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.

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.

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.

Novel Coumarin-Pyridine Hybrids as Potent Multi-Target Directed Ligands Aiming at Symptoms of Alzheimer's Disease.

In this research, a series of coumarin-based scaffolds linked to pyridine derivatives via a flexible aliphatic linkage were synthesized and assessed as multifunctional anti-AD agents. All the compounds showed acceptable acetylcholinesterase (AChE) inhibition activity in the nanomolar range (IC50 = 2-144 nM) and remarkable butyrylcholinesterase (BuChE) inhibition property (IC50 = 9-123 nM) compared to donepezil as the standard drug (IC50 = 14 and 275 nM, respectively). Compound 3f as the best AChE inhibitor (IC50 = 2 nM) showed acceptable BuChE inhibition activity (IC50 = 24 nM), 100 times more active than the standard drug. Compound 3f could also significantly protect PC12 and SH-SY5Y cells against H2O2-induced cell death and amyloid toxicity, respectively, superior to the standard drugs. It could interestingly reduce ß-amyloid self and AChE-induced aggregation, more potent than the standard drug. All the results suggest that compound 3f could be considered as a promising multi-target-directed ligand (MTDL) against AD.

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.

Antiplasmodial Effect of Nano Dendrimer G2 Loaded with Chloroquine in Mice Infected with Plasmodium berghei.

BACKGROUND: Malaria is a parasitic lethal disease caused by Plasmodium protozoa. The resistance and drugs' side effects have led to numerous researches for alternative suitable drugs with better efficiency and lower toxicity PURPOSE: In the present study, we investigated in vivo antimalarial effects of G2 linear dendrimer-based nano-chloroquine. METHODS: After the preparation of nano dendrimer G2, chloroquine loading was done. Determine the characterization of particles were specified by DLS, SLS and SEM. The LC-MS and FTIR were used for verifying the nano dendrimer G2 and the loading of chloroquine into the compound. The Solubility N-chloroquine and measurement of drug release rate were done. Antiplasmodial activity of N-chloroquine on BALB/c mice was performed by the microscope and enzymatic methods. At the end, In vivo toxicity of N-chloroquine on tissues was assayed. The RBC morphology and enzyme levels were identified. RESULTS: The results showed the synthesized N-chloroquine had suitable size and solubility. Highest inhibitory effect on Plasmodium parasitic growth was observed at 16 mg/kg dose of N-chloroquine, which eliminated 95% of the parasites (p > 0.05). ED50 is observed at 7.7 mg/kg of N-chloroquine dose. Biochemical findings showed the synthesized N-chloroquine was safer than chloroquine. The N-chloroquine no adverse effects were observed in examined tissues. CONCLUSION: Due to the better effect of the synthesized N-chloroquine on Plasmodium berghei in mice compared to chloroquine, this nanoparticle can be considered as an effective anti-plasmodium compound while more comprehensive research is recommended.

Lamivudine-conjugated and efavirenz-loaded G2 dendrimers: Novel anti-retroviral nano drug delivery systems.

Infection with human immunodeficiency virus (HIV)-1 causes immunological disorders and death worldwide which needs to be further assisted by novel anti-retroviral drug delivery systems. Consequently, finding newer anti-retroviral pharmaceuticals by using biocompatible, biodegradable nanomaterials comprising a nanoparticle as core and a therapeutic agent is of high global interest. In this experiment, a second generation of a negatively charged nano-biopolymer linear globular G2 dendrimer was carefully conjugated and loaded with well-known anti-HIV drugs lamivudine and efavirenz, respectively. They were characterised by a variety of analytical methods such as Zetasizer, Fourier-transform infrared spectroscopy, elemental analysis and liquid chromatography-mass spectroscopy. Additionally, conjugated lamivudine and loaded efazirenz with globular PEGylated G2 dendrimer were tested on an HEK293 T cell infected by single-cycle replicable HIV-1 virion and evaluated using XTT test and HIV-1 P24 protein load. The results showed that lamivudine-conjugated G2 significantly decreased retroviral activity without any cell toxicity. This effect was more or less observed by efavirenz-loaded G2. These nano-constructs are strongly suggested for further in vivo anti-HIV assays.

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.

A Review Study about the Effect of Chitosan Nanocarrier on Improving the Efficacy of Amphotericin B in the Treatment of Leishmania from 2010 to 2020.

In the present review study, the published articles from 2010-2020 that evaluated the effect of chitosan nanocarrier on the efficacy of amphotericin B (AmB) in the treatment of leishmaniasis, have been considered. Leishmania is a parasitic tropical disease in the world and is treated with AmB as one of the main therapeutic agents. However, the clinical application of AmB is limited due to its toxicity and insolubility issues. Using nanoparticles and, in particular, chitosan, nanocarrier seems a promising approach to overcome these problems. Therefore, various doses of AmB have been loaded in chitosan nanoparticles in different studies and the results of these studies demonstrated that by increasing the drug loading efficiency and decreasing the toxicity, the potency of the nanoformulation to inhibit and to kill the parasite is increased. In this regard, the results of a study performed in 2018, demonstrated that chitosan nanoparticles with the higher dose of drug loading were the most effective formulation to inhibit and kill the parasite. Thus, chitosan nanocarrier can consider as an appropriate candidate in the future to inhibit and kill the Leishmania parasite without causing side effects.

Chlorambucil-Chitosan Nano-Conjugate: An Efficient Agent Against Breast Cancer Targeted Therapy.

BACKGROUND: Discovering new chemotherapy drugs and techniques with the least side effects is one of the most important and challenging issues in recent years worldwide. Chlorambucil is an anticancer drug that is still commonly used as a primary treatment in treating some cancers, but it can cause side effects. OBJECTIVE: In this study, we decided to use chitosan as a carrier to enhance the uptake of chlorambucil and reduce the toxicity of this drug. METHODS: After producing this nanoconjugate compound and analysing its structure by FTIR, DLS and AFM analysis, we investigated the therapeutic and biological effects of this nanoconjugate compound on the MCF-7 cell line (breast cancer). RESULTS: The results of the MTT assay showed that this nanoconjugate compound not only retained its anticancer effect against chlorambucil but also showed less abnormal toxicity. In addition, in vitro cellular uptake by flow cytometry indicated the better uptake final product into the MCF-7 cells. The detection of apoptosis induced cell death was confirmed by RT-PCR. CONCLUSION: This study has created a prospective pathway for targeting cancer cells using chitosan.

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.

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 radiopharmaceutical (Technetium-99m)-(DOTA-NHS-ester)-Methionine as a SPECT-CT tumor imaging agent.

Breast cancer is the most common type of cancer in women worldwide. There have been many efforts for early breast cancer detection and among them molecular imaging have been extremely of high importance. Single-photon emission computed tomography (SPECT/CT) is a kind of imaging technique able to reveal crucial information with using radiopharmaceuticals. In this study, Technetium-99m-(DOTA-NHS-ester)-Methionine radiopharmaceutical was synthesized. Between 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid mono-N-hydroxysuccinimide ester (DOTA-HNS ester) (MACROCYCLICS, DOTA-NHS ester, Plano, Texas, USA) and methionine(marker) were conjugated. The DOTA-HNS ester-Methionine was labeled with Technetium-99m (Inter-Medical, Technetium-99m, Bergamo, Italy). The synthesized radiopharmaceutical was used in SPECT/CT imaging for breast cancer diagnosis. For radiopharmaceutical evaluation, MTT assay for cellular toxicity, biodistribution, cellular uptake and radiochemical purity were employed.Technetium-99m-(DOTA-NHS-ester)-Methionine radiochemical had less cellular toxicity in human embryonic kidney cells 293 cell line (HEK293). Cellular uptake was indicated higher percent with use of Methionine as a marker, and radiochemical purity was high. Based on the results Technetium-99m-(DOTA-NHS-ester)-Methionine radiochem may be a better option for early detection of breast cancer. Further study is recommended to confirm these findings in clinical practice.