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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.

Infected wounds caused by persistent inflammation exhibit poor vascularization and cellular infiltration. In order to rapidly control the inflammatory effect and accelerate wound healing, it is necessary to develop a novel drug vehicle addressing the need for infected wounds. Herein, we developed a novel dual-drug delivery system with micrometer-scale alginate fibers encapsulated in instant self-assembly peptide hydrogel. Short peptides with the sequence of Nap-Gly-Phe-Phe-Lys-His (Nap-GFFKH) could self-assemble outside the microfluidic-based alginate microfibers in weak acidic solution (pH ≈ 6.0) within 5 s. The gelation condition is close to the pH environment of the human skin. We further constructed recombinant bovine basic fibroblast growth factor (FGF-2) in fibrous alginate, which was encapsulated in antibiotic-loaded peptide hydrogel. The dual-drug delivery system exhibited good mechanical property and sustained release profiles, where antibiotic could be rapidly released from the peptide hydrogel, while the growth factor could be gradually released within 7 days. Both in vitro antibacterial experiments and in vivo animal experiments confirmed that such a dual-drug delivery system has good antibacterial activity and enhances wound healing property. We suggested that the dual-drug delivery system could be potentially applied for controlled drug release in infected wound healing, drug combination for melanoma therapy, and tissue engineering.

A fast and reliable method based on two-channel liquid chromatography coupled to tandem mass spectrometry was developed and successfully validated for quantification of busulfan. The drug vehicle polyethylene glycol 400 was quantified simultaneously in patient samples. The sample preparation consisted of simple protein precipitation using a mixture of methanol and zinc sulphate containing busulfan-d8 as internal standard. Chromatographic separation was performed on a short biphenyl column (30 mm × 3.0 mm, 5 μm particles) using a step gradient from 30 % to 85 % methanol, ensuring co-elution of the analyte and internal standard. Quantification was performed using the mass transition of 264.1 > 151.1 for busulfan and 272.1 > 159.1 for the internal standard. Using only 20 μL of plasma sample, the lower limit of quantification was 25 ng/mL. Signal to noise ratio at the lower limit of quantification exceeded 300. The assay performance was not adversely affected by matrix effects originating from drug formulation excipients or other sample components. The coefficient of variation was ≤4 % and the mean accuracy 101-108 % across the calibration range 25-5 000 ng/mL. Chromatographic run time was 2 min and 8 s, allowing an effective run-time of 1 min and 10 s when using two alternating LC-channels. The assay has been implemented in routine practice with accreditation according to the ISO 15189 standard, and performs well in external quality control assessments. We present for the first time that shortly after an IV infusion of busulfan, the plasma levels of polyethylene glycol 400 may be in the range of 400-800 mg/L. The presence of these levels of detergent in patient samples may have detrimental effects on assay performance in LC-MS/MS, not limited to busulfan assays. This may be a concern for any LC-MS/MS analysis performed on samples collected within the first 24 h after an IV infusion of busulfan.

Anesthetic-induced toxicity in early life may lead to risk of cognitive decline at later ages. Notably, multiple exposures to isoflurane (ISO) cause acute apoptotic cell death in the developing brain and long-term cognitive dysfunction. This study is the first to investigate whether levosimendan (LVS), known for its protective myocardial properties, can prevent anesthesia-induced apoptotic response in brain cells and learning and memory impairment. Postnatal day (P)7 Wistar albino pups were randomly assigned to groups consisting of an equal number of males and females in this laboratory investigation. We treated rats with LVS (0.8 mg/kg/day) intranasally 30 min before each ISO exposure (1.5%, 3 h) at P7+9+11. We selected DMSO as the drug vehicle. Also, the control group at P7+9+11 received 50% O-2 for 3 h instead of ISO. Neuroprotective activity of LVS against ISO-induced cognitive dysfunction was evaluated by Morris water maze. Expression of apoptotic-related proteins was detected in the whole brain using western blot. LVS pretreatment significantly prevented anesthesia-induced deficit in spatial learning (at P28-32) and memory (at P33, P60, and P90). No sex-dependent difference occurred on any day of the training and probe trial. Intranasal LVS was also found to significantly prevent the ISO-induced apoptosis by reducing Bax and cleaved caspase-3, and by increasing Bcl-2 and Bcl-xL. Our findings support pretreatment with intranasal LVS application as a simple strategy in daily clinical practice in pediatric anesthesia to protect infants and children from the risk of general anesthesia-induced cell death and cognitive declines. T.C. Health Ministry, Health Sciences University, Bagcilar Training and Research Hospital, Turkey

The mismatch of oxygen supply and demand during hemorrhagic shock disturbs endoplasmic reticulum (ER) homeostasis. The resulting accumulation of unfolded proteins in the ER lumen, which is a condition that is defined as ER stress, triggers the unfolded protein response (UPR). Since the UPR influences the extent of organ damage following hemorrhagic shock/reperfusion (HS/R) and mediates the protective effects of stress preconditioning before ischemia-reperfusion injury, the current study investigated the mechanisms of ER stress preconditioning and its impact on post-hemorrhagic liver damage. Male C56BL/6-mice were injected intraperitoneally with the ER stress inductor tunicamycin (TM) or its drug vehicle 48 h prior to being subjected to a 90 min pressure-controlled hemorrhagic shock (30±5 mmHg). A period of 14 h after hemorrhagic shock induction, mice were sacrificed. Hepatocellular damage was quantified by analyzing hepatic transaminases and hematoxylin-eosin stained liver tissue sections. Additionally, the topographic expression patterns of the ER stress marker binding immunoglobulin protein (BiP), UPR signaling pathways, and the autophagy marker Beclin1 were evaluated. TM injection significantly increased BiP expression and modified the topographic expression patterns of the UPR signaling proteins. In addition, immunohistochemical analysis of Beclin1 revealed an increased pericentral staining intensity following TM pretreatment. The histologic analysis of hepatocellular damage demonstrated a significant reduction in cell death areas in HS/R+TM (P=0.024). ER stress preconditioning influences the UPR and alleviates post-hemorrhagic liver damage. The beneficial effects were, at least partially, mediated by the upregulation of BiP and autophagy induction. These results underscore the importance of the UPR in the context of HS/R and may help identify novel therapeutic targets.

Traumatic optic neuropathy (TON) describes an injury to the optic nerve following either blunt or penetrating trauma, and remains an important cause of vision loss. No generalized treatment of TON has been established so far to restore the injured optic nerve. We developed an adherent drug-encapsulated bi-layered depot (DBP) as a dual drug vehicle for local treatment to protect the residual retinal ganglion cells (RGCs) and regenerate axons following optic nerve damage. The inner layer of the depot was prepared by co-electrospinning poly(D,L-lactide-co-glycolide acid) (PLGA: 75 : 25) and collagen (COL) with the hydrophobic corticosteroid triamcinolone acetonide (TA) loaded. The outer layer was made of PLGA and the hydrophilic neuroprotective agent Fasudil (FA). The DBP showed suitable morphology, hydrophilicity and mechanical properties, and slowly released TA and FA in vitro by undergoing time-dependent degradation and swelling. All depots showed good biocompatibility with L929 mouse fibroblasts, and DBP was helpful in maintaining the morphology of RGCs in vitro. In addition, direct implantation of DBP at the injured optic nerve in a rat model mitigated inflammation and the death of RGCs, and increased the expression of nerve growth-related protein GAP-43. Therefore, DBP maybe a promising local therapy against TON in future.

Background Epigallocatechin gallate (EGCG) acts as an antioxidant by preventing oxidative stress. The effect of EGCG on aluminum-induced testicular injury is not clear. Hence, the present study is planned to investigate the effect of EGCG on aluminum chloride (AlCl3)-induced changes in behavior, biochemical parameters, and spermatogenesis in male Sprague-Dawley rats. The rats were divided into six groups with six animals each. All the animals were administered with respective assigned treatment once daily for 28 days. The animals in groups I to VI were administered with drug vehicle, AlCl3, vitamin C, EGCG, vitamin C, and EGCG, respectively. The animals in groups V and VI were additionally challenged with AlCl3 (10 mg/kg) immediately after vitamin C and EGCG administration, respectively. Changes in behavior were measured on day 1, 14 and 28. At the end of the study, the blood sample was collected from all the animals, and the serum was separated and used for biochemical analysis. Later, the rats were subjected to bilateral orchiectomy; sperm was collected from the cauda epididymis for microscopic examination. Then, the animals were sacrificed, and the organs such as the brain, lungs, heart, liver, kidney, spleen, and testis were collected for organ weight analysis. Results The animal administered with AlCl3 showed a reduction in locomotor activity, grip strength, and escape latency time whereas vitamin C prevented the effect of AlCl3. But, EGCG did not show any significant changes in AlCl3-induced behavioral and biochemical changes. At the end of the study, vitamin C prevented AlCl3-induced behavioral and biochemical changes. The group of animals administered with AlCl3 showed a reduction in the number of spermatozoa whereas AlCl3 + vitamin C and AlCl3 + EGCG did not show any significant changes in the number of spermatozoa when compared to the control group. Conclusion EGCG prevented AlCl3-induced reduction in epididymal sperm count of male rats and did not show any significant effect on AlCl3-induced changes in behavior and biochemical parameters, whereas vitamin C had an ameliorative effect on AlCl3-induced changes in behavior, biochemical parameter, and spermatogenesis. Graphical abstract

Immunotherapy is one of the most promising approaches to inhibit tumor growth and metastasis by activating host immune functions. However, the arising problems such as low immune response caused by complex tumor microenvironment and extremely systemic immune storm still limit the clinical applications of immunotherapy. Here, we construct Poly I: C-encapsulated poly (lactic-co-glycolic acid) nanoparticles (PLP NPs) with a slow release profile. A biomimetic system (MPLP), which loads PLP NPs on the surface of bone marrow-derived macrophage (BMDM) via the maleimide-thiol conjugation, is synthesized to effectively deliver PLP, control drug release and activate the tumor-specific immune response in situ. The results show that PLP NPs loading does not affect the activity and function of BMDM. Then, BMDM acts as a living cell drug vehicle and promotes the accumulation of PLP NPs in tumors, where Poly I: C is released from PLP NPs and reprograms BMDM into tumoricidal M1 macrophage. Furthermore, MPLP triggers potent antitumor immune responses in vivo and effectively inhibits local and metastatic tumors without causing adverse pathological immune reactions. This study offers an inspiration to facilitate clinical translation through the delivery of drugs by living immune cells for future anticancer therapy.

Background Sustained morphine treatment for cancer pain has been limited due to analgesic tolerance. Opioid receptor internalization and desensitization mediated by downregulation of mu-opioid receptor (MOR) expression have been confirmed as one of the mechanisms of chronic morphine tolerance. In addition to the opiate system, the α2-adrenergic system is involved in the development of morphine tolerance. Several studies reported that co-administration of α2-adrenoceptor agonist dexmedetomidine inhibits morphine tolerance in normal or neuropathic pain animals. However, the effect of dexmedetomidine on morphine tolerance has not been studied in cancer pain. Therefore, we investigated the effect of intrathecal injection of dexmedetomidine on the development of morphine tolerance in cancer pain and on the expression of MOR in the spinal cord of morphine-tolerant cancer pain rats. Methods The model was established using a rat's right hind paw injection of Walker 256 cancer cells. Subcutaneous morphine (10mg/kg) was administrated twice daily for 7 days; meanwhile, the rats received intrathecal α2-adrenoceptor agonist dexmedetomidine (10μ/kg) or antagonist MK-467 (0.25mg/kg) in test groups. Rats receiving drug vehicle served as the control group. Antinociception was detected by von Frey filaments and hot-plate tests. The expression of MOR in the spinal cord was examined through real-time reverse transcription polymerase chain reaction and Western blotting. The data were analyzed via analysis of variance followed by Student t-test with Bonferroni correction. Results Seven-day chronic morphine administration elicited notable analgesic tolerance in the rats with cancer pain. Co-administration of α2-adrenoceptor agonist dexmedetomidine enhanced morphine analgesia and attenuated morphine tolerance, which could be blocked by α2-adrenoceptor antagonist MK-467. Furthermore, pre-treatment of dexmedetomidine significantly upregulated MOR protein expression without a notable change in MOR mRNA expression in the spinal cord. Conclusion Our findings suggest that intrathecal injection of dexmedetomidine enhanced morphine analgesia and attenuated morphine tolerance in cancer pain, potentially by upregulating MOR expression in the spinal cord. The α2-adrenoceptor agonist may provide a more versatile analgesia option for morphine treatment for cancer pain.

Melanoma is an aggressive cancer that utilizes multiple signaling pathways, including those that involve oncogenes, proto-oncogenes, and tumor suppressors. It has been suggested that melanoma formation requires cross-talk of the PI3K/Akt/mTOR and Ras-ERK pathways. This pathway cross-talk has been associated with aggressiveness, drug resistance, and metastasis; thus, simultaneous targeting of components of the different pathways involved in melanoma may aid in therapy. We have previously reported that bacterial cyclodipeptides (CDPs) are cytotoxic to HeLa cells and inhibit Akt phosphorylation. Here, we show that CDPs decreased melanoma size and tumor formation in a subcutaneous xenografted mouse melanoma model. In fact, CDPs accelerated death of B16-F0 murine melanoma cells. In mice, antitumor effect was improved by treatment with CDPs using cyclodextrins as drug vehicle. In tumors, CDPs caused nuclear fragmentation and changed the expression of the Bcl-2 and Ki67 apoptotic markers and promoted restoration of hyperactivation of the PI3K/Akt/mTOR pathway. Additionally, elements of several signaling pathways such as the Ras-ERK, PI3K/JNK/PKA, p27Kip1/CDK1/survivin, MAPK, HIF-1, epithelial-mesenchymal transition, and cancer stem cell pathways were also modified by treatment of xenografted melanoma mice with CDPs. The findings indicate that the multiple signaling pathways implicated in aggressiveness of the murine B16-F0 melanoma line are targeted by the bacterial CDPs. Molecular modeling of CDPs with protein kinases involved in neoplastic processes suggested that these compounds could indeed interact with the active site of the enzymes. The results suggest that CDPs may be considered as potential antineoplastic drugs, interfering with multiple pathways involved in tumor formation and progression.

The chain length of hyaluronan (HA) determines its physical as well as its physiological properties. Results of clinical research on HA eye drops are not comparable without this parameter. In this article methods for the assessment of the average molecular weight of HA in eye drops and a terminology for molecular weight ranges are proposed. The classification of HA eye drops according to their zero shear viscosity and viscosity at 1000 s−1 shear rate is presented. Based on the gradient of mucin MUC5AC concentration within the mucoaqueous layer of the tear film a hypothesis on the consequences of this gradient on the rheological properties of the tear film is provided. The mucoadhesive properties of HA and their dependence on chain length are explained. The ability of HA to bind to receptors on the ocular epithelial cells, and in particular the potential consequences of the interaction between HA and the receptor HARE, responsible for HA endocytosis by corneal epithelial cells is discussed. The physiological function of HA in the framework of ocular surface homeostasis and wound healing are outlined, and the influence of the chain length of HA on the clinical performance of HA eye drops is illustrated. The use of very high molecular weight HA (hylan A) eye drops as drug vehicle for the next generation of ophthalmic drugs with minimized side effects is proposed and its advantages elucidated. Consequences of the diagnosis and treatment of ocular surface disease are discussed.

This study was undertaken to investigate the possible ameliorative influences of febuxostat (FEB) on vitamin D3 plus nicotine (VDN)-induced vascular calcification (VC) in Wistar rats. VDN rats received a single dose of vitamin D3 (300.000 IU/kg, I.M) and two oral doses of nicotine (25 mg/kg) on day 1. They were then administrated FEB, in two doses (10 and 15 mg/kg/day, orally), or the drug vehicle, for 4 weeks. Age-matched normal rats served as control. At the end of the experiment, body weight, kidney function parameters, serum ionic composition, cardiovascular measures, aortic calcium deposition and aortic levels of oxidative stress markers, interleukin 1β (IL-1β), runt-related transcription factor 2 (Runx2) and osteopontin (OPN) were determined. Aortic immunoexpressions of tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), matrix metalloproteinase-9 (MMP-9) and α-smooth muscle actin (α-SMA) were evaluated. FEB significantly restored body weight loss, ameliorated kidney function and diminished serum disturbances of calcium and phosphorus in VDN rats. Moreover, FEB reduced VDN-induced elevations in aortic calcium deposition, SBP and DBP. FEB (15 mg/kg) markedly decreased left ventricular hypertrophy and bradycardia in VDN group. Mechanistically, FEB dose-dependently improved oxidative damage, decreased levels of IL-1β and Runx2, lessened expression of TNF-α, iNOS and MMP-9 and enhanced expression of OPN and α-SMA in VDN aortas relative to controls. These findings indicate that FEB, mainly at the higher administered dose (15 mg/kg), successfully attenuated VDN-induced VC. FEB may be useful in reducing VC in patients at high risk, including those with chronic kidney disease and diabetes mellitus.

Renal cell carcinoma (RCC) is the most common type of kidney cancer. Increasingly evidences indicate that extracellular vesicles (EVs) orchestrate multiple processes in tumorigenesis, metastasis, immune evasion, and drug response of RCC. EVs are lipid membrane-bound vesicles in nanometer size and secreted by almost all cell types into the extracellular milieu. A myriad of bioactive molecules such as RNA, DNA, protein, and lipid are able to be delivered via EVs for the intercellular communication. Hence, the abundant content of EVs is appealing reservoir for biomarker identification through computational analysis and experimental validation. EVs with excellent biocompatibility and biodistribution are natural platforms that can be engineered to offer achievable drug delivery strategies for RCC therapies. Moreover, the multifaceted roles of EVs in RCC progression also provide substantial targets and facilitate EVs-based drug discovery, which will be accelerated by using artificial intelligence approaches. In this review, we summarized the vital roles of EVs in occurrence, metastasis, immune evasion, and drug resistance of RCC. Furthermore, we also recapitulated and prospected the EVs-based potential applications in RCC, including biomarker identification, drug vehicle development as well as drug target discovery.

Polysaccharide-based aerogels are promising drug carriers. Being nanoporous with a high specific surface area allows their use as a drug vehicle for various delivery routes. Intratracheal and intravenous administration of free cisplatin causes toxicity in the rat liver, lungs, and kidneys. In this work, microspherical particles based on alginate-chitosan without a traditional crosslinker were evaluated for targeted delivery of cisplatin by intratracheal administration. The aerogel particles were prepared using the emulsion gelation method, followed by supercritical carbon dioxide extraction. Loading of cisplatin on the prepared porous particles was performed by impregnation using supercritical fluid technology. The prepared carrier and the loaded drug were evaluated for drug content, release, and in vivo acute and subacute toxicity. Cisplatin was successfully loaded (percent drug loading 76%) on the prepared carrier (particle size = 0.433 ± 0.091 μm) without chemically interacting with the carrier and without losing its crystal form. Sixty percent of cisplatin was released within 2 h, and the rest was loaded inside the polymer pores and had a sustained first-order release over 6 h. Loading cisplatin on the carrier developed herein reduced the cisplatin lung toxicity but increased the liver toxicity after intratracheal administration with nephrotoxicity being proportional to cisplatin dose in case of carrier-loaded cisplatin. Moreover, loading cisplatin on the carrier significantly reduced mortality rate and prevented weight loss in rats as compared to free cisplatin in subacute studies after intratracheal administration. Thus, the developed carrier showed high potential for targeted delivery of cisplatin for lung cancer treatment by inhalation. Graphical abstract.

Resveratrol (Res) has emerged as an extremely promising natural molecule due to its vast therapeutic prospects. However, the potential of the drug is immensely hindered by several limiting factors including poor water solubility, limited chemical stability and high metabolization. Herein we report a facile synthesis of a Res-loaded folate-terminated PEG-phospholipid coated reduced graphene oxide nanoassembly (FA-PEG-Lip@rGO/Res) by simply sonicating Res and rGO in FA-PEG linked liposome (FA-PEG-liposome) suspensions. The as-obtained FA-PEG-Lip@rGO/Res exhibits a nanoscale size (148 ± 7 nm), a negative surface potential (−23.6 mV), an excellent drug loading (69.5 ± 4.3%), a high drug entrapment efficiency (86.9 ± 5.6%), good monodispersity and controlled release. Additionally, the nanoassembly can protect Res from UV-light induced instability. Owing to the folate mediated targeted delivery, the robust FA-PEG-Lip@rGO/Res can deliver loaded Res to human MCF-7 breast cancer cells with high specificity and excellent efficiency. The cell toxicity viability shows that unloaded FA-PEG-Lip@rGO has no cytotoxicity, confirming its suitability as a drug vehicle. Furthermore, a systematic in vivo study shows that, under near-infrared (NIR) laser irradiation, FA-PEG-Lip@rGO/Res exhibits highly efficient combined chemotherapy and photothermal therapy to eradicate xenografted tumor with a single dose intratumoral (i.t.) injection. Thus, a facile, stable, biocompatible, and highly-effective Res delivery system has been developed, which may greatly advance the application of Res in biomedical research.

Corynetoxins, members of the tunicamycin group of antibiotics, produce a severe and frequently fatal neurological disorder in ruminant livestock, and guinea pigs are a useful model to study the pathology and pathogenesis of this disease. The aim of this study was to determine whether tunicamycin produced ocular damage in this species, which could have pharmacotherapeutic and diagnostic value. Four 8-week-old guinea pigs were treated with tunicamycin, and two control animals were given the drug vehicle only. Guinea pigs were injected subcutaneously with 400 μg/kg of tunicamycin, in dimethyl sulphoxide, and killed 48 h post-injection. The eyes were then examined by light microscopy. Immunohistochemistry for rhodopsin was also performed. The principal pathological finding was marked retinal photoreceptor damage, which was characterised by disruption and disorganisation of rods, sometimes progressing to necrosis and separation of the outer segment. The cytoplasm of some rods was focally distended by accumulated, proteinaceous material. Rhodopsin immunopositivity in injured rods was markedly diminished and associated with shrinkage and shortening of the injured rod's outer segment. Ocular pathology, in the form of reproducible and extensive retinal photoreceptor damage, was found in guinea pigs given tunicamycin, extending the range of species found to be susceptible to this toxic injury. The guinea pig could prove to be a good animal model to test potential therapeutic interventions, and as brain lesions are often minimal and liver pathology non-specific in intoxicated ruminants, any spontaneously arising ophthalmic injury found in these species could be diagnostically useful.

Silica nanoparticles as drug delivery systems (DDS) have received huge attention in nanomedicine research. However, their drug release processes were usually discussed in the absence of proteins, which are abundant in real delivery media and likely to affect the release behaviors. In this work, novel pH-sensitive silica-based DDSs were constructed using the endogenous protein, human serum albumin (HSA), as the gatekeeper, and their release properties in protein-containing media were measured for the first time. As-synthesized mesoporous silica nanorod (MSNR) was modified with zwitterions to suppress the nonspecific adsorption of protein and to improve the dispersity. HSA was fixed onto MSNR through drug-protein interactions and covalent bonds, respectively. Benzoic-imine bonds were introduced into the designs to realize pH responsiveness. The fluorescence quenching effect of drugs on HSA was used to monitor the drug release in simulated body fluids containing proteins. The results indicated that protein gating could effectively reduce premature release in normal blood environment. The endogenous protein capping, high dispersity and stability, considerable loading content, low cytotoxicity and favorable responsiveness to acidic microenvironment enable the present structures to be promising carriers for chemotherapy drugs.