Novel manganese carbon quantum dots as a nano-probe: Facile synthesis, characterization and their application in naproxen delivery (Mn/CQD/SiO2@naproxen).

This study for the first time pursues two crucial aims of using Naproxen as a non-steroidal anti-inflammatory drug in a better, non-invasive setting and introducing a simple and biocompatible nano-carrier (Mn/CQD/SiO2) which is a magneto carbon quantum dots modified with mesoporous silica probe which can be served as a drug delivery and tracer system. SiO2modification was doneby mesoporous silica which improves biocompatibility and provideslow cytotoxicity. Naproxen was conjugated to the nano-probe to form Mn/CQD/SiO2@naproxen and biodistribution was investigated. Physicochemical characteristics of the Mn/CQD/SiO2@naproxen were investigated using FT-IR, SEM, TEM, UV-Vis and BET. Antiproliferation assay using MTT assay was performed on HEK-293 cells to determine the cytotoxity of Mn/CQD/SiO2@naproxen. Relaxivity of Mn/CQD/SiO2 was examined thereafter. To investigate the imaging capability of Mn/CQD/SiO2@naproxen and biodistribution of Naproxen, fluorescent imaging was done. To confirm the data, then the levels of COX Gene expression was determined. The specific surface area, pore volume, and pore radius were 44.4 m2/g, 10.23 cm3/g, and 25.9 nm respectively. MTT assay showed no cytotoxicity. Relaxivity of Mn/CQD/SiO2 was higher than conventional Gd-based contrast agent. Fluorescence imaging of Mn/CQD/SiO2@naproxen showed the biodistribution of naproxen. COX Gene expression confirmed the biodistribution data. By increasing the accumulation in liver COX production reduced. All in all, unique features of Mn/CQD/SiO2 including biocompatibility, low toxicity, magnetic and fluorescence properties showed that it can be used in biomedical sciences.

Technetium-99 m-PEGylated dendrimer-G2-(Dabcyle-Lys6,Phe7)-pHBSP: A novel Nano-Radiotracer for molecular and early detecting of cardiac ischemic region.

In cardiac ischemic disorder, pyroglutamate helix B surface peptide (pHBSP) which derived from erythropoietin causes to increase cell stability. To improve the serum stability of pHBSP, two lipophilic amino acids Arg6, Ala7 were replaced with Fmoc-(Dabcyle)-Lys-OH and Fmoc-Phe-OH during the peptide synthesis. This peptide was subsequently conjugated to PEGylated dendrimer-G2 and labeled with 99mTcO4- to detect cardiac ischemic region. Radiochemical purity (RCP) of 99mTc-PEGylated dendrimer-G2-(Dabcyle-Lys6,Phe7)-pHBSP was evaluated by ITLC method. In addition, the radiopeptide was investigated for stability in human serum and binding affinity to hypoxic cells in myocardium H9c2 cell lines. Biodistribution and SPECT/CT scintigraphy were assessed in cardiac ischemic rats. Radiochemical yield indicated that the anionic dendrimer has a very high potential to complex formation with 99mTcO-4 (RCP > 94%) which was stable in human serum with RCP 89% up to 6 h. The binding of 99mTc- nanoconjugate to hypoxic cells was significantly more than normoxic cells (3-fold higher compared to normoxic cells at 1 h). In biodistribution studies, erythropoietin receptor-Beta common receptor (EPO-BcR)-positive uptake in the cardiac ischemic region was 3.62 ± 0.44% ID/g 30 min post injection. SPECT imaging showed a prominent uptake of 99mTc-nanoconjugate in EPO-BcR expressing ischemic heart.

Synthesis and characterization of novel 99mTc-DGC nano-complexes for improvement of heart diagnostic.

In this research, early diagnosis of cardiovascular diseases can reduce their mortality and burden. In our study, we developed a new nano-agent, 99mTc-Dendrimer Glyco Conjugate (99mTc-DGC), and assessed its safety and capability for myocardial viability scan. To develop 99mTc-DGC, we first synthesized the dendrimer and then, glucose has been conjugated. Afterwards, we measured toxicity of the product on normal cells by XTT and apoptosis/necrosis methods. We compared the myocardial viability scan (measured by SPECT and dynamic planar imaging) in two rabbit models, with and without infarction. We also assessed the biodistribution of 99mTc-DGC in rats with no infarction. DGC synthesis was confirmed by Fourier transform infrared (FT-IR), proton nuclear magnetic resonance (1H NMR), liquid chromatography-mass spectrometry (LC-MS), dynamic light scattering (DLS) and static light scattering techniques (SLS). Then radiochemical purity (RCP) was done to present the stability and potential of DGC to complex formation with 99mTc. In vitro cytotoxicity showed nontoxic concentration up to 8 mg/mL. Single Photon Emission Computed Tomography (SPECT) and dynamic planar imaging clearly showed the accumulation of 99mTc-DGC in myocardial. Biodistribution result showed the 2.60% accumulation of 99mTc-DGC in myocardial after 2 h. Our findings indicated 99mTc-DGC to be safe and can accurately diagnose myocardial infarctions at early stages. Human studies to further assess such effects are critical.

Synthesis and evaluation of a novel nanosized anionic linear globular dendrimer G2-ciprofloxacin conjugate against prostate cancer.

Prostate cancer is the second most common cancer in the world and the fifth cause of cancer deaths in men. Ciprofloxacin enables the inhabitation of the development of prostate cancer. In this regard, we plan to improve the anticancer effect of ciprofloxacin using the anionic G2 dendrimer in conjunction with ciprofloxacin. In the current study, we measured the size and the zeta potential as well as LC Mass to prove the fact that the conjugation was synthesized correctly. The anticancer activity among three groups including Ciprofloxacin, Ciprofloxacin -G2 dendrimer, and control was measured in vitro. In vitro studies showed that G2 anionic linear-globular polyethylene-glycol-based dendrimer, which conjugated to ciprofloxacin, was able to significantly improve the treatment efficacy over clinical ciprofloxacin alone with respect to proliferation assay. Maximal inhibitory concentration (IC50) was calculated as 200 µ/mL for ciprofloxacin alone and 30µ/mL for ciprofloxacin-G2 dendrimer. In addition, the growth of DU-145 cancerous cells was inhibited by ciprofloxacin-G2 dendrimer conjugate and the number of apoptotic and necrotic cells was increased significantly as evaluated by an annexin V-fluorescein isothiocyanate assay. Ciprofloxacin -G2 dendrimer conjugate was able to increase Bcl-2/Bax ratio in a large scale as compared with the control group and CBL alone. According to the above results, this compound could be considered as a good candidate for functional cancer treatment with low side effects.

Novel delivery based anionic linear globular dendrimerg2-zidovudine nano-conjugate significantly decreased retroviral activity.

Human diseases like viral organisms for example, hepatitis, HIV and etc., attack the health and caused large mortality in populations by many years. So finding novel delivery vehicles based antiviral drugs employing nano-materials is of high universal interest. In current approach a very biocompatible biodegradable nano-biopolymer anionic linear globular dendrimer second generation G2 was elaborately conjugated to a well-known anti-HIV drug Azidovudine and thereafter was characterized by different analytical techniques like AFM, Zeta sizer, 1HNMR, FTIR and LC-Mass spectroscopy. Then, Anionic Linear Globular DendrimerG2-Zidovudine Nano-Conjugate was assessed on human normal cells (toxicity assay by XTT test) and also HIV cell model and the results showed that Anionic Linear Globular DendrimerG2-Zidovudine Nano-Conjugate Significantly Decreased Retroviral Activity without any human cell toxicity respectively. Based on current experimental data such nano-compositions is proposed for further in vivo anti-HIV assays as well.

Novel trastuzumab-DM1 conjugate: Synthesis and bio-evaluation.

Antibody-drug conjugates are now of considerable interest and are recommended for the treatment of cancers. Linkers are having a crucial role in potency and efficacy of these drugs. Herein, for the first time, we have used a water-soluble poly-ethylene glycol based linker (succinimidyl-[(N-maleimido propionamido)-diethyleneglycol] [SM(PEG)2]) for lysine amide coupling of DM1 drug to trastuzumab considering evaluation of the effect of using a hydrophilic linker on physicochemical and biological properties of the resulting conjugate in comparison to the conjugate containing succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) linker, which has a relative hydrophobic nature. The physicochemical properties of synthesized conjugates were investigated in terms of drug to antibody ratio, size variants and free drug quantities. In vitro biological activity of trastuzumab-DM1 conjugates was assessed on breast cancer cell lines expressing different levels of HER2 using binding affinity, antiproliferative, apoptosis, and antibody-dependent cell-mediated cytotoxicity (ADCC) assays. Synthesized conjugate containing hydrophilic linker, showed higher drug to antibody ratio, no aggregated form and higher cellular toxicity in comparison to SMCC bearing conjugate. Binding affinity and ADCC potential of conjugates was not affected upon the usage of hydrophilic linker. In conclusion, application of SM(PEG)2 for coupling of DM1 to trastuzumab enhance desirable characteristics of the resulting conjugate.

A comprehensive review on the treatment approaches of multiple sclerosis: currently and in the future.

BACKGROUND: Multiple sclerosis (MS) is a chronic and autoimmune disease of the central nervous system (CNS), mainly characterized by inflammatory demyelination, which manifests as relapses and diffuse damage and brain volume loss, both accounting for neurodegeneration, and therefore, physical disability. MS typically affects young adults and is commonly diagnosed in the early years by acute relapses, which then followed through partial or complete remission period. The clinical course of MS is characterized as four major classifications, including relapsing-remitting (RRMS), primary progressive (PPMS), progressive relapsing (PRMS), and secondary progressive (SPMS). PURPOSE: This review provides comprehensive overview of the current treatments and future innovative approaches in the treatment of MS. RESULTS: Currently, there is no definite cure for MS. The treatment of MS has mainly been based on the prescription of immunosuppressive and immune-modulating agents. However, a number of disease-modifying treatments (DMTs) have been designed that reduce the attack rate and delay progression and mainly target inflammation settings in these patients. Although remarkable advancements have occurred in the therapy of MS, the rate of progressive disability and early mortality is still worrisome. Recently, a monoclonal antibody (ocrelizumab) was demonstrated to be beneficial in a clinical trial of primary progressive MS. Furthermore, novel treatment strategies concentrating on the remyelination or neuroprotection are under evaluation. CONCLUSIONS: In spite of prosperous experiences in MS therapy, the future research, hopefully, will bring substantial improvements in the understanding and approaches of MS therapy.

Reduction toxicity of Amphotericin B through loading into a novel nanoformulation of anionic linear globular dendrimer for improve treatment of leishmania major.

Amphotericin B (A) as an antileishmanial drug has limited clinical application owing to severe side-effects and low-water solubility. This is the first study reported using Anionic Linear Globular Dendrimer (ALGD) as A carrier for the increase of A solubility rate, decrease its toxicity, and improve its therapeutic effects. ALGD was synthesized and A was loaded into nanoparticles for the first time with the drug-loading efficiency of 82%. Drug loading was confirmed using characterization methods. The drug solubility rate was increased by 478-folds. The results of the study showed that the A toxicity was significantly decreased by 95% in vitro and in vivo environments, which was confirmed by pathology findings and enzymatic evaluation. Furthermore, the nanodrug caused that mortality rate was reached to zero. Moreover, the nanodrug was as potent as the free drug and glucantime (GUL) in reducing the parasite burden and parasite number. These findings indicated the potency of ALGD to decrease the drug side-effects, increase the drug solubility rate, and improve the drug efficacy. Moreover, the nanoformulation was a non-toxic and cost-effective formulation. The conformity between in vitro and in vivo results suggested that the A-loaded ALGD could be considered as a promising candidate in reducing the side-effects of A in leishmaniasis treatment.

Dispersion of magnetic graphene oxide nanoparticles coated with a deep eutectic solvent using ultrasound assistance for preconcentration of methadone in biological and water samples followed by GC-FID and GC-MS.

Magnetic graphene nanoparticles coated with a new deep eutectic solvent (Fe3O4@GO-DES) were developed for efficient preconcentration of methadone. The extracted methadone was then analyzed by gas chromatography-flame ionization detection (GC-FID) or gas chromatography-mass spectrometry (GC-MS). Fe3O4@GO-DES were characterized by Fourier transform IR and X-ray diffraction techniques. Ultrasound was used to enhance the dispersion of the sorbent, with a high extraction recovery. Some parameters affecting the extraction recovery, such as pH, type of deep eutectic solvent, sample volume, amount of sorbent, extraction time, and type of eluent, were investigated. Under optimum conditions, the method developed was linear in the concentration range from 3 to 45,000 µg L-1 for GC-FID and from 0.1 to 500 µg L-1 for GC-MS, with a detection limit of 0.8 µg L-1 for GC-FID and 0.03 µg L-1 for GC-MS. The relative standard deviations (n = 6) as the intraday and interday precisions of the methadone spike at a concentration of 100 µg L-1 were 5.8% and 8.4% respectively for GC-FID. The preconcentration factor was 250. Relative recoveries from spiked plasma, urine, and water samples ranged from 95.1% to 101.5%.

Evaluation of Truncated HCV-NS3 Protein for Potential Applications in Immunization and Diagnosis.

BACKGROUND: Hepatitis C virus infection is one of global health concern. No vaccine is available so far and nonstructural protein 3 (NS3) is one of the main target antigens for developing studies on therapeutic vaccine and diagnostic application. In the current study, we expressed a truncated recombinant HCV-NS3 protein under native condition and evaluated its potential applications in immunization and diagnosis. METHODS: The recombinant pET-NS3 containing a truncated form of HCV NS3 region was constructed, confirmed by sequencing reactions, and expressed into E.coli BL21-DE3 strain. The expressed protein was purified by affinity chromatography under native condition. Characterization of diagnostic value and immunogenicity of this recombinant protein were analyzed by using an indirect ELISA method. RESULTS: Our data showed that a truncated NS3 which contains the immunodominant region of this protein was successfully expressed and purified with a high yield of 3 mg/L. Our data showed that the immunogenicity of this truncated protein can induce a specific humoral response, as well as the usage for screening of HCV positive blood samples. CONCLUSIONS: Altogether, the present study provides a simple and efficient system for protein expression and purification of an immunodominant region of NS3-HCV in native conformation and its potential application for diagnosis and vaccine development in future.

Nanosilver based anionic linear globular dendrimer with a special significant antiretroviral activity.

HIV is commonly caused to a very complicated disease which has not any recognized vaccine, so designing and development of novel antiretroviral agents with specific application of nanomedicine is a globally interested research subject worldwide. In the current study, a novel structure of silver complexes with anionic linear globular dendrimer was synthesized, characterized and then assessed against HIV replication pathway in vitro as well. The results showed a very good yield of synthesis (up to 70%) for the nano-complex as well as a very potent significant (P < 0.05) antiretroviral activity with non-severe toxic effects in comparison with the Nevirapine as standard drug in positive control group. According to the present data, silver anionic linear globular dendrimers complex may have a promising future to inhibit replication of HIV viruse in clinical practice.

Pegylation, a Successful Strategy to Address the Storage and Instability Problems of Blood Products: Review 2011-2021.

Conjugation of polyethylene glycol (PEGylation) to blood proteins and cells has emerged as a successful approach to address some of the issues attributed to the storage of blood products, including their short half-life and instability. In this regard, this review study aims to compare the influence of different PEGylation strategies on the quality of several blood products like red blood cells (RBCs), platelets, plasma proteins, i.e., albumin, coagulation factor VIII, and antibodies. The results indicated that conjugating succinimidyl carbonate methoxyPEG (SCmPEG) to platelets could improve blood transfusion safety by preventing these cells from being attached to low-load hidden bacteria in blood products. Moreover, coating of 20 kD succinimidyl valerate (SVA)-mPEG to RBCs was able to extend the half-life and stability of these cells during storage, as well as immune camouflage their surface antigens to prevent alloimmunisation. As regards albumin products, PEGylation improved the albumin stability, especially during sterilization, and there was a relationship between the molecular weight (MW) of PEG molecules and the biological half-life of the conjugate. Although coating antibodies with short-chain PEG molecules could enhance their stabilities, these modified proteins were cleared from the blood faster. Also, branched PEG molecules enhanced the retention and shielding of the fragmented and bispecific antibodies. Overall, the results of this literature review indicate that PEGylation can be considered a useful tool for enhancing the stability and storage of blood components.

Antimalarial Effects of Nano Chloroquine Loaded Curcumin In vivo.

BACKGROUND: Malaria is still the deadliest parasitic disease caused by Plasmodium spp. Due to drug resistance and their unpleasant side effects, of conventional researchers are enormously seeking to achieve antimalarial drugs with more curative effective, less toxic and cost-affordable drugs using more advanced technology such as nanodrugs. PURPOSE: The present study aimed to examine the antimalarial effects of a novel synthesized nonochloroquine-loaded curcumin relying on dendrimer G2 in susceptible mice. METHODS: Antimalarial activity and toxicity of the nanocomposite were examined on BALB/C mice with microscopy, checking RBCs morphology and related enzymatic activity rate. RESULTS: The maximum inhibitory effect of the nanocomposite was seen at 10 mg/kg, killing 98% of P. berghei compared to sole chloroquine, whereas ED50 was reported at 5.5 mg/kg. The safety of the synthesized nanocomposite was confirmed with biochemical tests with no detrimental effects on mice. The sustainability and longevity of the nanodrug increased significantly with the NDC-CQ assay compared to the control groups. CONCLUSION: The study showed that nonochloroquine-loaded curcumin had a promising inhibitory effect on P. berghei growth in infected mice compared to standard drugs. However, further studies and clinical trials with large samples are recommended to study different aspects of using nanodrug.

Genotyping of human parechoviruses in Iranian young children with aseptic meningitis and sepsis-like illness.

Human parechoviruses (HPeV) are classified into 14 genotypes. HPeV1 and HPeV2 are the most prevalent genotypes in young children, which have been associated with mild to severe diseases. This study was conducted to investigate the involvement of HPeVs in aseptic meningitis and sepsis-like illness in Iran. Viral RNA was extracted from 148 cerebrospinal fluid samples from children <8 years old with primary diagnosis of aseptic meningitis and/or sepsis-like illness. Specific HPeV, HEV real-time PCR and HPeV typing were done to identify the infection rate of these viruses. HPeV and HEV were detected in 64 (43.24 %), 31 (20.94 %) of 148 patients with 10 (6.75 %) coinfection. VP1/VP3 junction region was successfully sequenced from 12 of the HPeV-positive specimens, and all of them were identified as HPeV1. HPeV was more prevalent than HEV in both aseptic meningitis and sepsis-like illness, so further studies are needed to understand the disease burden of HPeV infections, and clinical manifestations especially in specific illnesses of possible viral etiology. Direct detection of these viruses leads to reduce hospitalization and use of antibiotic, which are often followed by other complications in neonates and young children.

Therapeutic Application of Nanoparticles in Hepatitis Diseases: A Narrative Review (2011-2021).

Hepatitis, an inflammation of the liver parenchyma, is a viral disease. Addressing the challenges of hepatitis is very important. Therefore, using nanoparticles (NPs) in solving the problems of hepatitis diagnosis and treatment can be considered a promising approach. To the best of our knowledge, there are few studies to review the most widely used and effective NPs in the field of hepatitis. A literature review was performed on the publications available on the subject matter from 2011 to 2021. The keywords in different combinations such as "hepatitis," "nanobiosensor," "nanoparticles," "drug delivery," "vaccination," "HBV," and "HCV" were searched in databases of PubMed and Scopus. The collected data were then analyzed. Our review study for introducing the widely used metallic, polymeric and carbon-based NPs with more promising effects in the field of hepatitis virus infection shows that the most effective metallic NPs were gold nanoparticles for designing detection sensors. Also, among polymeric NPs, chitosan NPs seem to be the best nanocarriers in drug delivery and vaccination for hepatitis and among carbon-based NPs, carbon dots had more promising effects for biosensing of hepatitis. According to the results, it is suggested that more studies could be conducted on these NPs for further studies on hepatitis as well as other viral infectious diseases.

A Review of the Use of Metallic Nanoparticles as a Novel Approach for Overcoming the Stability Challenges of Blood Products: A Narrative Review from 2011-2021.

PURPOSE: To obtain safe and qualified blood products (e.g., platelets, plasma, and red blood cells), various limitations such as limited shelf life (especially for platelets) and stability must be addressed. In this review study, the most commonly used metal nanomaterials (e.g., gold, silver, iron, and magnetic) reported in the literature from 2011 to 2021 were discussed owing to their unique properties, which provide exciting approaches to overcome these limitations and improve the stability, safety, and quality of blood products. Novelty: This study reviews for the first time the results of studies (from 2011 to 2021) that consider the effects of various metallic nanoparticles on the different blood products. RESULTS: The results of this review study showed that some metallic nanoparticles are effective in improving the stability of plasma proteins. For this purpose, modified Fe3O4 magnetic nanoparticles and citrate-AuNPs protect albumin products against stressful situations. Also, SiO2 microspheres and silicacoated magnetite nanoparticles are highly capable of improving IgG stability. ZnO nanoparticles also reduced thrombin production, and protein-coated GMNP nanoparticles prevented unwanted leakage of factor VIII through blood vessels. Furthermore, the stability and longevity of erythrocytes can be improved by AuNP nanoparticles and Zr-based organic nanoparticles. In addition, platelet storage time can be improved using PEGylated Au and functionalized iron oxide nanoparticles. SUGGESTION: According to the results of this study, it is suggested that further research should be conducted on metal nanoparticles as the most promising candidates to prepare metal nanoparticles with improved properties to increase the stability of various blood products.

Synthesis of smart carriers based on tryptophan-functionalized magnetic nanoparticles and its application in 5-fluorouracil delivery.

Multifunctional nanocarriers, specifically for tumor targeting and traceable features, have been increasingly considered in cancer therapies. Herein, a novel targeting agent (TA), tryptophan (TRP), was proposed for the synthesis of functionalized (3-aminopropyl) triethoxysilane-iron oxide nanoparticles using two methods, creating a smart drug delivery system (DDS). In one method, two-step, glutaraldehyde (GA) as a linker, bonded TRP and amino-functionalized magnetite, and in the second method, one step, TRP binding was carried out by (3-dimethyl aminopropyl)-N'-ethyl carbodiimide hydrochloride (EDC)/N-hydroxysuccinimide ester. The synthesis yield of the second method was 7% higher than the first method. After synthesizing DDS, 5-fluorouracil (5-FU) was loaded on nanocarriers and was observed TRP functionalized nanoparticles by GA have better loading efficiency, which was 50% greater than the product from the one-step method. A pH-sensitive release profile was also studied for 5-FU/DDS with the release of almost 75% and 50% at pH 5.5 and 7.4, respectively. To analyze the biological aspects of nanocarriers, human breast cancer, MCF-7, and embryonic kidney, HEK293, cell lines were used for cellular uptake and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays.In vitrostudies confirmed that TRP can act as a TA as its cellular uptake through cancerous cells was 40% greater than normal cells, and the MTT assay confirmed that using DDS can increase and decrease the cell viability of normal cells and cancerous cells, respectively, compared to free drug. Therefore, it was concluded that advanced nano-assembly is a great candidate for breast cancer cell-targeted delivery.