs were determined by dynamic light scattering (DLS). The colloidal stability of FPLM NPs was evaluated in PBS containing bovine serum albumin (BSA). In vitro release of PTX loaded FPLM NPs was evaluated using the dialysis method. Cellular uptake and cytotoxity assayswere evaluated on human cervical cancer cells (HeLa) and lung cancer cells (A549). Tumor inhibition in vivo was investigated in M109 tumor-bearing mice via tail vein injection of Taxol formulation and PTX loaded NPs. Results The composition of FPLM NPs, including cholesteryl oleate, glyceryl trioleate, cholesterol, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and FPL peptides, was optimized to be 5:1:1:3:10 (w/w). FPLM NPs had a spherical shape with a mean diameter of 83 nm and a negative charge (-12 mV). FPLM NPs with optimum formulation had good colloidal stability in BSA solution.The release of PTX from FPLM NPs was slow and sustained. The uptake of FPLM NPs was higher in folate receptor (FR) overexpressing tumor cells (HeLa cells) than in FR deficient tumor cells (A549 cells). The intracellular distribution indicated that FPLM NPs had the lysosome escape capacity. The internalization mechanism of FPLM NPs was involved with clathrin- and caveolae-mediated endocytosis and FR played a positive role in the internalization of FPLM NPs. The CCK-8 assay demonstrated that FPLM NPs exhibited notably better anti-tumor effect than Taxol formulation in vitro. Moreover, PTX loaded FPLM NPs produced very marked anti-tumor efficiency in M109 tumor-bearing mice in vivo. Conclusion FPLM NPs is a promising nanocarrier which can improve the therapeutic effect and reduce the side effects of antitumor drugs.

Background:Nanotechnology is gaining significant attention worldwide for cancer treatment. Nanobiotechnology encourages the combination of diagnostics with therapeutics, which is a vital component of a customized way to deal with the malignancy. Nanoparticles are being used as Nanomedicine which participates in diagnosis and treatment of various diseases including cancer. The unique characteristic of Nanomedicine i.e. their high surface to volume ratio enables them to tie, absorb, and convey small biomolecule like DNA, RNA, drugs, proteins, and other molecules to targeted site and thus enhances the efficacy of therapeutic agents.Objective:The objective of the present article is to provide an insight of several aspect of nanotechnology in cancer therapeutics such as various nanomaterials as drug vehicle, drug release strategies and role of nanotechnology in cancer therapy.Methods:We performed an extensive search on bibliographic database for research article on nanotechnology and cancer therapeutics and further compiled the necessary information from various articles into the present article.Results:Cancer nanotechnology confers a unique technology against cancer through early diagnosis, prevention, personalized therapy by utilizing nanoparticles and quantum dots.Nano-biotechnology plays an important role in the discovery of cancer biomarkers. Quantum dots, gold nanoparticles, magnetic nanoparticles, carbon nanotubes, gold nanowires etc. have been developed as a carrier of biomolecules that can detect cancer biomarkers. Nanoparticle assisted cancer detection and monitoring involves biomolecules like proteins, antibody fragments, DNA fragments, and RNA fragments as the base of cancer biomarkers.Conclusion:This review highlights various approaches of cancer nanotechnology in the advancement of cancer therapy.

Objectives The aim of this study, conducted at the Military Institute of Hygiene and Epidemiology in Warsaw in 2017, was to evaluate the effects of a single (15 min) and repeated (5 times for 15 min) radio-frequency radiation (RFR) exposure of 1800 MHz frequency on the analgesic efficacy of morphine in healthy rats and rats with complete Freund's adjuvant (CFA) induced inflammation. Material and methods Rats were injected intraperitoneally with morphine (MF) in the dose of 8 mg/kg or drug vehicle 15 min before RFR exposure. The authors used the plantar analgesia meter and the radiant heat paw-withdrawal test to assess the pain threshold. Results A single RFR exposure slightly influenced paw withdrawal latency (PWL) in healthy rats in the single exposure baseline group, and influenced PWL, 30 and 60 min after morphine or vehicle injection, in the repeated exposure group. There were differences between the sham-exposed groups (vehicle), 30, 60 and 90 min after injection, both in the single and repeated RFR-exposure groups. The antinociceptive effect of morphine in healthy rats was slightly decreased by RFR exposure at 60 and 90 min, both in the single and repeated exposure groups. The PWL was slightly decreased, both in the single and repeated exposure groups with inflammation (CFA and CFA/MF), at 30, 60 and 90 min, and PWL was increased in the sham-exposed groups (CFA and CFA/MF), both in the single and repeated exposure groups, at 30, 60 and 90 min. The antinociceptive effect of morphine in healthy rats was significantly increased by RFR exposure at 30 min after drug injection in the single exposure group, and increased at 30 and 60 min in the repeated exposure group. Conclusions The authors observed a minor influence of RFR exposure on the antinociceptive effects of morphine in healthy rats after repeated exposures and a statistically significant influence of repeated exposure on morphine mediated antinociceptive effects in the inflammation group. Int J Occup Med Environ Health. 2019;32(4):465-74.

Over the past two decades, nano-sized biosystems have increasingly been utilized to deliver various pharmaceutical agents to a specific region, organ or tissue for controllable precision therapy. Whether solid nanohydrogel, nanosphere, nanoparticle, nanosheet, micelles and lipoproteins, or "hollow" nanobubble, liposome, nanocapsule, and nanovesicle, all of them can exhibit outstanding loading and releasing capability as a drug vehicle - in particular polymeric nanovesicle, a microscopic hollow sphere that encloses a water core with a thin polymer membrane. Besides excellent stability, toughness and liposome-like compatibility, polymeric nanovesicles offer considerable scope for tailoring properties by changing their chemical structure, block lengths, stimulus-responsiveness and even conjugation with biomolecules. In this review, we summarize the latest advances in stimulus-responsive polymeric nanovesicles for biomedical applications. Different functionalized polymers are in development to construct more complex multiple responsive nanovesicles in delivery systems, medical imaging, biosensors and so on.

Cannabis is the most commonly used illicit drug among pregnant women, and rates are likely to increase given recent legalization. In addition, half of pregnant women who report consuming cannabis also report drinking alcohol. However, little is known about the consequences of prenatal cannabis alone or combination with alcohol, particularly with cannabis products that are continually increasing in potency of the primary psychoactive constituent in cannabis, Δ9-tetrahydrocannabinol (THC). The current study investigated the effects of early exposure to cannabinoids during the brain growth spurt on early physical and motor development alone (Experiment 1) or in combination with alcohol (Experiment 2). In Experiment 1, Sprague-Dawley rat pups were exposed to a cannabinoid receptor agonist (CP-55,940 [CP]; 0.1, 0.25, 0.4 mg/kg/day), the drug vehicle, or a saline control from postnatal days (PD) 4-9. In Experiment 2, rat pups were exposed to CP (0.4 mg/kg/day) or the vehicle, and were additionally intubated with alcohol (11.9% v/v; 5.25 g/kg/day) or received a sham intubation. Subjects in both experiments were tested on a motor development task (PD 12-20) and a motor coordination task during adolescence (PD 30-32). Both developmental cannabinoid and alcohol exposure separately decreased body growth throughout development, and combined exposure exacerbated these effects, although only alcohol exposure induced long-term body weight reductions. Developmental cannabinoid exposure advanced early motor development, whereas alcohol exposure delayed development, and subjects given combined exposure did not differ from controls on some measures. Alcohol exposure impaired motor coordination later in life. In contrast, cannabinoid exposure, by itself did not significantly affect long-term motor coordination, but did exacerbate alcohol-related impairments in motor coordination among females. These results suggest that cannabinoid exposure may not only alter development by itself, but may exacerbate alcohol’s teratogenic effects in specific behavioral domains. These findings have important implications not only for individuals affected by prenatal exposure, but also for establishing public policy for women regarding cannabis use during pregnancy.

Transcatheter arterial chemoembolization (TACE) is well known as an effective treatment for inoperable hepatocellular carcinoma (HCC). In this study, a novel embolic agent of ion-exchange poly(hydroxyethyl methacrylate-acrylic acid) microspheres (HAMs) was successfully synthesized by the inverse suspension polymerization method. Then, HAMs were assessed for their activity as an embolic agent by investigating morphology, particle size, water retention capability, elasticity and viscoelasticity, microcatheter/catheter deliverability, cytotoxicity, renal arterial embolization to rabbits and histopathological examinations. The ability of drug loading and drug eluting of HAMs was also investigated by using doxorubicin (Dox) as the model drug. HAMs showed to be feasible and effective for vascular embolization and to be as a drug vehicle for loading positively charged molecules and potential use in the clinical interventional chemoembolization therapy. STATEMENT OF SIGNIFICANCE: A novel embolic agent of ion-exchange poly(hydroxyethyl methacrylate-acrylic acid) microspheres (HAMs) was successfully synthesized by the inverse suspension polymerization method and was used as a drug vehicle to load positively charged molecules by ion absorption. Then, a series of assessments including physicochemical properties, mechanical properties, drug-loading capability, and embolic efficacy were performed. Surface and cross-section morphology and pore size of fully hydrated HAMs were first investigated by Phenom ProX SEM, which intuitively disclosed the "honeycomb" network morphology. HAMs also showed to be feasible and effective for vascular occlusion and have potential use in clinical interventional embolization therapy.

Due to the outstanding synergistic effects and low-toxicity, combination therapy exhibits more considerable potential in antitumor activity than monotherapy. Herein, a core-shell magnetic gold nanostar (Fe3O4@GNS, MGNS)-based system for codelivery of a mitochondrial targeting amphipathic tail-anchoring peptide (ATAP) and a membrane-associated cytokine (tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) was constructed. The magnetic core can facilitate delivery of the drug vehicle by external magnetic field, which results in accurate accumulation and enhances tumor cellular uptake for preliminary targeting. TRAIL and ATAP could sequentially target and be released toward the plasma membrane and mitochondria, initiating the extrinsic and intrinsic apoptosis pathways, respectively. The gold shell of MGNS can cause local tumor hyperthermia due to broad-band plasmon resonances in the near-infrared region, which can act as a complement with the peptide drug to further enhance apoptosis. Both in vitro and in vivo experiments revealed that rationally integrating extrinsic apoptosis, intrinsic apoptosis and hyperthermia for triplexed synergistic therapy, enabled the smart drug vehicle with pinpoint peptide drug delivery capabilities, and minimized side effects, enhancing the antitumor efficiency.

Introduction: TK1 plays a crucial role in DNA synthesis and is a well-established marker of cell proliferation. We and others have previously described the potential role of TK1 activity (TKa) as predictive biomarker of response to endocrine therapy in HR+/HER2 negative metastatic breast cancer patients. TK1 synthesis is regulated by the E2F pathway, the target pathway of CDK4/6 inhibitors, and TKa has recently been reported as a potential circulating pharmacodynamic marker of CDK4/6 inhibition in breast cancer. However, modulations of TK1 levels and activity during palbociclib treatment and in the development of treatment resistance are unknown. Here, we report how TK1 expression and TKa are modulated in response to palbociclib in a panel of HR+ breast cancer cell lines: both palbociclib-sensitive (PDS) and with acquired resistance to (PDR). Material and methods: We used a panel of 7 PDR HR+ breast cancer models previously developed in our lab via chronic exposure of parental cells (MCF7, T47D, ZR75-1, BT474, MDAMB361 and two MCF7 endocrine resistant derivatives) to escalating doses of palbociclib, from a Starting Treatment Concentration (STC) of 50 nM or 350 nM according to the cell line, up to 1 μM. We analyzed gene expression profiles of PDS cells treated with drug vehicle (DMSO) as a control or palbociclib at STC for 3 days, and PDR cells grown with palbociclib 1 μM. Cell proliferation was assessed by methylene blue assay in MCF7 and BT474 PDS and PDR treated for 3, 6 and 9 days with DMSO, palbociclib STC and 1 μM. In parallel, TKa was measured in cell lysates at 3 days of treatment using the DiviTumTM assay (Biovica, Sweden). Results: Among E2F target genes, gene expression data demonstrated that TK1 was one of the most differentially expressed genes between PDR and PDS treated cells. In PDS cells compared to control, treatment with palbociclib resulted in reduced TK1 expression, with the HER2 positive models (BT474 and MDAMB361) showing the highest reduction. In PDR cells, TK1 expression was higher, but remained slightly inhibited compared to untreated PDS cells. TKa was significantly reduced in PDS cells treated with palbociclib for 3 days compared to vehicle (p Conclusions: TK1 expression and activity are regulated by palbociclib in HR+ breast cancer cell lines, particularly in HER2 positive models. Ongoing studies of TKa in patients treated with palbociclib will assess the role of TKa as a circulating biomarker for predicting and monitoring response to CDK4/6 inhibitors. Citation Format: Bonechi M, Migliaccio I, Benelli M, Romagnoli D, Bergqvist M, Mattsson K, Boccalini G, Capaccioli G, De Luca F, Galardi F, Biagioni C, Risi E, McCartney A, Rossi L, Osborne CK, Schiff R, De Angelis C, Guarducci C, Di Leo A, Malorni L. Effects of palbociclib on thymidine kinase-1 (TK1) in hormone receptor positive (HR+) breast cancer cell lines [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-09-02.

Zinc(II) (5), indium(III) (6), and lutetium(III) (7) phthalocyanines (Pcs) peripherally substituted with poly (ethylene glycol) (PEG) monomethyl ether 2000 (PEGME-2000) blocks were synthesized via Sonogashira coupling reaction with high yields and their photophysical, photochemical and photobiological properties were investigated. We elucidated the interactions of these compounds with calf thymus DNA and bovine serum albumin (BSA), and determined K(DNA) and K(BSA) binding constants at degrees of 105 and 106, respectively. Singlet oxygen quantum yields were found (Ф∆ = 0.44, 0.54, and 0.68 for 5, 6, and 7, respectively). Thermodynamic parameters, as well as thermal denaturation profile of double-stranded CT-DNA were examined to determine the type of binding mode. According to our experimental data, we report that PEGME-2000 favors the formation of binary complex between DNA, and phthalocyanine complexes. Therein, thermodynamic data suggest that this binding mode is indeed spontaneous under reported conditions, and rather non-specific. Additionally, Pcs 5, 6, and 7 substituted with PEGME-2000 blocks showed antimicrobial activity against Gram-positive and Gram-negative bacteria, as well as fungi (yeast), and Pc 5 had the highest antimicrobial activity among them, as revealed by disc diffusion assay results. In short, our results suggest that these compounds could be used for photodynamic therapy, they have both antibacterial and antifungal activity, and the binding ability of new phthalocyanines 5, 6, and 7 with BSA paves the way for their utilization as drug vehicle in blood plasma.

Functionalized-nanoparticles have been developed as novel therapeutic delivery platform for simultaneous drug loading and therapy over the past decade. Rationally-designed biocompatible nanosystem simultaneously with multistimuli-responsive property and synergistic therapeutic potential are highly desirable for modern biological applications. Herein, Cu2Se nanoparticles (Cu2SeNPs) with suitable size have been functionalized by bull serum albumin (BSA) through a simply, facile and controllable method. As a result, Cu2SeNPs modified by BSA (BSA-Cu2SeNPs) showed excellent biocompatibility and stability. The strong absorbance of BSA-Cu2SeNPs at near infrared region imparts them with high photothermal efficiency. Then loading doxorubicin (DOX, anticancer drug) on the surface of BSA-Cu2SeNPs, and consequently, a novel multifunctional nanosystem of BSA-Cu2SeNPs-DOX is designed. The BSA-Cu2SeNPs can achieve high DOX loading capacity (approximately 157 μg DOX per mg of Cu2Se). Furthermore, a rational and precise release of DOX from the BSA-Cu2SeNPs-DOX could be easily realized under the stimulates of the pH and temperature, which remarkably improved antitumor efficacy of combined chemotherapy and photothermal therapy triggered by 808 nm NIR laser. Thus, the BSA-Cu2SeNPs-DOX could serve as an ideal nanoplatform for cancer diagnosis and treatment in future. The results of cell experiments show that the BSA-Cu2SeNPs-DOX exhibited favorable selective cellular uptake cells. Under the NIR laser irradiation, BSA-Cu2SeNPs-DOX could induce the excessive expression of ROS, eventually leading to the death of U251 cells. Both in vitro and in vivo experiments indicate that the nanosystem of BSA-Cu2SeNPs-DOX showed excellent synergistic therapeutic effect and multistimuli-responsive drug vehicle, which will exert huge potential for future clinical application.

Glioblastoma (GB) is an aggressive cancer with high microvascular proliferation, resulting in accelerated invasion and diffused infiltration into the surrounding brain tissues with very low survival rates. Treatment options are often multimodal, such as surgical resection with concurrent radiotherapy and chemotherapy. The development of resistance of tumor cells to radiation in the areas of hypoxia decreases the efficiency of such treatments. Additionally, the difficulty of ensuring drugs effectively cross the natural blood–brain barrier (BBB) substantially reduces treatment efficiency. These conditions concomitantly limit the efficacy of standard chemotherapeutic agents available for GB. Indeed, there is an urgent need of a multifunctional drug vehicle system that has potential to transport anticancer drugs efficiently to the target and can successfully cross the BBB. In this review, we summarize some nanoparticle (NP)-based therapeutics attached to GB cells with antigens and membrane receptors for site-directed drug targeting. Such multicore drug delivery systems are potentially biodegradable, site-directed, nontoxic to normal cells and offer long-lasting therapeutic effects against brain cancer. These models could have better therapeutic potential for GB as well as efficient drug delivery reaching the tumor milieu. The goal of this article is to provide key considerations and a better understanding of the development of nanotherapeutics with good targetability and better tolerability in the fight against GB.

Aims Hemorrhagic cystitis (HC) is a major urotoxic complication of cyclophosphamide (CPA) therapy. This study investigated the uroprotective effect of montelukast on CPA-induced HC, compared to the efficacy of 2-mercaptoethane sulfonate sodium (MESNA). Main methods Male albino rats were pretreated with MESNA (40 mg/kg/day, IP) or montelukast (10 mg/kg/day, orally) for three days then received a single dose of CPA (200 mg/kg, IP), 1 h after the last dose, and compared to CPA-treated rats receiving drug vehicle. Age-matched rats were used as controls. Bladders of rats were assessed biochemically, macroscopically and microscopically by light and electron microscope 24 h later. Key findings CPA injection contributed to increased bladder weight, urothelial ulceration, vascular congestion, hemorrhage, increased collagen deposition and mast cell infiltration, compared to control rats. Montelukast preconditioning suppressed mast cell infiltration and inflammatory mediators to greater extent than MESNA. Also, montelukast enhanced autophagosomes formation in detrusor myocytes and up-regulated the autophagy-related proteins (beclin-1 & LC3-II), likely through inhibition of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Montelukast preconditioning offset the up-regulation of transient receptor potential vanilloid 4 (TRPV4) in urothelial tissue of CPA-treated rats, to greater extent than MESNA. Significance These results demonstrate the uroprotective effect of montelukast on CPA-induced HC, which appears to be more superior to MESNA. These findings suggest that montelukast can emerge as a novel strategy to protect against CPA-induced urotoxicity.