Mesoporous silica coated SPIONs containing curcumin and silymarin intended for breast cancer therapy.

INTRODUCTION: Super-paramagnetic iron oxide nanoparticles (SPIONs) are known as promising theranostic nano-drug carriers with magnetic resonance imaging (MRI) properties. Applying the herbaceous components with cytotoxic effects as cargos can suggest a new approach in the field of cancer-therapy. In this study mesoporous silica coated SPIONs (mSiO2@SPIONs) containing curcumin (CUR) and silymarin (SIL) were prepared and evaluated on breast cancer cell line, MCF-7. METHODS: Nanoparticles (NPs) were formulated by reverse microemulsion method and characterized by DLS, SEM and VSM. The in vitro drug release, cellular cytotoxicity, and MRI properties of NPs were determined as well. The cellular uptake of NPs by MCF-7 cells was investigated through LysoTracker Red staining using confocal microscopy. RESULTS: The MTT results showed that the IC50 of CUR + SIL loaded mSiO2@SPIONs was reduced about 50% in comparison with that of the free drug mixture. The NPs indicated proper MRI features and cellular uptake through endocytosis. CONCLUSION: In conclusion the prepared formulation may offer a novel theranostic system for breast cancer researches.

Effects of Ellagic Acid on Oxidative Stress Index, Inflammatory Markers and Quality of Life in Patients With Irritable Bowel Syndrome: Randomized Double-blind Clinical Trial.

Irritable bowel syndrome (IBS) is a common disorder that affects the large intestine. Oxidative stress and inflammation play a major role in IBS. Considering the antioxidant properties of ellagic acid (EA), this study was designed to evaluate the effect of EA on oxidative stress index, inflammatory markers, and quality of life in patients with IBS. This research was conducted as a randomized, double-blind, placebo-controlled clinical trial; 44 patients with IBS were recruited. Patients who met the inclusion criteria were randomly allocated to consume a capsule containing 180 mg of EA per day (n = 22) or a placebo (n = 22) for 8 weeks. Serum levels of total antioxidant capacity (TAC), malondialdehyde (MDA), C-reactive protein (CRP), and interleukin-6 (IL-6) were measured at the beginning and the end of the study. Also, quality of life was assessed using a self-report questionnaire for IBS patients (IBS-QOL). At the end of the study, we saw a significant decrease and increase in the MDA and TAC in the intervention group, respectively (p < 0.05). Also, EA consumption reduced CRP and IL-6 levels, and these changes were significant in comparison with placebo group changes (p < 0.05). The overall score of IBS-QOL significantly decreased, and quality of life was increased (p < 0.05), but there were no significant changes in the placebo group. According to these findings, receiving polyphenols, such as EA, may help maintain intestinal health by modulating inflammation and oxidative stress and ultimately improving the quality of life in IBS patients. Trial Registration: Iranian Registry of Clinical Trials Identifier: IRCT20141025019669N11.

Improving Effect of Ellagic Acid on Sleep Quality and Gastrointestinal Symptoms in Patient With Irritable Bowel Syndrome: Randomized Double-Blind Clinical Trial.

BACKGROUND: The quality of sleep in people with irritable bowel syndrome (IBS) is reduced by increased oxidative stress and clinical problems. Assessing the effects of ellagic acid (EA) on sleep quality and gastrointestinal symptoms in patients with IBS was the aim of this study. METHODS: In this research that was conducted as a randomized, double-blind, placebo-controlled clinical trial, 44 patients with IBS were enlisted. Individuals approved by the project clinical counselor were divided into two intervention groups to receive 180 mg of EA per day (n = 22) and a placebo group (n = 22) for 2 months. Petersburg's Sleep Quality (PSQI) questionnaire and IBS severity score system (IBSSS) were assessed at the beginning and end of the study. Statistical analysis was performed using SPSS software. RESULTS: At the end of the study, changes in mean PSQI and scores related to sleep subgroups were significant between the two groups (P < .05). Also, the significant changes were not seen in sleep and sleep subgroups scores in the placebo group at the end of the study (P > .05). EA consumption reduced IBSSS score and IBS symptoms in the intervention group after 2 months (P < .05). DISCUSSION: The results arisen from this study indicated that receiving EA had a beneficial effect on sleep quality and gastrointestinal symptoms in IBS patients. The antioxidant and anti-inflammatory properties of EA may be responsible for these beneficial effects.

The Drug Release Kinetics and Anticancer Activity of the GO/PVA-Curcumin Nanostructures: The Effects of the Preparation Method and the GO Amount.

The Graphene Oxide (GO) incorporated polyvinyl alcohol/sodium alginate (PVA-SA) composites with curcumin were prepared by the solvent casting and electro-spinning techniques. The GO was incorporated into PVA-SA nano-fiber and film matrixes, and the performance of these nano-composites as drug carriers was investigated. The effects of production method (film or mat) and GO amount on the water absorption properties and delivery of curcumin behaviors were investigated. The swelling and releasing were studied at the specific interval times in deionized water and phosphate buffer solution (pH = 7.4), respectively. The release kinetics was evaluated to find a suitable mechanism of the release. Finally, the anticancer activity of composite nano-fibers on the cancer cells was investigated. The XRD and FTIR analyses confirmed nanocomposites structures, and the successful incorporation was shown by scanning electron microscopy (SEM). The results showed that addition of the GO to PVA/SA decreased swelling ratio of the films (up to 31%) and increased the swelling ratio of the mats (up to 37.5%). However, for both film and mat, increasing of the GO amount reduced the curcumin release. Drug release decreasing up to 22.5% was observed for film, while a very high release decreasing up to about 70% was seen for mat. Also, both film and mat structures showed significant anti-cancer activity on MCF-7 cells. The lower cell viability was about 40 and 30% for film and mat, respectively. The kinetics evaluations suggested a Korsmeyer-Peppas model and Fickian controlled drug release.

Design and fabrication of dual-targeted delivery system based on gemcitabine-conjugated human serum albumin nanoparticles.

Dual-targeted drug delivery system has established their reputation as potent vehicles for cancer chemotherapies. Herein, gemcitabine (Gem) was conjugated to human serum albumin (HSA) via dithiodipropionic anhydride to fabricate Gem-HSA nanoparticles. It was hypothesized that this system can enhance the low stability of Gem and can improve its intracellular delivery. Furthermore, folate was applied as targeting agent on HSA nanoparticles for increasing the tumor selectivity of Gem. To evaluate the structural properties of synthesized products, 1 H NMR and FT-IR were performed. Moreover, HPLC was implemented for confirming the conjugation between HSA and Gem. Nanoparticles have shown spherical shape with negative charge. The release rate of Gem was dependent to the concentration of glutathione and pH. Folate-targeted HSA nanoparticles have shown higher cytotoxicity, cellular uptake, and apoptosis induction on folate receptor overexpressing MDA-MB-231 cells in comparison to non-targeted nanoparticles. Finally, it is considered that the developed dual-targeted nanoparticles would be potent in improving the stability and efficacy of intracellular delivery of Gem and its selective delivery to cancer cells.

Pegylated magnetic mesoporous silica nanoparticles decorated with AS1411 Aptamer as a targeting delivery system for cytotoxic agents.

Fulfilling the purpose of developing a NP with theragnostic capabilities, the current study describes the synthesis of an aptamer-functionalized PEG-coated SPION/mesoporous silica core-shell nanoparticle for concurrent cancer targeted therapy and magnetic resonance imaging. SPIONs were synthesized according to a thermal decomposition method and served as cores for SPION/mesoporous silica core/shell nanoparticles (MMSNs). Doxorubicin was then successfully loaded in MMSNs which were then coated with di-carboxylic acid functionalized polyethylene glycol (PEG-MMSNs). AS1411 aptamers were at the end covalently attached to NPs (APT-PEG-MMSNs). The mean diameter of synthesized NPs was about 89 nm and doxorubicin encapsulation efficacy was ≈67.47%. Results of MTT based cell cytotoxicity assay demonstrated a significantly higher toxicity profile for APT-PEG-MMSNs against MCF7 cells compared to non-decorated MMSNs, while no significant differences were spotted against NIH-3T3 cells. Meanwhile, formation of protein corona around APT-PEG-MMSNs in biological medium significantly attenuated observed cytotoxicity against MCF7 cell line. Examining NPs uptake by MCF7 cells using confocal laser scanning microscopy also confirmed superiority of APT-PEG-MMSNs over PEG-MMSNs. Finally, APT decorated NPs induced highest signal intensity reduction in T2-weighted images during in vitro MRI assay. In conclusion, developed NPs may serve as promising multifunctional vehicles for simultaneous cancer targeted therapy and MRI imaging.

Formulation and in vitro evaluation of curcumin-lactoferrin conjugated nanostructures for cancerous cells.

Curcumin, a natural polyphenol, exhibits anti-oxidant, anti-inflammatory, anti-neoplastic and chemopreventive properties. In fact, targeting of this natural anticancer agent has received a great deal of attention during the recent years. In this study, we proposed that curcumin conjugation with lactoferrin molecules may lead to a potential drug delivery system targeted toward cancerous cells through both active and passive targeting. In this regard, curcumin conjugated lactoferrin was developed via a carbodiimide-based coupling reaction and the resulting conjugates were appraised for their molecular properties as a potential targeted drug delivery system. The mean diameter of the designed nanostructure was about 165 ± 26 nm with a PDI of 0.308 ± 0.045. The conjugated nanostructures showed a considerably improved cytotoxicity on HCT116 cells as illustrated by MTT assay along with a higher level of cellular uptake. Cellular uptake and targeting capability of conjugated samples were further investigated by confocal microscopy and the conjugated curcumin nanostructures showed an enhanced efficacy compared to curcumin. Furthermore, flow cytometry analysis proved that early apoptosis occurred in HCT116 cell line, after 24 h incubation with conjugated curcumin.

Formulation and evaluation of targeted nanoparticles for breast cancer theranostic system.

Theranostic polymeric NPs developed for both cancer diagnosis and cancer therapy. This multifunctional polymeric vehicle was prepared by a single emulsion evaporation method, using carboxyl-terminated PLGA. LHRH as a targeting moiety, was conjugated to the surface of polymeric carrier by applying polyethylene glycol. The results indicated that the diameter of NPs was ~185.4±4.6nm as defined by DLS. The entrapment efficacy of docetaxel, silibinin, and SPIONs was 84.6±4.1%, 80.6±2.7%, and 77.9±4.3%, respectively. The NPs showed a triphasic in-vitro drug release pattern. MTT assay was done on two cell lines, MCF-7 and SKOV-3. Enhanced cellular uptake ability of the targeted NPs to MCF-7 was evaluated in-vitro by confocal laser scanning microscopy. The results indicated that compared to non-targeted NPs, the LHRH targeted NPs had significant efficacy at IC50 concentration. The effect of the NPs on VEGF expression in MCF-7 and SKOV-3 cells was investigated by Real-Time PCR method. VEGF mRNA level expression in MCF-7 cell line reduced by 83% in comparison to control cell line. The designed NPs can be used as promising multifunctional platform for detection and targeted drug delivery in breast cancer.

Docetaxel-Chitosan nanoparticles for breast cancer treatment: cell viability and gene expression study.

Docetaxel acts through the inhibition of tubulin polymerization and reduction in the expression of BCL-2 gene. In this study, nanoparticles containing Docetaxel were prepared and their effects on the gene expression levels of BCL-2 and BAX genes were investigated. The drug was first conjugated to chitosan, and the nanoparticles were assembled in the presence of hyaluronic acid. Conjugations were confirmed by 1 H-NMR, and the obtained nanoparticles were characterized by dynamic light scattering and SEM. Cytotoxicity of the nanoparticles, cellular uptake, and cell death were evaluated. Finally, the effect of nanoparticles on the expression of BAX and BCL-2 genes in MCF-7 cells were investigated through real-time PCR. The results revealed that the prepared NPs had spherical shape with narrow size distribution of <200 nm with positive zeta potentials. In vitro cytotoxicity of Cs nanoparticles and free Docetaxel investigations revealed that increasing the treatment time with nanoparticles led to decrease in the rate of cell viability. BAX and BCL-2 gene expressions were decreased in nanoparticle-treated cells in comparison with intact cells, while the BAX/BCL-2 ratio was significantly elevated compared with free drug-treated cells after 72 h. Docetaxel-conjugated NPs may offer a promising treatment with low off-target toxicity for breast cancer.

Fabrication and biological evaluation of chitosan coated hyaluronic acid-docetaxel conjugate nanoparticles in CD44(+) cancer cells.

BACKGROUND: Hyaluronic acid (HA) has been used for target-specific drug delivery because of strong affinity to CD44, a marker in which overexpressed in cancer cells and cancer stem cells. Conjugation of HA to the cytotoxic agents via active targeting can improve efficacy, biodistribution, and water solubility. To be able to benefit from passive targeting as well, a nanoparticulate system by counter ion using a polycation like chitosan may lead to a perfect delivery system. METHODS: Water soluble Hyaluronic acid-Docetaxel (HA-DTX) conjugate was prepared and used to formulate chitosan-coated HA-DTX nanoparticles by polyelectrolyte complex (PEC) method and optimized using Box-Behnken design. Biological evaluation of nanoparticles was done in CD44+ cancer cells. RESULTS AND DISCUSSION: Biological evaluation of optimized formula showed IC50 of nanoparticles for 4 T1 and MCF-7 cell lines were 45.34 µM and 354.25 µM against 233.8 µM and 625.9 µM for DTX, respectively with increased cellular uptake showed by inverted confocal microscope. CONCLUSION: Chitosan-coated HA-DTX nanoparticles were more effective against CD44+ cells than free DTX. Chitosan coated hyaluronic acid-docetaxel conjugate nanoparticles fabricated and evaluated in CD44+ cancer cells.

Protein corona hampers targeting potential of MUC1 aptamer functionalized SN-38 core-shell nanoparticles.

Nanoparticles have been considered to improve delivery and physicochemical characteristics of bioactive agents in recent years. In this study, a core-shell chitosan nanoparticulate system was prepared for the targeted delivery of SN-38. SN-38, an active metabolite of camptothecin, conjugated to hyaluronic acid (HA) was used as the shell of chitosan nanoparticles decorated with MUC1 aptamer. The conjugation was confirmed by UV and (1)H NMR techniques. Targeting efficiency was evaluated by confocal microscopy and flow cytometry. It was shown that MUC1 decoration increased the uptake of nanoparticles by HT29 cells, MUC1 positive cell line, while CHO as MUC1 negative cell line showed no enhanced uptake of decorated nanoparticles. Compared to non-targeted nanoparticles, flow cytometric annexin V/PI analyses showed that the nanoparticles exert cytotoxicity through apoptosis. It was, however, shown that protein corona adsorption at the surface of nanoparticles hampered the cytotoxicity of nanoparticles, as there was no difference between the cytotoxicity of targeted and non-targeted nanoparticles, when treated with bovine serum albumin prior to cytotoxicity study.