Concentrations Of Doxorubicin Research Articles

Fabrication of novel carbon dots/cerium oxide nanocomposites for highly sensitive electrochemical detection of doxorubicin

In the current study, carbon dots/cerium oxide (CDs/CeO2) nanocomposites-modified screen printed carbon electrode, SPCE (CDs/CeO2/SPCE) was developed for the highly sensitive and selective detection of doxorubicin (DOX), an anticancer drug. Here, firstly we have synthesized cerium oxide nanoparticles (CeO2NPs) from ammonium cerium nitrate and urea by simple refluxing, and then CDs were synthesized by using taurine (an essential amino acid) via thermal decomposition method. After that CDs/CeO2 nanocomposites have been synthesized with different wt% of CDs (0.5–5 wt%) via a facile hydrothermal method. The synthesized nanocomposites exhibited higher efficiency towards the electrochemical detection of DOX as compared to bare CeO2NPs and CDs by promoting electron transfer reaction at SPCE surface with increasing amount of CDs. The 5 wt% nanocomposite (CDs-5.0/CeO2) showed the highest oxidation response towards DOX (20 μM) at an optimized pH of 5. The cyclic voltammograms revealed that CDs-5.0/CeO2/SPCE sensing system exhibited a linear response (correlation coefficient, R2 = 0.98) between oxidation peak current and DOX concentration in the range of 0.2–20 μM, with a low detection limit of 0.09 μM. Moreover, the modified CDs-5.0/CeO2/SPCE sensor exhibited superior selectivity towards DOX in the presence of common interferents. This work demonstrated that the novel CDs/CeO2/SPCE sensor can be effectively applied to detect DOX in pharmaceutical samples or in biological fluids.

Synergistic anti-cancer effects of Nigella sativa seed oil and conventional cytotoxic agent against human breast cancer.

Breast cancer is the most commonly diagnosed invasive non-skin malignancy in women worldwide, and it is the leading cause of cancer-related deaths in them. Nigella sativa Linn. seed oil has been found to be effective in cancer treatment as well as having anti-cancer properties in some other types of cancers. The study looked into the synergistic cytotoxic effects of N.sativa Linn. seed oil and doxorubicin in the treatment of human breast cancer cells (MCF-7). Nigella sativa Linn. seed oil was used to evaluate its effect on human breast cancer cells, either alone or in conjunction with doxorubicin. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) tests were used to examine cell proliferation and cell viability, while phase-contrast inverted microscopy was used to examine cellular morphology. Furthermore, the role of N.sativa seed oil in decreasing cell tumorigenicity features was highlighted by testing the cancer cell migration using the wound healing assay. Results showed that higher concentrations (50μg/mL) of N.sativa Linn. seed oil changed the breast cancer cell morphology and decreased the cell proliferation and viability. Breast cancer cells treated with black seed oil decreased cell movement after 24hours compared to the untreated cell in the wound healing assay. Whereas, only the higher concentration of doxorubicin (0.5-2.5μg/mL) reduced cell proliferation and cell viability. Moreover, the combination treatment of 50μg/mL of black seed oil with different concentrations of doxorubicin caused a significant cell proliferation reduction and decreased cell viability. The activity was seen optimum at lower concentration (0.1µg/mL) of doxorubicin. There was decreased cell proliferation and cell viability when N.sativa seed oil was used alone or in conjunction with doxorubicin in Breast cancer cells (MCF-7) revealing potential opportunities in the field of cancer treatment.

Ozone combined with doxorubicin exerts cytotoxic and anticancer effects on Luminal-A subtype human breast cancer cell line.

We aimed to examine the potential anticancer effects of ozone applied after chemotherapeutic treatment with different concentrations of doxorubicin in Luminal-A subtype of human breast cancer cell line (MCF-7) and compare the results with effects on L929 fibroblast cell line. Both cell lines were incubated with increasing doses of doxorubicin (1-50 μM) for 24 h at 37°C. Then, half of groups were incubated with 30 μg/mL ozone for 25 min as combination groups. Cell viability was analyzed by MTT assay, apoptosis by flow cytometry, and levels of tumor necrosis factor alpha, transforming growth factor beta, and matrix metalloproteinase-2 and MMP-9 by immunocytochemistry. Doxorubicin + ozone treatment enhanced viability of L929 (p<0.01) but reduced viability of MCF-7 compared to only doxorubicin-applied cells without ozone treatment (p<0.001). This combined treatment also enhanced apoptotic effect of doxorubicin on MCF-cells (p<0.001), but not on L929. It significantly increased all protein levels of L929 compared with those of other groups (p<0.05 for tumor necrosis factor alpha and MMP-2; p<0.01 for transforming growth factor beta and MMP-9). This treatment reversed the effect of doxorubicin on tumor necrosis factor alpha levels and considerably reduced MMP-2 and MMP-9 levels of MCF-7 compared with those of control group (p<0.01 and p<0.001, respectively). Ozone treatment potentiated the apoptotic and anticancer activities of doxorubicin in MCF-7 cells and showed repairing and healing effect on healthy fibroblast cells, which were damaged from cytotoxic effects of chemotherapeutic agent. MCF-7 cells may acquire sensitivity against the doxorubicin combined with ozone treatment through activating tumor necrosis factor alpha, MMP-2, and MMP-9 expressions.

The Effect of Snake Venom (Naja Naja Oxiana) on Proliferation Rate of cancer Cells

Aims Because cancer is the leading cause of death worldwide, finding a better way to treat it seems essential. Doxorubicin is one of the most common drugs in the treatment of cancer, which has many negative and toxic effects. Therefore, efforts to produce effective anticancer drugs through screening natural compounds, such as animal toxins continue. This study aimed to evaluate the effect of Naja naja oxiana snake venom in comparison with doxorubicin on the proliferation rate and concentration of malondialdehyde in the human cervical cancer cell line (HeLa) and fibroblast cells (HFF). Methods &amp; Materials HeLa and normal fibroblast cancer cell lines were exposed to different concentrations of snake venom and doxorubicin for 24 and 48 hours. The amplification rate was determined using trypan blue staining and malondialdehyde (MDA) concentration was measured to evaluate the effects of oxidative stress. Data were analyzed using SPSS software, version 19. Findings The results showed that with increasing concentration and treatment time with snake venom and doxorubicin, the cell proliferation rate decreases, and MDA content increases. The highest decrease in proliferation rate and increase in MDA concentration were observed in the HeLa cancer cell line treated with 500 µg/mL of snake venom for 48 hours. Conclusion In comparison with doxorubicin, snake venom has a significant inhibitory effect on the HeLa cancer cell line with minimal effect on normal fibroblast cells.

Antimalarial Effect of Doxorubicin on Plasmodium Falciparum: An in Vitro Study in FCR-3 Strain

Plasmodium falciparum is the most common species of Plasmodium that causes malaria in Southeast Asia. Artemisinin, a drug with the mechanism of action by inducing oxidative stress in infected red blood cells (RBC) is currently used as the main therapy for malaria, after resistance to chloroquine has been found. However, evidence of artemisinin resistance was discovered in several regions in Southeast Asia. Therefore, a research is required to prove the existence of other drugs that have anti-malaria effects. A drug candidate, doxorubicin also can induce the formation of oxidative stress inside the cells. This study aims to determine the activity of doxorubicin to inhibit the development of P. falciparum in vitro. Red blood cell (RBC) infected with P. falciparum were treated with various concentrations of doxorubicin. Giemsa technique was applied to detect P. falciparum inside RBC. After 48 hours of incubation, the culture was observed to measure the number and the confluence of RBC and P. falciparum in the medium. This study revealed that doxorubicin reduced the number of RBC infected with P. falciparum lysis. The effective dose of doxorubicin-inhibit RBC cell lysis is 0.4 μM, which only reduces 81% RBC cell lysis compared to the control group that reduces 95% RBC cell lysis. At this concentration also found a decrease in the number of P. falciparum cells in the medium. The results proved that doxorubicin has an inhibitory effect on the development of P. falciparum and can decrease the lysis of RBC due to P. falciparum infection. This findings provide an insight that doxorubicin is a potential candidate for antimalarial drugs.

Bacterial diversity in the intestinal mucosa of heart failure rats treated with Sini Decoction

BackgroundSini Decoction (SND), a classic Chinese medicine prescription, has been proved to have a good effect on heart failure (HF), whereas its underlying mechanism is still unclear. In order to explore the therapeutic mechanism of SND, we combined with 16S rRNA gene sequencing to analyze the composition of gut microflora in rats with HF.Material and methodsTwenty Sprague–Dawley (SD) rats were divided into four groups (n = 5): normal group, model group, SND treatment group (SNT group), and metoprolol (Met) treatment group (Meto group). All the rats except the normal group were intraperitoneally injected with doxorubicin (concentration 2 mg/mL, dose 0.15 mL/100 g) once a week to induce HF. After successfully modeling, SND and Met were gavaged to rats, respectively. After the treatment period, blood was collected for hematological analyses, myocardial tissue and colon tissues were collected for Hematoxylin–Eosin (H&E) staining, and mucosal scrapings were collected for Illumina Miseq high-throughput sequencing.ResultsEchocardiographic results suggested that both left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS) in Model rats decreased compared with normal rats. The results of H&E staining showed that compared with the model group, the structures of myocardial tissue and colon tissue in the SNT group and Meto group showed a recovery trend. Alpha results showed that the model group had higher species diversity and richness compared with the normal group. After treatment, the richness and diversity of intestinal bacteria in the SNT group were significantly restored, and Met also showed the effect of adjusting bacterial diversity, but its effect on bacterial richness was not ideal. At the Family level, we found that the number of several bacteria associated with HF in the model group increased significantly. Excitingly, SND and Met had shown positive effects in restoring these HF-associated bacteria. Similarly, the results of Linear discriminant analysis (LDA) showed that both SND and Met could reduce the accumulation of bacteria in the model group caused by HF.ConclusionCollectively, SND can improve HF by regulating the intestinal flora. This will provide new ideas for the clinical treatment of patients with HF.

A ratiometric fluorescence strategy based on copper nanoclusters/carbon dots for sensitive detection of doxorubicin.

Sensitive detection of doxorubicin (DOX) is critical for clinical theranostics. A novel ratiometric fluorescence strategy based on the inner filter effect (IFE) has been established for the sensitive detection of DOX by designing a ratiometric fluorescence probe. In the presence of DOX, the fluorescence intensity of copper nanoclusters (CuNCs) at 485 nm decreases, and the fluorescence intensity of carbon dots at 560 nm increases. Therefore, DOX can be quantitatively detected by measuring the ratio of the fluorescence intensities at 560 and 485 nm (F560 /F485 ). The F560 /F485 ratio exhibits a linear correlation with the DOX concentration in the range from 1.0×10-8 M to 1.0×10-4 M with the detection limit of 3.7 nM. Furthermore, this method was also successfully applied to the analysis of DOX in human plasma samples, affording an effective platform for drug safety management.

Polyethylene Glycol Drug-Eluting Embolic Microspheres Loaded with Doxorubicin for the Treatment of Hepatocellular Carcinoma: Feasibility, Safety, and Pharmacokinetic Study

PurposePolyethylene glycol drug-eluting microspheres (PEG-DEMs) can be loaded to elute doxorubicin. The current study evaluated the pharmacokinetic profile and safety of PEG-DEMs in the treatment of patients with hepatocellular carcinoma (HCC). Materials and methodsThe current prospective, multicenter, dose-escalation study enrolled 25 patients (68% men) with early or intermediate stage HCC and a performance status of 0. Patients in Cohort I were assigned to receive target doxorubicin doses of 75, 100, or 150 mg. Analyses were performed on the basis of the specific dose of doxorubicin that the patients received because some patients received less than the assigned dose. Patients in Cohort II received the maximum safe tested dose. Adverse events were classified according to the Common Terminology Criteria for Adverse Events version 4.03. The tumor response was evaluated every 3 months according to the European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors. ResultsThe maximum tested safe dose of doxorubicin was 150 mg. For the groups that received ≤75, 75–100, and 101–150 mg of doxorubicin, the peak plasma concentrations were 286.7 ng/mL ± 220.1, 157.1 ng/mL ± 94.6, and 245.4 ng/mL ± 142.8, respectively; the areas under the curves calculated from 0 to 24 h were 421.7 (ng × h)/mL ± 221.2, 288.1 (ng × h)/mL ± 100.9, and 608.3 (ng × h)/mL ± 319.3, respectively, with almost complete clearance at 24 h. There was no death within 30 d. The best objective response rate was 81%, and the disease control rate was 91%. The median overall survival was 27.2 months (95% confidence interval [CI], 17.5 months to not evaluated [n.e.]); the median progression-free survival was 9.8 months (95% CI, 5.5 months to n.e.). ConclusionsPEG-DEMs demonstrated a favorable safety profile with low systemic concentration of doxorubicin, and promising efficacy.

Micro- and Nanosecond Pulses Used in Doxorubicin Electrochemotherapy in Human Breast and Colon Cancer Cells with Drug Resistance.

(1) Background: Pulsed electric field (PEF) techniques are commonly used to support the delivery of various molecules. A PEF seems a promising method for low permeability drugs or when cells demonstrate therapy resistance and the cell membrane becomes an impermeable barrier. (2) Methods: In this study, we have used doxorubicin-resistant and sensitive models of human breast cancer (MCF-7/DX, MCF-7/WT) and colon cancer cells (LoVo, LoVoDX). The study aimed to investigate the susceptibility of the cells to doxorubicin (DOX) and electric fields in the 20–900 ns pulse duration range. The viability assay was utilized to evaluate the PEF protocols’ efficacy. Cell confluency and reduced glutathione were measured after PEF protocols. (3) Results: The obtained results showed that PEFs significantly supported doxorubicin delivery and cytotoxicity after 48 and 72 h. The 60 kV/cm ultrashort pulses × 20 ns × 400 had the most significant cytotoxic anticancer effect. The increase in DOX concentration provokes a decrease in cell viability, affected cell confluency, and reduced GSSH when combined with the ESOPE (European Standard Operating Procedures of Electrochemotherapy) protocol. Additionally, reactive oxygen species after PEF and PEF-DOX were detected. (4) Conclusions: Ultrashort electric pulses with low DOX content or ESOPE with higher DOX content seem the most promising in colon and breast cancer treatment.

Cone-Beam Computed Tomography-Based Spatial Prediction of Drug Dose After Transarterial Chemoembolization Using Radiopaque Drug-Eluting Beads in Woodchuck Hepatocellular Carcinoma.

The aims of this study were to develop a model to estimate drug dose delivered to tumors after transarterial chemoembolization (TACE) with radiopaque drug-eluting beads (DEBs) based on DEB density on cone-beam computed tomography (CT) and to evaluate drug penetration into tissue in a woodchuck hepatoma model. Transarterial chemoembolization was performed in woodchucks with hepatocellular carcinoma (N = 5) using DEBs (70-150 μm, LC Bead LUMI) loaded with doxorubicin. Livers were resected 45 minutes after embolization, immediately frozen, and cut using liver-specific, 3D-printed sectioning molds. Doxorubicin levels in tumor specimens were measured by high-performance liquid chromatography and correlated with DEB iodine content that was measured using prototype cone-beam CT-based embolization treatment planning software. Doxorubicin penetration into tissue surrounding DEBs was assessed by fluorescence microscopy of tumor sections. Fluorescence intensity was converted into doxorubicin concentration using calibration standards. Intensity-thresholded color heatmaps were generated representing extravascular drug penetration. Consistent segmentation of DEBs on cone-beam CT was achieved using a semiautomated intensity thresholding method. A positive linear correlation (0.96) was found between DEB iodine content measured on cone-beam CT and the amount of doxorubicin measured in tumor specimens. Prediction of doxorubicin levels in tumor sections that were not included in model development was accurate, with a root-mean-square error of 0.08 mg of doxorubicin. Tumor penetration of eluted doxorubicin resulted in concentration gradients where drug content decreased with increasing distance from blood vessels containing DEBs. Drug penetration was greater for blood vessels containing DEB clusters compared with single DEB, with higher doxorubicin concentrations extending further away from the vessels. Estimation of drug dose delivered during transarterial chemoembolization in a woodchuck hepatocellular carcinoma model was possible using DEB radiopacity on cone-beam CT as a surrogate marker. Doxorubicin penetration was greatest adjacent to vessels containing DEB clusters compared with single DEB. Intraprocedural estimation of the spatial distribution of drug dose within the tumor could enable real-time adjustments to DEB delivery, to maximize treatment coverage or identify regions of tumor at risk for undertreatment.

Combination Effects of Abelmoschus manihot (L.) Medik of N-Hexane extracts and Doxorubicin in Breast cancer 4T1 Cells Line

Introduction: Breast Cancer is one of the diseases, which the ranks are first on death to the female sex. breast cancer characterized by the growth of uncontrolled breast cancer cells and ability to attack the local organs like as metastases and spread in breast tisue including ducts and lobules. Alternative treatment for breast cancer is combined with chemotherapy and chemopreventive non-toxic agent to breast cancer cells Objective: The research of the study is to evaluate potential synergism the in-vitro cytotoxicity combination effects from a combination of the Abelmoschus manihot (L.) Medik of (N-Hexane) extracts and Doxorubicin in breast cancer 4T1 cells line. Methods: The study is suggested combination effects of Abelmoschus manihot (L.) Medik of (N-Hexane) extracts and Doxorubicin in breast cancer 4T1 cells line, where carried out against with use table of concentration from Abelmoschus manihot (L.) Medik extracts (N-Hexane) and Doxorubicin as a Chemotherapy agent. Results: The potential of Abelmoschus manihot (L.) Medik of n-hexane extract can be combination with cytotoxicity agent Doxorubicin on 4T1 breast cancer cells line with concentration of N-Hexane extract 185,0 µg/ml and the concentration of Doxorubicin 25 nM, where the Combination Index (CI) values 0,89 &lt; 1 shows synergist combination. Conclusion: The Abelmoschus manihot (L.) Medik of n-hexane extract is synergism with cytotoxic agent Doxorubicin in 4T1 breast cancer cells line.

Tumor-Selective Cascade-Amplified Dual-Prodrugs Activation for Synergistic Oxidation-Chemotherapy

Tumor-Selective Cascade-Amplified Dual-Prodrugs Activation for Synergistic Oxidation-Chemotherapy

Effective adsorption of doxorubicin hydrochloride on zirconium metal-organic framework: Equilibrium, kinetic and thermodynamic studies

Zirconium metal organic framework (Zr-MOF) has been synthesized by hydrothermal method and various spectroscopic methods were used to characterize the samples. The adsorption of doxorubicin (DOX) onto Zr-MOF was studied. The effects of starting DOX concentration, contact time, solution pH, and temperature in an aqueous system in a batch mode were examined. Scanning electron microscopy (SEM) was used to determine surface properties of Zr-MOF. Nitrogen adsorption/desorption tests at 77 K revealed the surface area and pore volume of Zr-MOF to be 1498 m2/g and 0.957 cm3/g, respectively. The adsorption efficiency of Zr-MOF for DOX was at pH 6 than in alkaline solution, according to the results of the experiments. To characterize the equilibrium isotherms and estimate the isotherm values, the Langmuir, Freundlich, Temkin, and Dubinin-Radushkevich adsorption systems were used. The activation energy of adsorption was also determined to be 13.27 kJ/mol, showing that the adsorption mechanism involves chemisorption. The kinetic data were described using the pseudo-first-order, pseudo-second-order, intra-particle diffusion, and Elovich model. The pseudo-second-order kinetic data fit the dynamic data nicely. Isotherms include things like ΔGo, ΔHo and ΔSo The adsorption mechanism was computed and determined to be a spontaneous and endothermic reaction. The docking active place interactions were assessed to see if DOX might bind to the lung cancer 5C5S and liver cancer-2LEO receptor.

Primary Nasal Epithelial Cells as a Surrogate Cell Culture Model for Type-II Alveolar Cells to Study ABCA-3 Deficiency.

ATP Binding Cassette Subfamily A Member 3 (ABCA-3) is a lipid transporter protein highly expressed in type-II alveolar (AT-II) cells. Mutations in ABCA3 can result in severe respiratory disease in infants and children. To study ABCA-3 deficiency in vitro, primary AT-II cells would be the cell culture of choice although sample accessibility is limited. Our aim was to investigate the suitability of primary nasal epithelial cells, as a surrogate culture model for AT-II cells, to study ABCA-3 deficiency. Expression of ABCA3, and surfactant protein genes, SFTPB and SFTPC, was detected in primary nasal epithelial cells but at a significantly lower level than in AT-II cells. ABCA-3, SP-B, and SP-C were detected by immunofluorescence microscopy in primary nasal epithelial cells. However, SP-B and SP-C were undetectable in primary nasal epithelial cells using western blotting. Structurally imperfect lamellar bodies were observed in primary nasal epithelial cells using transmission electron microscopy. Functional assessment of the ABCA-3 protein demonstrated that higher concentrations of doxorubicin reduced cell viability in ABCA-3 deficient nasal epithelial cells compared to controls in an assay-dependent manner. Our results indicate that there may be a role for primary nasal epithelial cell cultures to model ABCA-3 deficiency in vitro, although additional cell culture models that more effectively recapitulate the AT-II phenotype may be required.

Photosensitive EGFR-Targeted Nanocarriers for Combined Photodynamic and Local Chemotherapy.

The major limitation of any cancer therapy lies in the difficulty of precisely controlling the localization of the drug in the tumor cells. To improve this drawback, our study explores the use of actively-targeted chemo-photo-nanocarriers that recognize and bind to epidermal growth factor receptor-overexpressing cells and promote the local on-demand release of the chemotherapeutic agent doxorubicin triggered by light. Our results show that the attachment of high concentrations of doxorubicin to cetuximab-IRDye700DX-mesoporous silica nanoparticles yields efficient and selective photokilling of EGFR-expressing cells mainly through singlet oxygen-induced release of the doxorubicin from the nanocarrier and without any dark toxicity. Therefore, this novel triply functionalized nanosystem is an effective and safe nanodevice for light-triggered on-demand doxorubicin release.

Hyperthermia-induced doxorubicin delivery from thermosensitive liposomes via MR-HIFU in a pig model

PurposeEncapsulation of cytotoxic drugs for a localized release is an effective way to increase the therapeutic window of such agents. In this article we present the localized release of doxorubicin (DOX) from phosphatidyldiglycerol (DPPG2) based thermosensitive liposomes using MR-HIFU mediated hyperthermia in a swine model. Materials and methodsGerman landrace pigs of weights between 37.5 and 53.5 kg received a 30-min infusion of DOX containing thermosensitive liposomes (50 mg DOX/m2). The pigs' biceps femoris was treated locally in two separate target areas with mild hyperthermia using magnetic resonance guided high intensity focused ultrasound, starting 10 min and 60 min after initiation of the infusion, respectively. The pharmacokinetics and biodistribution of DOX were determined and an analysis of the treatment parameters' influence was performed. ResultsCompared to untreated tissue, we found a 15-fold and a 7-fold increase in DOX concentration in the muscle volumes that had undergone hyperthermia starting 10 min and 60 min after the beginning of the infusion, respectively. The pharmacokinetic analysis showed a prolonged circulation time of DOX and a correlation between the AUC of extra-liposomal DOX in the bloodstream and the amount of DOX accumulated in the target tissue. ConclusionsWe have demonstrated a workflow for MR-HIFU hyperthermia drug delivery that can be adapted to a clinical setting, showing that HIFU-hyperthermia is a suitable method for local drug release of DOX using DPPG2 based thermosensitive liposomes in stationary targets. Using the developed pharmacokinetic model, an optimization of the drug quantity deposited in the target via the timing of infusion and hyperthermia should be possible.

Doxorubicin-Loaded Metal-Organic Framework Nanoparticles as Acid-Activatable Hydroxyl Radical Nanogenerators for Enhanced Chemo/Chemodynamic Synergistic Therapy.

Doxorubicin (DOX) is a widely used first-line antitumor agent; however, acquired drug resistance and side effects have become the main challenges to effective cancer therapy. Herein, DOX is loaded into iron-rich metal–organic framework/tannic acid (TA) nanocomplex to form a tumor-targeting and acid-activatable drug delivery system (MOF/TA-DOX, MTD). Under the acidic tumor microenvironment, MTD simultaneously releases DOX and ferrous ion (Fe2+) accompanied by degradation. Apart from the chemotherapeutic effect, DOX elevates the intracellular H2O2 levels through cascade reactions, which will be beneficial to the Fenton reaction between the Fe2+ and H2O2, to persistently produce hydroxyl radicals (•OH). Thus, MTD efficiently mediates chemodynamic therapy (CDT) and remarkably enhances the sensitivity of chemotherapy. More encouragingly, the cancer cell killing efficiency of MTD is up to ~86% even at the ultralow equivalent concentration of DOX (2.26 µg/mL), while the viability of normal cells remained >88% at the same concentration of MTD. Taken together, MTD is expected to serve as drug-delivery nanoplatforms and •OH nanogenerators for improving chemo/chemodynamic synergistic therapy and reducing the toxic side effects.

Supplementing Soy-Based Diet with Creatine in Rats: Implications for Cardiac Cell Signaling and Response to Doxorubicin

Nutritional habits can have a significant impact on cardiovascular health and disease. This may also apply to cardiotoxicity caused as a frequent side effect of chemotherapeutic drugs, such as doxorubicin (DXR). The aim of this work was to analyze if diet, in particular creatine (Cr) supplementation, can modulate cardiac biochemical (energy status, oxidative damage and antioxidant capacity, DNA integrity, cell signaling) and functional parameters at baseline and upon DXR treatment. Here, male Wistar rats were fed for 4 weeks with either standard rodent diet (NORMAL), soy-based diet (SOY), or Cr-supplemented soy-based diet (SOY + Cr). Hearts were either freeze-clamped in situ or following ex vivo Langendorff perfusion without or with 25 μM DXR and after recording cardiac function. The diets had distinct cardiac effects. Soy-based diet (SOY vs. NORMAL) did not alter cardiac performance but increased phosphorylation of acetyl-CoA carboxylase (ACC), indicating activation of rather pro-catabolic AMP-activated protein kinase (AMPK) signaling, consistent with increased ADP/ATP ratios and lower lipid peroxidation. Creatine addition to the soy-based diet (SOY + Cr vs. SOY) slightly increased left ventricular developed pressure (LVDP) and contractility dp/dt, as measured at baseline in perfused heart, and resulted in activation of the rather pro-anabolic protein kinases Akt and ERK. Challenging perfused heart with DXR, as analyzed across all nutritional regimens, deteriorated most cardiac functional parameters and also altered activation of the AMPK, ERK, and Akt signaling pathways. Despite partial reprogramming of cell signaling and metabolism in the rat heart, diet did not modify the functional response to supraclinical DXR concentrations in the used acute cardiotoxicity model. However, the long-term effect of these diets on cardiac sensitivity to chronic and clinically relevant DXR doses remains to be established.

Drug Combinations: A New Strategy to Extend Drug Repurposing and Epithelial-Mesenchymal Transition in Breast and Colon Cancer Cells.

Despite the progressive research and recent advances in drug therapy to treat solid tumours, the number of cases and deaths in patients with cancer is still a major health problem. Drug repurposing coupled to drug combination strategies has been gaining interest among the scientific community. Recently, our group proposed novel drug combinations for breast and colon cancer using repurposed drugs from different classes (antimalarial and central nervous system (CNS)) and chemotherapeutic agents such as 5-fluorouracil (5-FU), paclitaxel (PTX), and found promising results. Here, we proposed a novel drug combination using different CNS drugs and doxorubicin (DOX), an antineoplastic used in breast cancer therapy, and studied their anticancer potential in MCF-7 breast cancer cells. Cells were treated with each drug alone and combined with increasing concentrations of DOX and cell viability was evaluated by MTT and SRB assays. Studies were also complemented with morphological evaluation. Assessment of drug interaction was performed using the CompuSyn and SynergyFinder software. We also compiled our previously studied drug pairs and selected the most promising ones for evaluation of the expression of EMT biomarkers (E-cadherin, P-cadherin, vimentin, and β-catenin) by immunohistochemistry (IHC) to assess if these drug combinations affect the expression of these proteins and eventually revert EMT. These results demonstrate that combination of DOX plus fluoxetine, benztropine, and thioridazine at their IC50 can improve the anticancer effect of DOX but to a lesser degree than when combined with PTX (previous results), resulting in most of the drug interactions being antagonist or additive. This suggests that the choice of the antineoplastic drug influences the success of the drug combination. Collectively, these results also allow us to conclude that antimalarial drugs as repurposed drugs have enhanced effects in MCF-7 breast cancer cells, while combination with CNS drugs seems to be more effective in HT-29 colon cancer cells. The IHC results demonstrate that combination treatments increase E-cadherin expression while reducing P-cadherin, vimentin, and β-catenin, suggesting that these treatments could induce EMT reversal. Taken together, these results could provide promising approaches to the design of novel drug combinations to treat breast and colon cancer patients.

Synthesis and characterization of a novel multi-functionalized reduced graphene oxide as a pH-sensitive drug delivery material and a photothermal candidate

In this work, we describe a simple and effective method for the synthesis of a novel multi-functionalized reduced graphene oxide (rGO/DA/Au NPs/DOX) through the successive reaction of graphene oxide (GO) with dopamine (DA), HAuCl4/NaBH4 and doxorubicin (DOX) under mild conditions. The rGO/DA/Au NPs/DOX hybrid nanomaterial was characterized by Fourier-transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), energy dispersive X-ray (EDS), X-ray diffraction (XRD), Raman spectroscopy, transmission electron microscopy (TEM), atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), UV–visible absorption analyses, dispersion stability, zeta potential and dynamic light scattering (DLS) analysis. A good dispersion stability of rGO/DA/Au NPs/DOX material was observed with an average size of about 75 nm. The DOX loading capacity of rGO/DA/Au NPs was determined to be 0.852 mg/mg at an initial DOX concentration of 0.171 mg/mL. Then, the rGO/DA/Au NPs/DOX was explored for DOX release under various pH values of 9.4, 7.4 and 5.4. It was found that the rate of DOX release from the rGO/DA/Au NPs/DOX hybrid nanomaterial was pH-dependent with a DOX release of 67% under acidic (pH = 5.4) conditions. Due to the different DOX release rates under different pH values, the multi-functionalized rGO can be used as a suitable candidate material for intelligent drug release. The photothermal properties of rGO/DA/Au NPs/DOX hybrid nanomaterial were assessed under simulated solar sun irradiation. A rapid increase of the temperature was recorded upon irradiation, suggesting that rGO/DA/Au NPs/DOX hybrid material has good potential as a new photothermal agent.