Micellar Curcumin Research Articles

Enhancing the effects of curcumin on oxidative stress injury in brain vascular endothelial cells using lactoferrin peptide nano-micelles: antioxidant activity and mechanism.

Curcumin is widely known for its antioxidant and anti-inflammatory properties, but its mechanism of action in mitigating oxidative stress injury in brain vascular endothelial cells remains unclear. Due to the poor bioavailability of curcumin, it is challenging to achieve effective concentrations at the target sites. Nano-micelles are known for their ability to improve the solubility, stability, and bioavailability of hydrophobic compounds like curcumin. This study investigated the effects and mechanisms of free curcumin and curcumin embedded in nano-micelles (M(Cur)) on oxidative stress-induced injury in bEnd.3 cells. At a protective concentration of 10 μg mL-1, micellar curcumin was better able to recover the morphology of bEnd.3 cells under oxidative stress while increasing cell viability, restoring mitochondrial membrane electrical potential, and effectively inhibiting reactive oxygen species generation with a positive cell rate of 2.21%. These results indicate that curcumin significantly improves H2O2-induced oxidative stress damage in endothelial cells by maintaining the cellular antioxidant balance. This study adds to knowledge regarding the role of nano-micelles in curcumin intervention for endothelial cell oxidative damage and provides insights for the development of curcumin-based dietary supplements. © 2024 Society of Chemical Industry.

Investigating the Combinational Effect of Micellar Curcumin and Metformin on the Invasion of PC3 Prostate Cancer Cell Line

Introduction: Adverse side effects, non-specific function, and increasing tolerability of tumor cells to chemotherapy demand therapeutic strategies with fewer side effects and better efficacy. Curcumin and metformin have been shown to have anticancer properties, according to emerging research. Therefore, micellar curcumin and metformin were combined and analyzed on cancer cell line PC3. Material and Methods: Cell viability after drug treatment, individually and in combination, was evaluated using an MTT assay. In order to determine the type of interaction between micellar curcumin and metformin, the median-effect method was employed. Subsequently, the expression of MMP-2 and MMP-9 of cells treated with single drugs and a synergistic combination of compounds was assessed using Gelatin Zymography test. Moreover, evaluating the number of invasive cells under treatment with drugs alone and in combination through matrigel invasion assay. Results: The results demonstrated that the cell proliferation treated with micellar curcumin and metformin alone and in combination decreased significantly (P<0.05) during 24 and 48 h. Besides, co-treatment of compounds showed synergy within 48 h. Although all the cells treated, whether with single drugs or the synergistic combination of both, showed a decline in expressing MMP-2, MMP-9, and the number of migrated cells, the maximum reduction was seen when micellar curcumin and metformin were combined. Conclusion: This study showed that metformin and micellar curcumin together have a synergistic effect on cell proliferation inhibition in the PC3 cell line. Metformin and micellar curcumin were more effective as a combination in decreasing the PC3 cell line invasion by reducing MMP-2 and MMP-9.

Green Synthesis and the Evaluation of a Functional Amphiphilic Block Copolymer as a Micellar Curcumin Delivery System.

Polymer micelles represent one of the most attractive drug delivery systems due to their design flexibility based on a variety of macromolecular synthetic methods. The environmentally safe chemistry in which the use or generation of hazardous materials is minimized has an increasing impact on polymer-based drug delivery nanosystems. In this work, a solvent-free green synthetic procedure was applied for the preparation of an amphiphilic diblock copolymer consisting of biodegradable hydrophobic poly(acetylene-functional carbonate) and biocompatible hydrophilic polyethylene glycol (PEG) blocks. The cyclic functional carbonate monomer 5-methyl-5-propargyloxycarbonyl-1,3-dioxane-2-one (MPC) was polymerized in bulk using methoxy PEG-5K as a macroinitiator by applying the metal-free organocatalyzed controlled ring-opening polymerization at a relatively low temperature of 60 °C. The functional amphiphilic block copolymer self-associated in aqueous media into stable micelles with an average diameter of 44 nm. The copolymer micelles were physico-chemically characterized and loaded with the plant-derived anticancer drug curcumin. Preliminary in vitro evaluations indicate that the functional copolymer micelles are non-toxic and promising candidates for further investigation as nanocarriers for biomedical applications.

Micellar Curcumin Substantially Increases the Antineoplastic Activity of the Alkylphosphocholine Erufosine against TWIST1 Positive Cutaneous T Cell Lymphoma Cell Lines.

Cutaneous T-cell lymphoma (CTCL) is a rare form of cancer with local as well as systemic manifestations. Concomitant bacterial infections increase morbidity and mortality rates due to impaired skin barrier and immune deficiency. In the current study, we demonstrated that the in vitro anti-lymphoma potential of erufosine is diminished by TWIST1 expression and micellar curcumin substantially increases its antineoplastic activity. Pharmacokinetic analysis showed that the micellar curcumin (MCRM) used in our study was characterized by low zeta potential, slow release of curcumin, and fast cell membrane penetration. The combination ratio 1:4 [erufosine:MCRM] achieved strong synergism by inhibiting cell proliferation and clonogenicity. The combined antiproliferative effects were calculated using the symbolic mathematical software MAPLE 15. The synergistic combination strongly decreased the expression of TWIST1 and protein kinase B/Akt as proven by western blotting. Significant reductions in NF-κB activation, induction of apoptosis, and altered glutathione levels were demonstrated by corresponding assays. In addition, the synergistic combination enhanced the anti-staphylococcal activity and prevented biofilm formation, as shown by crystal violet staining. Taken together, the above results show that the development of nanotechnological treatment modalities for CTCL, based on rational drug combinations exhibiting parallel antineoplastic and antibacterial effects, may prove efficacious.

Uptake and time-dependent subcellular localization of native and micellar curcumin in intestinal cells.

Uptake into intestinal cells and intracellular distribution into metabolically competent organelles, such as the endoplasmic reticulum, are important processes potentially limiting the bioavailability of xenobiotics. The incorporation of curcumin into polysorbate 80 micelles improves its naturally low oral bioavailability in humans. Here, we investigated uptake and time-dependent localization of curcumin in intestinal cells when administered as native or micellar formulation. Differentiated Caco-2 cells were incubated with 200 μmol/L native or micellar curcumin for up to 180 min and cellular uptake was quantified. Intracellular curcumin was detected already after 30 min and did not differ significantly between formulations or over time. Subcellular localization of native and micellar curcumin in Caco-2 cells was studied by density gradient centrifugation. After 30 min, curcumin from both formulations was mainly associated with mitochondria and lysosomes, after 180 min native curcumin was associated with mitochondria and peroxisomes, micellar curcumin with peroxisomes only. Uptake and localization of native and micellar curcumin in intestinal cells do not differ significantly and consequently do not explain differences in bioavailability in humans. The temporary co-localization with lysosomes is in agreement with the previously proposed role of endocytosis in cellular uptake of curcumin and warrants further investigation.

Increasing Post-Digestive Solubility of Curcumin Is the Most Successful Strategy to Improve its Oral Bioavailability: A Randomized Cross-Over Trial in Healthy Adults and In Vitro Bioaccessibility Experiments.

Different mechanistic approaches to improve the low oral bioavailability of curcumin have been developed, but not yet directly compared in humans. In a randomized, double-blind, cross-over trial with 12 healthy adults, the 24 h pharmacokinetics of a single dose of 207mg curcumin is compared from the following formulations: native, liposomes, with turmeric oils, with adjuvants (including piperine), submicron-particles, phytosomes, γ-cyclodextrin complexes, and micelles. No free, but only conjugated curcumin is detected in all subjects. Compared to native curcumin, a significant increase in the area under the plasma concentration-time curve is observed for micellar curcumin (57-fold) and the curcumin-γ-cyclodextrin complex (30-fold) only. In vitro digestive stability, solubility, and micellization efficiency of micellar curcumin (100%, 80%, and 55%) and curcumin-γ-cyclodextrin complex (73%, 33%, and 23%) are higher compared to all other formulations (<72%, <8%, and <4%). The transport efficiencies through Caco-2 cell monolayers of curcumin from the digested mixed-micellar fractions did not differ significantly. The improved oral bioavailability of micellar curcumin, and to a lesser extent of γ-cyclodextrin curcumin complexes, appears to be facilitated by increased post-digestive stability and solubility, whereas strategies targeting post-absorptive processes, including inhibition of biotransformation, appear ineffective.

Intranasal micellar curcumin for the treatment of chronic asthma

Curcumin is a natural phytoconstituent obtained from the rhizomes of Curcuma longa (turmeric) and is known for its diverse anti-oxidant and anti-inflammatory benefits, but its clinical utility is limited by its poor aqueous solubility and rapid metabolism, which ultimately affects its bioavailability. The present study is focused on the formulation of curcumin loaded micellar dispersion for intranasal delivery for the treatment of chronic asthma. Micellar dispersion was prepared by film formation method using poly-(ethylene oxide)-block-distearoyl phosphatidyl-ethanolamine (mPEG5000-DSPE) as lipid surfactant and characterized for its physic-chemical properties. The curcumin micelles were evaluated for their anti-asthmatic action in ovalbumin (OVA)-induced allergic asthma model in male wistar rats against standard drug dexamethasone. The micelles showed mean particle size in the range of 20.03 nm–26.48 nm. The micellar dispersion exhibited negative zeta potential in the range of −26.22 to −25.52 mV. Incorporation of curcumin into micelles helped in enhancing the solubility of curcumin besides providing it protection against degradation. In vitro studies showed sustained relase of curcumin up to 36 h. A 14- fold increase in the bioaviability of the curcumin was measured when administered as micelles. In addition, 4.4- fold higher concentration of drug was measured in the lungs for micellar curcumin. Comparable reduction in the levels of intracellular ROS was observed for i.n. curcumin-micelles (approx.57.6%) and dexamethasone (59.3%). Also, micellar curcumin produced significant supression (p < 0.05) in the release of nitric oxide. Through the present study, we can suggest the potential application of curcumin micelles in the treatment of asthma.

Cytotoxic, Genotoxic and Senolytic Potential of Native and Micellar Curcumin

Background: Curcumin, a natural polyphenol and the principal bioactive compound in Curcuma longa, was reported to have anti-inflammatory, anti-cancer, anti-diabetic and anti-rheumatic activity. Curcumin is not only considered for preventive, but also for therapeutic, purposes in cancer therapy, which requires a killing effect on cancer cells. A drawback, however, is the low bioavailability of curcumin due to its insolubility in water. To circumvent this limitation, curcumin was administered in different water-soluble formulations, including liposomes or embedded into nanoscaled micelles. The high uptake rate of micellar curcumin makes it attractive also for cancer therapeutic strategies. Native curcumin solubilised in organic solvent was previously shown to be cytotoxic and bears a genotoxic potential. Corresponding studies with micellar curcumin are lacking. Methods: We compared the cytotoxic and genotoxic activity of native curcumin solubilised in ethanol (Cur-E) with curcumin embedded in micells (Cur-M). We measured cell death by MTT assays, apoptosis, necrosis by flow cytometry, senolysis by MTT and C12FDG and genotoxicity by FPG-alkaline and neutral singe-cell gel electrophoresis (comet assay). Results: Using a variety of primary and established cell lines, we show that Cur-E and Cur-M reduce the viability in all cell types in the same dose range. Cur-E and Cur-M induced dose-dependently apoptosis, but did not exhibit senolytic activity. In the cytotoxic dose range, Cur-E and Cur-M were positive in the alkaline and the neutral comet assay. Genotoxic effects vanished upon removal of curcumin, indicating efficient and complete repair of DNA damage. For inducing cell death, which was measured 48 h after the onset of treatment, permanent exposure was required while 60 min pulse-treatment was ineffective. In all assays, Cur-E and Cur-M were equally active, and the concentration above which significant cytotoxic and genotoxic effects were observed was 10 µM. Micelles not containing curcumin were completely inactive. Conclusions: The data show that micellar curcumin has the same cytotoxicity and genotoxicity profile as native curcumin. The effective concentration on different cell lines, including primary cells, was far above the curcumin concentration that can be achieved systemically in vivo, which leads us to conclude that native curcumin and curcumin administered as food supplement in a micellar formulation at the ADI level are not cytotoxic/genotoxic, indicating a wide margin of safety.

Anti-inflammatory effect of different curcumin preparations on adjuvant-induced arthritis in rats

BackgroundCurcumin, a natural polyphenolic substance, has been known for more than two millennia as having strong anti-inflammatory activity towards multiple ailments, including arthritis. The main drawback of curcumin is its poor solubility in water, which leads to low intestinal absorption and minimal bioavailability. In this study, we aimed to compare the anti-arthritic in vivo effect of different curcumin preparations – basic curcumin extract, micellar curcumin, curcumin mixture with piperine, and microencapsulated curcumin.MethodsArthritis was induced in Wistar rats by complete Freund’s adjuvant, and the severity of arthritis was evaluated daily using the arthritis score system. Curcumin preparations were given to animals per os daily for 20 consecutive days, starting at 6th day after arthritis induction. To determine the inflammatory background, pro-inflammatory cytokines were determined using the ELISA test. In addition, hematologic test, weight change, and limb swelling were tracked.ResultsOur results indicate that curcumin had a rather weak effect on arthritis progression in the Wistar rat model, microencapsulated curcumin effectively prevented the progression of arthritis – the disease stabilized after 10 days of supplementation. It also reduced the levels of immune cells (neutrophils and leukocytes), as well as pro-inflammatory cytokines – TNFα, IL-1, and IL-6, which levels were close to arthritis-free control. Other formulations of curcumin had lower or no effect on arthritis progression.ConclusionOur study shows that the same concentrations of curcumin had a distinctly expressed positive anti-inflammatory effect depending on the form of its delivery. Specifically, we found that microencapsulated curcumin had the most promising effect for treatment.Graphical abstract

Antineoplastic effect of a novel nanosized curcumin on cutaneous T cell lymphoma.

Cutaneous T cell lymphomas (CTCLs) are a group of heterogeneous, life-threatening, extra-nodal and lymphoproliferative T cell neoplasms. Since chronic inflammation serves a key role in CTCL progression, curcumin, a natural pigment with proven anti-inflammatory and antineoplastic properties, as well as minimal toxicity, may be used as a therapeutic agent. In the present study, two formulations of curcumin (standard ethanolic and a Pluronic®P-123/F-127 micellar solution) were compared regarding their cytotoxic efficacy and speed of internalization in three CTCL cell lines, namely HuT-78, HH and MJ. In addition, the modulating effect of curcumin on selected proteins involved in the proliferation and progression of the disease was determined. The results indicated the superiority of the Pluronic®P-123/F-127 micellar curcumin over the standard ethanol solution in terms of cellular internalization efficiency as determined by spectrophotometric analysis. Notably, the presence of commonly used media components, such as phenol red, may interfere when interpreting the cytotoxicity of curcumin, due to their overlapping absorbance peaks. Therefore, it was concluded that phenol red-free media are superior over media with phenol red in order to correctly measure the cytotoxic efficacy and cell penetration of curcumin. Depending on the cell line, the IC50 values of micellar curcumin varied from 29.76 to 1.24 µΜ, with HH cells demonstrating the highest sensitivity. This cell line had the lowest expression levels of the Wilms' tumor-1 transcription factor. Performing western blot analyses of treated and untreated CTCL cells, selective signal transduction changes were recorded for the first time, thus making curcumin nano-formulation an attractive and prospective option with therapeutic relevance for CTCL as a rare orphan disease.

Characteristics and antitumor activity of polysorbate 80 curcumin micelles preparation by cloud point cooling

Curcumin is a natural bioactive compound with known potential for cancer treatment and prevention. However, a major barrier for clinical application is its poor solubility and bioavailability. Nanotechnology is an effective approach to enhance the bioavailability of insoluble drugs. We explored a novel way to prepare micellar curcumin in the common food additive, polysorbate 80, by utilizing the process of micelle formation that occurs during slow cooling below its cloud point. Curcumin molecules were thus dissolved and encapsulated. Micellar curcumin was stable during storage and was more tolerant to harsh pH conditions than free curcumin. The ~20 nm-sized nanocurcumin micelles showed improved antitumor effect than free curcumin in SUM149 human breast cancer xenografts in mice. This new method overcame the difficulty of dissolving curcumin in aqueous solution of polysorbate 80, and may find application in the production of other functional nutraceuticals.

Structural and therapeutic properties of curcumin solubilized pluronic F127 micellar solutions and hydrogels

Curcumin, the principle active constituent of turmeric, is known to have broad range of therapeutic properties. Its poor aqueous solubility and low bioavailability however, act as constraints for its biomedical applications. Recent studies have shown that incorporation of curcumin in nano-carriers like micelles, vesicles, polymeric nanoparticles etc. can help in overcoming these issues and improve its therapeutic abilities quite significantly. In this manuscript, we report preparation of curcumin solubilized pluronic F127 micellar solutions and hydrogels, along with their structural and therapeutic properties as obtained from SANS, rheological, anti-cancer and wound healing studies. Pluronic F127 being approved by FDA has been used quite extensively as excipient for drug delivery applications. Curcumin solubilization in the aqueous pluronic F127 system was carried out by briefly heating the copolymer solutions with curcumin at 90 °C. The concentrations of curcumin thus obtained were found to be comparable to those obtained by conventional methods of solubilization like thin film hydration or solvent evaporation method, and three orders of magnitude higher than that in pure water. SANS and rheological studies show that curcumin solubilization does not bring about any significant change in the structural and rheological properties of F127 micellar solutions and hydrogels. Curcumin solubilized F127 micellar solutions can be reconstituted after lyophilization, suggesting that curcumin remains nano-dispersed in lyophilized state. Micellar encapsulated curcumin exhibits very good stability in solution state in ambient condition but fails to show cytotoxicity against MCF7 cancer cells, presumably due to shielding of curcumin by large corona region of F127 micelles. Micellar curcumin containing F127 hydrogels on the other hand, exhibit wound healing abilities in mice model upon topical application. The results give an account of how some of the therapeutic properties of curcumin are manifested under micellar encapsulation and the role of pluronic F127 as excipient in those therapeutic applications.

Curcumin Administered as Micellar Solution Suppresses Intestinal Inflammation and Colorectal Carcinogenesis

Colorectal cancer (CRC) is one of the most common cancers and preventive strategies based on natural compounds are highly desirable. Curcumin, the principal bioactive compound in Curcuma longa, was described to have multiple beneficial health effects. A drawback, however, is the low bioavailability due to its insolubility in water. Here, we studied whether nanoscaled micellar curcumin with improved bioavailability administered in drinking water reduces inflammation and CRC formation in a mouse model. C57BL6 wild-type (WT) mice and a strain defective in the DNA repair enzyme O6 -methylguanine-DNA methyltransferase (MGMT) were used, in which tumors were induced by azoxymethane (AOM) followed by dextran sodium sulfate (DSS). Inflammation and tumor formation were determined by mini-colonoscopy. Micellar curcumin (mCur) administered in drinking water significantly reduced AOM/DSS-induced colorectal inflammation in both WT and MGMT-deficient mice as compared to animals receiving drinking water with micelles not containing curcumin. In line with this, the tumor yield and tumor score were significantly lower in mCur-treated mice compared to the control group. No adverse effects were observed in animals receiving mCur daily for at least three months. Overall, our data show that chronic oral administered micellar curcumin is well tolerated and reduces chemical-induced gut inflammation and CRC formation in mice. Impact: The study shows that micellar curcumin with high bioavailability chronically administered at low and physiologically relevant concentration suppresses inflammation and carcinogenesis in a mouse colorectal tumor model.

Micellar curcumin improves the antibacterial activity of the alkylphosphocholines erufosine and miltefosine against pathogenic Staphyloccocus aureus strains

In the light of the emerging bacterial resistance to broad-spectrum antibiotics, the search for new antibacterial therapeutics and drug combinations is one of the most challenging topics nowadays. In the present study, we investigated for the first time the antibacterial and biofilm inhibitory effects of the third generation anticancer alkylphosphocholine (APC) erufosine against pathogenic Staphylococcus aureus strains in comparison to the prototype of this pharmacological class of drugs, miltefosine. We also searched for synergistic antibacterial combinations between both APCs and curcumin incorporated in copolymeric micelles based on Pluronic® P123 or a mixture of Pluronic® P123 and Pluronic® F127 (P123/F127). The obtained quantitative redox-activity experimental data and drug–drug interactions were evaluated by using mathematical models in the MAPLE software. Similar to miltefosine, erufosine showed a moderate bacteriostatic effect in clinically relevant concentrations (50 ÷ 60 µmol/L) and inhibited the redox activity of the treated bacteria up to 90% at minimal inhibitory concentrations. The effect of both APCs towards methicillin resistant staphylococci was enhanced by combinations with P123/F127 micellar CRM at a ratio of 1:1. Erufosine showed a stronger median biofilm inhibition at lower concentrations (MBIC50 = 1.87 µmol/L) than miltefosine (MBIC50 = 6.0 µmol/L) and curcumin (MBIC50 = 24.84 µmol/L) as demonstrated by quantification of biofilm-bound bacteria. In conclusion, the estimated antibacterial activity of erufosine widens the spectrum of its useful pharmacological effects, which is important for its clinical development. The established synergistic and additive drug combinations could be beneficial for the application of both APCs in cancer therapy, since numerous malignancies are accompanied by bacterial infections.

Micellar solubilisation enhances the antiinflammatory activities of curcumin and boswellic acids in rats with adjuvant-induced arthritis.

Native extracts of curcumin and boswellia are known to exert antiinflammatory properties but have poor bioavailability when given orally. Using advanced micellation technology, it has been possible to produce stable solubilisates of these extracts with markedly enhanced bioavailability. In the present study, we compared the chronic antiinflammatory activities of native and micellar curcumin in the rat adjuvant arthritis model, using diclofenac as a reference drug. Adjuvant arthritis was induced by injecting Freund's complete adjuvant (FCA) into the right hind paw of rats and monitoring paw volume over 3 wk. The drugs were given daily for 3 wk, starting from the day of adjuvant inoculation. The serum was collected at end of the experiment for the assay of inflammatory and oxidative stress parameters. Statistical comparisons between different groups were carried out by one-way analysis of variance followed by Tukey-Kramer multiple comparison test. Solubilized curcumin showed better antiinflammatory activity than its native form. The reduction in paw volume was reflected in corresponding changes in relevant mediators of inflammation like tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), myeloperoxidase (MPO), and lipid peroxidation markers. The combination of curcumin and boswellia solubilisates synergistically produced an even more potent therapeutic effect. The findings confirm that micellar solubilisation of curcumin and boswellia not only increases their bioavailability, but also enhances their biological activity. Micellar curcumin, in particular in combination with micellar boswellia, may thus represent a promising concomitant tool for antiinflammatory treatment and a potential antiinflammatory alternative to synthetic drugs.

Photochemical inhibition of Trichophyton rubrum by different compoundings of curcumin.

Recently, we had shown that conidia-derived growth of many dermatophytes can be inhibited by curcumin plus exposure to visible light. This method of photo inactivation should be developed further aiming for an option to stop mycelial growth in superficial tinea. Wells of microtitre plates were inoculated with either mycelial or conidial elements collected from 5 strains of Trichophyton rubrum. Then either micellar curcumin or curcumin dissolved with DMSO was added and after 20min the wells were filled up with Sabouraud broth. Thereafter the assays were irradiated once with visible light (wave length 420nm, 20J/cm2 ) and fungal growth was monitored photometrically. Identical effects were measured with conidia and mycelial elements of all 5 T.rubrum strains. Curcumin dissolved with DMSO plus irradiation had a marked dose-dependent inhibitory effect on fungal growth that was almost complete with 5.0mg/L (P<.01) over a period of 9days. In contrast, the same procedure with micellar curcumin had no inhibitory effect on growth obtained from conidia or mycelial elements. Mycelial elements of T.rubrum and its conidia are equally sensitive to photochemical inactivation with curcumin and the galenic compounding of curcumin is essential to achieve this photochemical effect.

Targeting STAT3 to Suppress Systemic Pro-Oncogenic Effects from Hepatic Radiofrequency Ablation.

Purpose To (a) identify key expressed genes in the periablational rim after radiofrequency ablation (RFA) and their role in driving the stimulation of distant tumor growth and (b) use adjuvant drug therapies to block key identified mediator(s) to suppress off-target tumorigenic effects of hepatic RFA. Materials and Methods This institutional animal care and use committee-approved study was performed in C57BL6 mice (n = 20) and F344 rats (n = 124). First, gene expression analysis was performed in mice after hepatic RFA or sham procedure; mice were sacrificed 24 hours to 7 days after treatment. Data were analyzed for differentially expressed genes (greater than twofold change) and their functional annotations. Next, animals were allocated to hepatic RFA or sham treatment with or without STAT3 (signal transducer and activator of transcription 3) inhibitor S3I-201 for periablational phosphorylated STAT3 immunohistochemistry analysis at 24 hours. Finally, animals with subcutaneous R3230 adenocarcinoma tumors were allocated to RFA or sham treatment with or without a STAT3 inhibitor (S3I-201 or micellar curcumin, eight arms). Outcomes included distant tumor growth, proliferation (Ki-67 percentage), and microvascular density. Results At 24 hours, 217 genes had altered expression (107 upregulated and 110 downregulated), decreasing to 55 genes (27 upregulated and 28 downregulated) and 18 genes (four upregulated, 14 downregulated) at 72 hours and 7 days, respectively. At 24 hours, STAT3 occurred in four of seven activated pathways associated with pro-oncogenic genes at network analysis. Immunohistochemistry analysis confirmed elevated periablational phosphorylated STAT3 24 hours after RFA, which was suppressed with S3I-201 (percentage of positive cells per field: 31.7% ± 3.4 vs 3.8% ± 1.7; P < .001). Combined RFA plus S3I-201 reduced systemic distant tumor growth at 7 days (end diameter: 11.8 mm ± 0.5 with RFA plus S3I-201, 19.8 mm ± 0.7 with RFA alone, and 15 mm ± 0.7 with sham procedure; P < .001). STAT3 inhibition with micellar curcumin also suppressed postablation stimulation of distant tumor growth, proliferation, and microvascular density (P < .01). Conclusion Gene expression analysis identified multiple pathways upregulated in the periablational rim after hepatic RFA, of which STAT3 was active in four of seven. Postablation STAT3 activation is linked to increased distant tumor stimulation and can be suppressed with adjuvant STAT3 inhibitors. © RSNA, 2017.

Enhanced apoptosis, survivin down-regulation and assisted immunochemotherapy by curcumin loaded amphiphilic mixed micelles for subjugating endometrial cancer

Survivin is up-regulated in 83% of endometrial cancer leading to resistance development. As endometrial tumor advances, it also elicits chronic inflammation characterized by increased cytokine secretion and immune cells infiltration. The present study was designed to engineer mixed micellar curcumin loaded formulation for investigating survivin down-regulation, its anti-cancer and cytokine modulatory potential against endometrial cancer Ishikawa cells. Flory–Huggins interaction parameter (χpd) was applied to predict the compatibility between curcumin and surfactant mixture. The developed and characterized formulations were used to comparatively assess hemolysis, cellular uptake, cell-viability, apoptosis, mitochondrial membrane potential loss, rhodamine accumulation and bioavailability. In-vitro cytotoxicity in Vero cells demonstrated no deleterious effects on cell population. We saw better bioavailability, significant rhodamine accumulation, changes in protein expression and modulation in TNF-α, IL-6 and IL-10 levels. In conclusion, developed formulation warrants exploring the therapeutic interventions for overcoming resistance development in endometrial cancer.

Transepithelial Transport of Curcumin in Caco-2 Cells Is significantly Enhanced by Micellar Solubilisation

Curcumin, the active constituent of Curcuma longa L. (family Zingiberaceae), has gained increasing interest because of its anti-cancer, anti-inflammatory, anti-diabetic, and anti-rheumatic properties associated with good tolerability and safety up to very high doses of 12 g. Nanoscaled micellar formulations on the base of Tween 80 represent a promising strategy to overcome its low oral bioavailability. We therefore aimed to investigate the uptake and transepithelial transport of native curcumin (CUR) vs. a nanoscaled micellar formulation (Sol-CUR) in a Caco-2 cell model. Sol-CUR afforded a higher flux than CUR (39.23 vs. 4.98 μg min−1 cm−2, respectively). This resulted in a higher Papp value of 2.11 × 10−6 cm/s for Sol-CUR compared to a Papp value of 0.56 × 10−6 cm/s for CUR. Accordingly a nearly 9.5 fold higher amount of curcumin was detected on the basolateral side at the end of the transport experiments after 180 min with Sol-CUR compared to CUR. The determined 3.8-fold improvement in the permeability of curcumin is in agreement with an up to 185-fold increase in the AUC of curcumin observed in humans following the oral administration of the nanoscaled micellar formulation compared to native curcumin. The present study demonstrates that the enhanced oral bioavailability of micellar curcumin formulations is likely a result of enhanced absorption into and increased transport through small intestinal epithelial cells.

In vitro evaluation of antioxidant and neuroprotective effects of curcumin loaded in Pluronic micelles

ABSTRACTCurcumin is a polyphenolic substance with attractive pharmacological activities (e.g. antioxidant, anti-inflammatory, anticancer). Incorporation of curcumin in polymeric micelles could overcome the problems associated with its instability and low aqueous solubility. The aim of this study was to load curcumin in polymeric micelles based on Pluronic® P 123 or Pluronic® F 127 triblock copolymers and evaluate the antioxidant and neuroprotective effects after micellization. The micelles were prepared and loaded with curcumin by applying the dissolution method. Higher encapsulation efficiency was observed in the micelles formulated with Pluronic® P 123. These micelles were characterized with small size and narrow size distribution. The effects of micellar curcumin were investigated in two in vitro models. First, the capacity of micellar curcumin to inhibit iron/ascorbic acid-induced lipid peroxidation in rat liver microsomes was evaluated. Micellar curcumin and free drug showed similar inhibition of lipid peroxidation. Second, micellar curcumin and free curcumin showed protective potential in a model of 6-hydroxydopamine induced neurotoxicity in rat brain synaptosomes. The results from both methods indicated preservation of antioxidant and neuroprotective activity of curcumin in micelles. The small micellar size, high loading capacity and preservation of antioxidant activity of curcumin into Pluronic micelles, suggested their further evaluation as a curcumin delivery system.