Synergistic effect of curcumin and tamoxifen loaded in pH-responsive gemini surfactant nanoparticles on breast cancer cells.

BACKGROUND: Drug combination therapy is preferred over monotherapy in clinical research to improve therapeutic effects. Developing a new nanodelivery system for cancer drugs can reduce side effects and provide several advantages, including matched pharmacokinetics and potential synergistic activity. This study aimed to examine and determine the efficiency of the gemini surfactants (GSs) as a pH-sensitive polymeric carrier and cell-penetrating agent in cancer cells to achieve dual drug delivery and synergistic effects of curcumin (Cur) combined with tamoxifen citrate (TMX) in the treatment of MCF-7 and MDA-MB-231 human BC cell lines. METHODS: The synthesized NPs were self-assembled using a modified nanoprecipitation method. The functional groups and crystalline form of the nanoformulation were examined by Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), differential scanning calorimetry (DSC), and dynamic light scattering (DLS) used to assess zeta potential and particle size, and the morphological analysis determined by transmission electron microscopy (TEM). The anticancer effect was evaluated through an in vitro cytotoxicity MTT assay, flow cytometry analysis, and apoptosis analysis performed for mechanism investigation. RESULTS: The tailored NPs were developed with a size of 252.3 ± 24.6 nm and zeta potential of 18.2 ± 4.4 mV capable of crossing the membrane of cancer cells. The drug loading and release efficacy assessment showed that the loading of TMX and Cur were 93.84% ± 1.95% and 90.18% ± 0.56%, respectively. In addition, the drug release was more controlled and slower than the free state. Polymeric nanocarriers improved controlled drug release 72.19 ± 2.72% of Tmx and 55.50 ± 2.86% of Cur were released from the Tmx-Cur-Gs NPs after 72 h at pH = 5.5. This confirms the positive effect of polymeric nanocarriers on the controlled drug release mechanism. moreover, the toxicity test showed that combination-drug delivery was much more greater than single-drug delivery in MCF-7 and MDA-MB-231 cell lines. Cellular imaging showed excellent internalization of TMX-Cur-GS NPs in both MCF-7 and MDA-MB-231 cells and synergistic anticancer effects, with combination indices of 0.561 and 0.353, respectively. CONCLUSION: The combined drug delivery system had a greater toxic effect on cell lines than single-drug delivery. The synergistic effect of TMX and Cur with decreasing inhibitory concentrations could be a more promising system for BC-targeted therapy using GS NPs.

Folic acid grafted mixed polymeric micelles as a targeted delivery strategy for tamoxifen citrate in treatment of breast cancer.

The objective of this study was to develop folic acid (FA) grafted mixed polymeric micelles loaded with Tamoxifen citrate (TMXC) to enhance its antitumor activity in breast tissues. The conjugated folic acid Pluronic 123 (FA-P123) was prepared using carbonyl diimidazole cross-linker chemistry and confirmed using FTIR and 1HNMR. TMXC-loaded P123/P84 (unconjugated) and TMXC-loaded FA-P123/P84 (conjugated) micelles were examined for encapsulation efficiency, particle size, surface charge, in vitro drug release, cytotoxic effect, and cellular uptake by a breast cancer cell line. The conjugated TMXC-loaded micelle exhibited a nanoparticle size of 35.01 ± 1.20 nm, a surface charge of-20.50 ± 0.95 mV, entrapped 87.83 ± 5.10% and released 67.58 ± 2.47% of TMXC after 36 h. The conjugated micelles exhibited a significantly higher cellular uptake of TMXC by the MCF-7 cell line and improved in vitro cytotoxicity by 2.48 folds compared to the TMXC-loaded unconjugated micelles. The results of in vivo studies indicated that TMXC-loaded FA-P123/P84 has a potential antitumor activity, as revealed by a significant reduction of tumor volume in tumor-bearing mice compared to TMXC-loaded unconjugated micelles. In conclusion, the obtained results suggested that conjugated FA-P123/P84 micelles could be an encouraging carrier for the treatment of breast cancer with TMXC.

Machine learning model for anti-cancer drug combinations: Analysis, prediction, and validation.

Drug combination therapy is a highly effective approach for enhancing the therapeutic efficacy of anti-cancer drugs and overcoming drug resistance. However, the innumerable possible drug combinations make it impractical to screen all synergistic drug pairs. Moreover, biological insights into synergistic drug pairs are still lacking. To address this challenge, we systematically analyzed drug combination datasets curated from multiple databases to identify drug pairs more likely to show synergy. We classified drug pairs based on their MoA and discovered that 110 MoA pairs were significantly enriched in synergy in at least one type of cancer. To improve the accuracy of predicting synergistic effects of drug pairs, we developed a suite of machine learning models that achieve better predictive performance. Unlike most previous methods that were rarely validated by wet-lab experiments, our models were validated using two-dimensional cell lines and three-dimensional tumor slice culture (3D-TSC) models, implying their practical utility. Our prediction and validation results indicated that the combination of the RTK inhibitors Lapatinib and Pazopanib exhibited a strong therapeutic effect in breast cancer by blocking the downstream PI3K/AKT/mTOR signaling pathway. Furthermore, we incorporated molecular features to identify potential biomarkers for synergistic drug pairs, and almost all potential biomarkers found connections between drug targets and corresponding molecular features using protein-protein interaction network. Overall, this study provides valuable insights to complement and guide rational efforts to develop drug combination treatments.

Preparation and Characterization of Chitosan and Inclusive Compound-Layered Gold Nanocarrier to Improve the Antiproliferation Effect of Tamoxifen Citrate in Colorectal Adenocarcinoma (Caco-2) and Breast Cancer (MCF-7) Cells.

Objectives: Cancer diseases have been linked to a huge number of causes that led to deaths in this century along with cardiovascular and lung diseases. Most death-leading types of cancer are colon, lung, breast, and prostate cancers. Due to the remarkable properties of gold (Au) nanocarrier, they are used to deliver and improve tamoxifen (Tam) citrate activity in Caco-2 and MCF-7 cells. Materials and Methods: In this study, preparation of Au nanoparticles (NPs), zeta-potential and size, high resolution transient electron microscopy (HRTEM), high-performance liquid chromatography, ultraviolet-visible spectra, fluorescence microscopy, fourier infrared spectroscopy, and real-time cellular analysis xCELLigence technology were investigated. Results: The zeta-average size of the Tam- ß-cyclodextrin (ß-CD)-hyaluronic acid (HA)-chitosan (Chi)-Au nanocomposite is 82.02 nm with a negative zeta potential of -23.6. Furthermore, HRTEM images showed that, successful formulation of polymer shell around Au core and the Au NP shape is mostly spherical, triangle and irregular. Furthermore, the fluorescence microscope image showed proper cellular uptake of the Tam-ß-CD-HA-Chi-Au nanocomposite in MCF-7 and Caco-2 cells. Additionally, Tam-ß-CD-HA-Chi-Au nanocomposite significantly improved the cytotoxic activity of Tam citrate on Caco-2 cells. IC50 value of Tam reduced from 8.55 µM to 5.32 µM, after 48 h of incubation time (p value <0.00001). Conclusion: This study showed that Tam-ß-CD-HA-Chi-Au nanocomposite is a potential nanocarrier for delivering the drug to Caco-2 and MCF-7 cancer cells, since it has improved Tam citrate activity on colorectal cancer cells. After all, the developed formula showed more effect on Caco-2 than MCF-7. The prepared nanocomposite could be used to improve the cancer therapy in clinical trials.

Tamoxifen Citrate Containing Topical Nanoemulgel Prepared by Ultrasonication Technique: Formulation Design and In Vitro Evaluation.

The present study aims to design and develop a nanoemulgel formulation of Tamoxifen citrate (TAM), a water-insoluble, potent anticancer drug, using the spontaneous emulsification method to improve topical delivery, achieve high accumulation at the tumour site, and spare the healthy tissues. The oil-based selection was related to the TAM solubility, while the surfactant and co-surfactant were chosen based on the droplets' thermodynamic stability and size. Afterwards, a pseudo-ternary phase diagram was built for the most promising formulation using two oils, olive and sesame, with a varied mix of Tween 40 as the surfactant and Trascutol HP as the co-surfactant (Smix), by the optimisation of experiments. The nanoemulsion (NE) formulations that were prepared were found to have an average droplet size of 41.77 ± 1.23 nm and 188.37 ± 3.53 nm, with suitable thermodynamic stability and physicochemical properties. Both olive and sesame oils are natural food additives due to their associated antioxidant effects; therefore, they showed no toxicity profile on breast cell lines (MCF-7, ATCC number HTB-22). The TAM-NE preparations revealed a prolonged and doublings superior cumulative percentage of in vitro release of TAM compared to TAM plain gel suspension over 24 h. The release data suggested that the Higuchi model was the best fitting kinetical model for the developed formulations of NE1, NE9, and NE18. The extended release of the drug as well as an acceptable amount of the drug permeated TAM via nanogel preparations suggested that nanoemulgel (NEG) is suitable for the topical delivery of TAM in breast cancer management. Thus, this work suggests that a nanogel of TAM can improve anticancer properties and reduce systemic adverse effects compared to a suspension preparation of TAM when applied in the treatment of breast cancer.

Hyaluronic Acid and Graphene Oxide-incorporated Hyaluronic Acid Hydrogels for Electrically Stimulated Release of Anticancer Tamoxifen Citrate.

Transdermal drug delivery is the transport of drug across the skin and into the systemic circulation. Patch is a one of transdermal device that is used to attach on skin and contains drug. The drug matrices from hyaluronic acid (HA) and graphene oxide (GO) incorporated HA hydrogel were fabricated for the release of tamoxifen citrate (TMX) as the anticancer drug under applied electrical field. The pristine HA hydrogels as the matrix and GO as the drug encapsulation host were fabricated for transdermal patch by the solution casting using citric acid as the chemical crosslinker. In vitro drug release experiment was investigated by utilizing the modified Franz-diffusion cell under the effects of crosslinking ratio, electric potential, and GO. The TMX release behaviors from the hydrogels were found to be from the three mechanisms: the pure Fickian diffusion; the anomalous or non-Fickian diffusion; and Super case II transport depending on the crosslinking conditions. The TMX diffusion and release amount from the pristine HA hydrogels were increased with smaller crosslinking ratios. With applied electrical potential, the enhanced TMX diffusion and release amount were observed when compared to that without due to the electro-repulsive force. Furthermore, the TMX diffusion from the HA hydrogel with GO as the drug encapsulation host was higher by two orders of magnitude than without GO.

Polycaprolactone nanofibers as an adjuvant strategy for Tamoxifen release and their cytotoxicity on breast cancer cells.

Breast cancer is the second leading cause of death in women, and tamoxifen citrate (TMX) is accepted widely for the treatment of hormone receptor-positive breast cancers. Several local drug-delivery systems, including nanofibers, have been developed for antitumor treatment. Nanofibers are biomaterials that mimic the natural extracellular matrix, and they have been used as controlled release devices because they enable highly efficient drug loading. The purpose of the present study was to develop polycaprolactone (PCL) nanofibers incorporating TMX for use in the treatment of breast tumors. Pristine PCL and PCL-TMX nanofibers were produced by electrospinning and characterized physiochemically using different techniques. In addition, an in vitro study of TMX release from the nanofibers was performed. The PCL-TMX nanofibers showed sustained TMX release up to 14 h, releasing 100% of the TMX. The Resazurin reduction assay was used to evaluate the TMX cytotoxicity on MCF-7 breast cancer cell line and PBMCs human. The PCL-TMX nanofiber was cytotoxic toPBMCs and MCF-7. Based on these results, the PCL-TMX nanofibers developed have potential as an alternative for local chronic TMX use for breast cancer treatment, however tissue tests must be done.

Design and Characterization of Maltoheptaose-b-Polystyrene Nanoparticles, as a Potential New Nanocarrier for Oral Delivery of Tamoxifen.

Tamoxifen citrate (TMC), a non-steroidal antiestrogen drug used for the treatment of breast cancer, was loaded in a block copolymer of maltoheptaose-b-polystyrene (MH-b-PS) nanoparticles, a potential drug delivery system to optimize oral chemotherapy. The nanoparticles were obtained from self-assembly of MH-b-PS using the standard and reverse nanoprecipitation methods. The MH-b-PS@TMC nanoparticles were characterized by their physicochemical properties, morphology, drug loading and encapsulation efficiency, and release kinetic profile in simulated intestinal fluid (pH 7.4). Finally, their cytotoxicity towards the human breast carcinoma MCF-7 cell line was assessed. The standard nanoprecipitation method proved to be more efficient than reverse nanoprecipitation to produce nanoparticles with small size and narrow particle size distribution. Moreover, tamoxifen-loaded nanoparticles displayed spherical morphology, a positive zeta potential and high drug content (238.6 ± 6.8 µg mL-1) and encapsulation efficiency (80.9 ± 0.4 %). In vitro drug release kinetics showed a burst release at early time points, followed by a sustained release profile controlled by diffusion. MH-b-PS@TMC nanoparticles showed higher cytotoxicity towards MCF-7 cells than free tamoxifen citrate, confirming their effectiveness as a delivery system for administration of lipophilic anticancer drugs.

Formulation, characterization, and cellular toxicity assessment of tamoxifen-loaded silk fibroin nanoparticles in breast cancer.

Silk fibroin (SF) is a natural polymeric biomaterial that is widely adopted for the preparation of drug delivery systems. Herein, we aimed to fabricate and characterize SF nanoparticles loaded with the selective estrogen receptor modulator; tamoxifen citrate (TC-SF-NPs) and to assess their in vitro efficacy against breast cancer cell lines (MCF-7 and MDA-MB-231). TC-loaded SF-NPs were characterized for particle size, morphology, entrapment efficiency, and release profile. In addition, we examined the in vitro cytotoxicity of TC-SF-NPs against human breast cancer cell lines and evaluated the anticancer potential of TC-SF-NPs through apoptosis assay and cell cycle analysis. Drug-loaded SF-NPs showed an average particle size of 186.1 ± 5.9 nm and entrapment efficiency of 79.08%. Scanning electron microscopy (SEM) showed the nanoparticles had a spherical morphology with smooth surface. Tamoxifen release from SF-NPs exhibited a biphasic release profile with an initial burst release within the first 6 h and sustained release for 48 h. TC-SF-NPs exerted a dose-dependent cytotoxic effect against breast cancer cell lines. In addition, flow cytometry analysis revealed that cells accumulate in G0/G1 phase, with a concomitant reduction of S- and G2-M-phase cells upon treatment with TC-SF-NPs. Consequently, the potent anticancer activities of TC-SF-NPs against breast cancer cells were mainly attributed to the induction of apoptosis and cell cycle arrest. Our results indicate that SF nanoparticles may represent an attractive nontoxic nanocarrier for the delivery of anticancer drugs.

Long-Term Outcomes of Tamoxifen Citrate Therapy and Histo- and Immunopathological Properties in Riedel Thyroiditis.

BACKGROUND: Riedel thyroiditis (RT) is a rare form of thyroiditis; thus, data about the disease course and treatment options are limited. Therefore, we aimed to assess the clinical, serological, radiological, and histopathological features, as well as short- and long-term follow-up of RT patients under glucocorticoid (GC) and tamoxifen citrate (TMX). Parameters related to IgG4-related diseases (IgG4-RD) were also investigated. METHODS: Eight patients with RT diagnosed between 2000 and 2019 were enrolled. Data were collected in a retrospective and prospective manner. The diagnosis was confirmed with histopathological features in all patients. Results of the treatment with GCs on short- to mid-term, followed by TMX in the long term, were evaluated. RESULTS: The mean age at diagnosis was 40.5 ± 6.8 years; female predominance was observed (F/M:7/1). Parameters related to IgG4-RD, like increase in IgG4 serum levels, total plasmablast counts, and IgG4+ plasmablasts, were negative in most of our patients in both active and inactive states of the disease. Likewise, an increased ratio of IgG4/IgG-positive plasma cells >40% could only be observed in 2 cases. GCs followed by TMX were given to the patients with an over-all median follow-up time of 67 (8-216) months. All the patients considerably improved clinically and had a reduction in the size of the mass lesion on GCs, followed by TMX therapy. None of the patients had a recurrence under TMX therapy for a median period of 18.5 (7-96) months. CONCLUSION: Even though RT is suggested to be a member of IgG4-RD, serologic or histological evidence of IgG4 elevation or positivity is only useful for diagnosis and follow-up of RT. The diagnosis should be based on clinical and radiological evidence and confirmed by histopathology. GCs are effective for initial treatment, and TMX is a successful and safe therapeutic option for long-term maintenance therapy.

Combination of structure-performance and shape-performance relationships for better biphasic release in electrospun Janus fibers.

In nature, the combination of composition, structure, and shape determines the matter's functional performance to a large extent. Inspired by which, two electrospun Janus nanofiber formulations were created using side-by-side electrospinning in this work. Tamoxifen citrate (TAM) was used as a model drug and ethyl cellulose (EC) and polyvinylpyrrolidone K60 (PVP) as the polymer carrier matrices. The fibers have linear cylindrical morphologies and distinct Janus structures by scanning electron microscopy. One side of the fibers took a round shape, while the other was crescent-shaped. The drug was present in both polymer matrices in the form of amorphous solid dispersions, owing to strong intermolecular interactions between drug and polymer. In vitro dissolution tests demonstrated that both sets of fibers could provide biphasic drug release due to the difference in solubility of PVP and EC. The different shape of TAM-EC and TAM-PVP side of the Janus structure resulted in a considerable variation in the drug release profiles. The Janus structure with crescent TAM-PVP side and round TAM-EC side gave a more rapid burst release in the first phase of release, and slower sustained release in the second phase. This work thus reports a new strategy for systematically developing advanced functional nanomaterials based on both shape- and structure-performance relationships.

In Vitro Cytotoxicity and Cellular Uptake of Tamoxifen Citrate-Loaded Polymeric Micelles.

The main intent of this treatise was to encapsulate tamoxifen citrate (TMXC) into polymeric micellar delivery system and evaluate the influence of TMXC-loaded micelles as a promising carrier on the in vitro cytotoxicity and cellular uptake of TMXC in treatment of breast cancer. Different formulae of polymeric micelles loaded with TMXC using mixtures of different Pluronic polymers were fabricated by thin-film hydration method and evaluated for morphology, drug entrapment efficiency, particle size, surface charge, in vitro liberation of TMXC, uptake by cancer cell lines, and cytotoxic effect against breast cancer cell lines such as MCF-7. The optimal TMXC-loaded micelles exhibited nano-sized particles and entrapped about 89.09 ± 4.2% of TMXC. In vitro liberation study revealed an extended TMXC escape of about 70.23 ± 5.9% over a period of 36 h. The optimized TMXC-loaded micelles formula showed enhanced cellular uptake of TMXC by 2.28 folds and showed a significant cytotoxic effect with MCF-7 breast cancer cells compared to TMXC solution. The obtained yield proposed that Pluronic micelles could be a promising potential delivery system for anticancer moieties.

Development and evaluation of polymeric micelle containing tablet formulation for poorly water-soluble drug: tamoxifen citrate.

Poor aqueous solubility is one of the key reasons for slow dissolution rate and poor intestinal absorption and finally that causes low therapeutic efficacy of many existing drugs. Tamoxifen citrate (TMX) (BCS Class II drug) with low water solubility has poor oral bioavailability in the range of 20%-30%, therefore, high doses are required for treatment with TMX. Self-assemblage of amphiphilic polymers leads to the formation of polymeric micelles which makes them unique nano-carriers with excellent biocompatibility, low toxicity, enhanced blood circulation time, and solubilization of poorly water-soluble drugs. In this study poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) triblock copolymer, which has been approved by FDA for oral application was used to benefit its micellar solubilization effect. Self-assembled micelles were prepared for the delivery of TMX and this way TMX solubility was increased approximately 60 times. TMX-treated cells showed 38.06 ± 1.5% viability at 50 µM concentration for 24 h; 66.71 ± 11.6% viability at 25 µM concentration for 48 h, at the same conditions TMX-loaded micelles exhibited 24.994 ± 0.25% and 43.36 ± 4.37% cell viability, respectively (p < 0.05). These results showed that the encapsulation of TMX into PEG-PPG-PEG micelles facilitated the cellular uptake, which led to an increased cytotoxicity in MCF-7 cancer cells. Tablet formulation containing lyophilized TMX-loaded micelles was showed an improved dissolution than commercial TMX tablet (Tamoxifen® TEVA). It can be reasonably expected that the obtained drug dissolution rate and increased cytotoxicity to tumor cells will result in an increase of TMX bioavailability and tolerability associated with an important dose reduction and decreased side effects.

Antimicrobial, Antitumor and Side Effects Assessment of a Newly Synthesized Tamoxifen Analog.

BACKGROUND: Tamoxifen citrate is a very prevalent drug marketed under several trade names like Apo-Tamox, Nolvadex, Tamec, Tamizam, and Tamoplex. This molecule is approved by the FDA for breast cancer treatment. Some studies have shown that tamoxifen has anti-tuberculosis and antiparasitic activities. Like any drug, tamoxifen possesses side effects, more or less dangerous. AIMS: Basically, this work is a comparative study that aims to: primarily compare the antimicrobial and antitumor activities of tamoxifen and a newly synthesized tamoxifen analog; and to determine the molecule with lesser side effects. METHODS: Three groups of mice were injected with tamoxifen citrate and compound 2(1,1-bis[4-(3- dimethylaminopropoxy)phenyl]-2-phenyl-but-1-ene dihydrochloride) at doses corresponding to C1 (1/10), C2 (1/50), and C3 (1/100) to compound 2 lethal dose (LD50 = 75 mg/kg) administered to adult mice. A group of noninjected mice served as a study control. RESULTS: Experimental results suggest that compound 2 has better antitumor and antimicrobial activity than tamoxifen citrate besides its lower toxicity effects. CONCLUSION: The results obtained from the present study confirmed the antitumor and antimicrobial effect of tamoxifen citrate and its hematological side effects. Compound 2 seems to be more effective than tamoxifen citrate for antitumor and antimicrobial treatment while having less hematological side effects and less disruption of the blood biochemical parameters. These findings encourage us to perform further studies on compound 2 and test it for other therapeutic uses for which tamoxifen was found effective.

Observation on Honghua Xiaoyao Granules combined with tamoxifen in treatment of polycystic ovary syndrome / 中国综合临床

Objective@#To investigate the clinical effect of Honghua Xiaoyao granule combined with tamoxifen citrate tablets in the treatment of polycystic ovary syndrome (PCOS).@*Methods@#From June 2017 to January 2019, 92 patients with PCOS admitted to Chengde maternal and child health care hospital were selected as the study objects, and divided into control group (46 cases) and treatment group (46 cases) according to the order of admission.The patients in the control group took tamoxifen citrate tablets, 2 tablets/time, 1 time/day from the 5th day of menstrual cycle.The patients in the treatment group were treated with safflower Xiaoyao granules on the basis of tamoxifen citrate tablets, 3 bags/time, 3 times/day.After 21 days of continuous administration, 5 days of discontinuation was a course of treatment, and the two groups of patients were treated for 3 consecutive courses.The clinical effect, ovulation, blood glucose, insulin resistance index, sex hormone level and oxidative stress of the two groups were compared before and after treatment.@*Results@#The total effective rate of the treatment group was 95.65% (44/46), the ovulation rate was 97.83% (45/46), the control group was 80.43% (37/46), 84.78% (39/46), the difference between the two groups was statistically significant (χ2 value was 5.06, 4.93, P value was 0.025, 0.029). .Before and after treatment, the fasting insulin were (20.31±3.06) mU/L and (12.49±2.34) mU/L, and the homeostatic model assessment of insulin resistance were 4.84±1.30 and 2.92±0.83 in the treatment group, which were (20.14±2.55) mU/L, (16.15±2.17) mU/L, 4.86±1.08 and 3.86±0.93 in control group.There all were differences in two groups about the insulin resistance index before and after treatment, and there all were differences between two groups about the insulin resistance index after treatment (tvalue was 26.15 , 16.10, 19.68 and 12.17; all P<0.001). and there were statistically significant differences between the two indexes after treatment (t=0.77, 5.11, all P<0.001). Before and after treatment, the luteinizing hormone were (19.98±2.22) and (12.61±2.55) U/L, and the follicle stimulating hormone were (5.97±0.69) U/L and (4.52±0.79) U/L, and testosterone was (5.38±0.88) and (3.62±0.60) nmol/L, which was (20.44±2.23) U/L, (16.18±2.65) U/L, (6.09±0.59) U/L, (5.31±0.86) U/L, (5.44±0.77) nmol/L and (4.48±0.62) nmol/L in control group.The difference between the two groups before and after treatment was statistically significant (t value was 23.32, 15.29, 13.70, 8.67, 19.80 and 12.30, respectively; all P<0.001); and the difference between the groups after treatment was statistically significant (t value was 6.58, 4.61 and 6.70, respectively, all P<0.001). Before and after treatment, the malondialdehyde were (9.20±1.15) μmol/L and (5.63±0.94) μmol/L, and the superoxide dismutase were (62.99±5.37) U/L and (89.63±8.81) U/L, which were (9.45±1.08) μmol/L, (7.48±0.85) μmol/L, (61.88±5.78) U/L and (75.60±6.87) U/L in control group.There all were differences in two groups about the oxidative stress index before and after treatment, and there all were differences between two groups about the oxidative stress index after treatment (t value was 40.00, 19.84, 28.14, 15.24, 9.88 and 8.52, respectively, all P<0.001).@*Conclusion@#Honghua Xiaoyao Granules combined with Tamoxifen Citrate Tablets can effectively improved the clinical symptoms of patients with PCOS, promoting ovulation, reducing sex hormone level, improving insulin resistance and oxidative stress, which has a certain clinical application value.

Breast cancer drugs perturb fundamental vascular functions of endothelial cells by attenuating protein S-nitrosylation.

Cardiovascular side effects of broadly used chemotherapeutic drugs such as Tamoxifen citrate (TC), Capecitabine (CP) and Epirubicin (EP) among cancer survivors are well established. Nitric oxide (NO) is known to protect cardiovascular tissues under conditions of stress. NO can act through cyclic guanosine monophosphate (cGMP)-dependent and -independent pathways. Particularly, the S-nitrosylation of SH-groups in a protein by NO falls under cGMP-independent effects of NO. TC, CP, and EP are hypothesized as interfering with cellular protein S-nitrosylation, which, in turn, may lead to endothelial dysfunctions. The results show that all three drugs attenuate nitrosylated proteins in endothelial cells. A significant reduction in endogenous S-nitrosylated proteins was revealed by Saville-Griess assay, immunofluorescence and western blot. Incubation with the drugs causes a reduction in endothelial migration, vasodilation and tube formation, while the addition of S-nitrosoglutathione (GSNO) has a reversal of this effect. In conclusion, results indicate the possibility of decreased cellular nitrosothiols as being one of the reasons for endothelial dysfunctions under TC, CP and EP treatment. Identification of the down-regulated S-nitrosylated proteins so as to correlate their implications on fundamental vascular functions could be an interesting phenomenon.

Development of Hot Melt Extruded Solid Dispersion of Tamoxifen Citrate and Resveratrol for Synergistic Effects on Breast Cancer Cells.

Primary standard therapy for ER-positive breast cancer being tamoxifen, newer delivery approach for enhancement of dissolution and therapeutic efficiency of tamoxifen through oral route could be a possible solution. In the present study, we investigated combination of tamoxifen (TAM) with resveratrol (RES) and observed that the combination is effective on MCF-7 breast cancer cells. To ensure co-delivery of the drugs, we explored the hot melt extrusion technique for simultaneously extruding two drugs together in order to enhance their bioavailability. As both are class II drugs with dissolution limited bioavailability, detailed formulation and process parameter analyses were carried out. Detailed characterization using microscopy, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRD) confirmed that both the drugs were molecularly dispersed in the matrix of Soluplus, CremophorRH40, and Poloxamer188, and no interactions between the ingredients were there during hot melt extrusion (HME) process. Dissolution studies confirmed that HME extrudates were able to release drug more rapidly than simple suspension formulation. Further, pharmacokinetic studies in rats were carried out for tamoxifen. Results demonstrated that extrusion significantly increased the tamoxifen oral bioavailability (p < 0.05) (Tmax = 2.00 ± 0.56 h, Cmax = 3.66 ± 1.49 µg/mL, AUC = 39.80 ± 16.24 µg h/mL, MRT = 20.49 ± 5.71) compared to the conventional suspension of tamoxifen (Tmax = 2.00 ± 0.71 h, Cmax = 2.41 ± 0.84 µg/mL, AUC = 12.82 ± 3.99 µg h/mL, MRT = 18.24 ± 5.95 h). In vitro cytotoxicity studies of TAM, RES, and their combination (TAM-RES) were evaluated with MCF7 cells. The combination showed significantly lower IC50 compared to TAM with increasing ratio of RES which is a result of apoptosis. HME-based simultaneous extrusion of TAM and RES formulation provides a suitable formulation strategy for breast cancer treatment and establishes proof of concept for extruding multiple drugs simultaneously for other applications in future.

Simultaneous TLC-densitometric determination of tamoxifen citrate and medroxyprogesterone acetate and UV-degradation kinetic study of medroxyprogesterone acetate.

Coadministration of tamoxifen citrate (TMC) and medroxyprogesterone acetate (MPA) is preferred to increase the response rate and the percentage recovery in patients with endometrial carcinoma. Administration of TMC and MPA and their combination affects estrogen and progestin receptor concentrations in advanced endometrium carcinoma by affecting 17ß-hydroxyl steroid dehydrogenase activity and serum hormone concentrations. A sensitive, accurate and robust thin-layer chromatography method has been established for simultaneous analysis of TMC and MPA. Method development was carried out on silica gel F254 using butanol-acetic acid-water (6:0.5:0.5, v/v/v) as mobile phase. Densitometric scanning was carried out at 241 nm for simultaneous detection of TMC and MPA. Retardation factor (Rf ) values for TMC and MPA were 0.21 and 0.85, respectively. The method was validated according to ICH guidelines. Regression plots revealed linear relationships in the concentration range of 50-500 and 25-250 ng/band for TMC and MPA, successively. Accuracy was ≥99.60 and 98.72% for TMC and MPA, respectively. Forced degradation studies using UV photodegradation was applied on MPA after exposure to UV light for different times and applying a kinetic study for calculating the degradation rate constant (k) and half-life time (t1/2 ).

Fast dissolving drug delivery membrane based on the ultra-thin shell of electrospun core-shell nanofibers.

Structural nanocomposites that provide fast dissolving drug release profiles are highly in demand in pharmaceutics. In this study, a poorly water-soluble drug such as quercetin or tamoxifen citrate (TC) was selected as a model active pharmaceutical ingredient. Core-shell nanofibers with ultra-thin shells were designed and prepared using modified coaxial electrospinning. Polyvinylpyrrolidone (PVP) K90 or Polycaprolactone (PCL) was selected as core. The drugs and PVP K10 were selected as shell. All types of solutions can be used as the shell fluids in modified coaxial process regardless of their electrospinnability, which means the increasing functional ingredients and unspinnable matrix can be processed. Evaluations via SEM and TEM demonstrated that the core-shell nanofibers had linear morphology with a shell thickness smaller than 100 nm. XRD and FTIR results showed that the model drug was distributed in the polymeric matrix amorphously and that PVP K10 had good compatibility with quercetin or TC. In vitro dissolution tests suggested that the core-shell nanofibers with ultra-thin shells released the loaded cargoes in the dissolution media within 1 min. The present investigation paved a new way for implementing the modified coaxial processes, which can be utilized to fabricate structural nanocomposites with ultra-thin shells for enhancing the fast dissolution of poorly water-soluble drugs.

Tamoxifen citrate loaded chitosan-gellan nanocapsules for breast cancer therapy: development, characterisation and in-vitro cell viability study.

The objective of this study was to evaluate the potential of chitosan-gellan nanocapsules (CGNCs) for encapsulation and sustained release of Tamoxifen citrate (TMC) for breast cancer therapy. Polyelectrolyte complex coacervation method was used for production of CGNCs. Interaction studies were conducted by Fourier-transform infra-red (FT-IR), differential scanning colorimetric (DSC), and X-ray diffraction (XRD) to investigate any interaction between drug and excipients. Physicochemical parameters, in vitro drug release and release kinetic were studied. In vitro cell viability study using Michigan Cancer Foundation-7 (MCF-7) breast cancer cells was also investigated. CGNCs had a smooth surface and nanosize range with a positive surface charge and exhibited sustained drug release. Further, TMC loaded CGNCs were found to be more cytotoxic than the free drug in MCF-7. Thus CGNCs may be suitable for breast cancer treatment due to delivering the drug at the site of action for a prolonged period of time.