Microcurrent Cloth-Assisted Transdermal Penetration and Follicular Ducts Escape of Curcumin-Loaded Micelles for Enhanced Wound Healing.

Purpose: Larger nanoparticles of bioactive compounds deposit high concentrations in follicular ducts after skin penetration. In this study, we investigated the effects of microcurrent cloth on the skin penetration and translocation of large nanoparticle applied for wound repair applications. Methods: A self-assembly of curcumin-loaded micelles (CMs) was prepared to improve the water solubility and transdermal efficiency of curcumin. Microcurrent cloth (M) was produced by Zn/Ag electrofabric printing to facilitate iontophoretic transdermal delivery. The transdermal performance of CMs combined with M was evaluated by a transdermal system and confocal microscopy. The CMs/iontophoretic combination effects on nitric oxide (NO) production and inflammatory cytokines were evaluated in Raw 264.7 cells. The wound-healing property of the combined treatment was assessed in a surgically created full-thickness circular wound mouse model. Results: Energy-dispersive X-ray spectroscopy confirmed the presence of Zn/Ag on the microcurrent cloth. The average potential of M was measured to be +214.6 mV in PBS. Large particle CMs (CM-L) prepared using surfactant/cosurfactant present a particle size of 142.9 nm with a polydispersity index of 0.319. The solubility of curcumin in CM-L was 2143.67 µg/mL, indicating 250-fold higher than native curcumin (8.68 µg/mL). The combined treatment (CM-L+M) demonstrated a significant ability to inhibit NO production and increase IL-6 and IL-10 secretion. Surprisingly, microcurrent application significantly improved 20.01-fold transdermal performance of curcumin in CM-L with an obvious escape of CM-L from follicular ducts to surrounding observed by confocal microscopy. The CM-L+M group also exhibited a better wound-closure rate (77.94% on day 4) and the regenerated collagen intensity was approximately 2.66-fold higher than the control group, with a closure rate greater than 90% on day 8 in vivo. Conclusion: Microcurrent cloth play as a promising iontophoretic transdermal drug delivery accelerator that enhances skin penetration and assists CMs to escape from follicular ducts for wound repair applications.

Multifunctional PLGA-based nanoparticles as a controlled release drug delivery system for antioxidant and anticoagulant therapy.

BACKGROUND: Ischemia/reperfusion (I/R) injury causes the generation of many ROS such as H2O2 and leads to vascular thrombosis, which causes tissue damage. PURPOSE: In this investigation, poly (lactideco-glycolide) (PLGA)-based nanoparticles are used for their anticoagulant and antioxidant properties in vascular therapy. METHODS: Both heparin and glutathione are entrapped on PLGA-stearylamine nanoparticles by layer-by-layer interactions. RESULTS: The drug release rate is successfully controlled with only 10.3% of the heparin released after 96 hours. An H2O2-responsive platform is also developed by combining silk fibroin and horse peroxidase to detect H2O2 in this drug delivery system. Besides, hyaluronic acid was decorated on the surface of nanoparticles to target the human bone marrow mesenchymal stem cells (hBMSCs) for cell therapy. The results of an in vitro study indicate that the nanoparticles could be taken up by hBMSCs within 2 hours and exocytosis occurred 6 hours after cellular uptake. CONCLUSION: We propose that the multifunctional nanoparticles that are formed herein can be effectively delivered to the site of an I/R injury via the hBMSC homing effect. The proposed approach can potentially be used to treat vascular diseases, providing a platform for hBMSCs for the controlled delivery of a wide range of drugs.

Morphological transformation of hBMSC from 2D monolayer to 3D microtissue on low-crystallinity SF-PCL patch with promotion of cardiomyogenesis.

The effects of the stiffness of substrates on the cell behaviours of human bone marrow-derived mesenchymal stem cells (hBMSC) have been investigated, but the effects of the secondary structures of proteins in the substrates on the morphological transformation and differentiation of hBMSC have yet been elucidated. To investigate these issues, silk fibroin-poly(ε-caprolactone) SP cardiac patches of poly(ε-caprolactone; P), on which is grafted by silk fibroin (SF) with various ß-sheet contents (or crystallinity) to provide various degrees of stiffness, were produced to examine the in vitro behaviours of hBMSC during proliferation, and cardiomyogenesis on the SP patches. ß-sheet contents of SF from 20% to 44% (SP20 to SP44, respectively) were induced on patches, which were examined by attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy, and analysed using the Fourier self-deconvolution method. The stiffness of the SP patches, quantified by their Young's moduli and elasticities, increased with the crystallinity of the SF. During 3 days of proliferation, hBMSC migrated and morphologically transformed into 3D microtissues with diameters of approximately 150-200 µm on low-stiffness SP20 and SP30 patches, whereas 2D monolayers were observed on the SP37 and SP44 patches. The 3D microtissues/patch yielded more extensive in vitro cardiomyogenesis of hBMSC than the 2D cell monolayer with significantly higher expressions of all examined cardiac-specific proteins after induction by 5-aza. Notably, in vivo subcutaneously growing 3D microtissues on SP20 patches and a 2D monolayer on SP44 patches were preliminarily demonstrated in a rat model. Morphological transformations of hBMSC from a 2D monolayer to a 3D microtissue by low-stiffness SP cardiac patches, promoting cardiomyogenesis, provide a new opportunity for cardiac tissue engineering.

Kinetics of Tyrosinase Inhibitory Activity Using Vitis vinifera Leaf Extracts.

Natural medical plant is considered as a good source of tyrosinase inhibitors. Red vine leaf extract (RVLE) can be applied to a wide variety of medical disciplines, such as treatments for chronic venous insufficiency over many decades. This study investigated the tyrosinase inhibitory activity of RVLE containing gallic acid, chlorogenic acid, epicatechin, rutin, and resveratrol which are effective for skin hyperpigmentation. The five components contents are 1.03, 0.2, 18.55, 6.45, and 0.48 mg/g for gallic acid, chlorogenic acid, epicatechin, rutin, and resveratrol. The kinetic study showed the tyrosinase inhibitory of RVLE via a competitive reaction mechanism. RVLE solution has an IC50 (the half inhibitory concentration) value of 3.84 mg/mL for tyrosinase inhibition, that is, an effective tyrosinase inhibitory activity, and can be used as a whitening agent for cosmetic formulations in the future.

Development of a controlled-release drug delivery system by encapsulating oxaliplatin into SPIO/MWNT nanoparticles for effective colon cancer therapy and magnetic resonance imaging.

The development of a controlled-release drug delivery system has been an important objective for cancer therapy. To achieve the goal of sustained drug release for preventing the biotoxicity of platinum drugs, oxaliplatin was encapsulated into PEGylated multiwalled carbon nanotubes (MWNTs) decorated with superparamagnetic iron oxide (SPIO) for magnetic resonance imaging (MRI). The superparamagnetic properties and purification of SPIO/MWNT composites were achieved by annealing treatment during the fabrication process; the better hydrophilicity and biocompatibility were also accomplished subsequently after modification with polyethylene glycol (PEG). Oxa/MagMWNT-PEG 7 presented the ability of sustained release, as only 36.25% of loaded oxaliplatin leaked within 12 h and 55.48% lasted over 144 h. An in vitro study revealed that compared with free oxaliplatin and Oxa/MagMWNT 8, Oxa/MagMWNT-PEG 7 showed a slightly decreased cytotoxic effect when the cell viability was assessed at 12 and 24 h; however, a drastic enhancement in cytotoxicity was observed at 96 h. Platinum-DNA quantification on HCT116 cells showed that the internalization of oxaliplatin lasted up to 96 h, which was due to the sustained release of nanomedicine. An in vivo study showed that the nanomedicine-treated group exhibited effective antitumor efficacy similar to the free drug-treated group, but without inducing death in mice. After intravenous administration, the T2-weighted MRI signal revealed that Oxa/MagMWNT-PEG7 had an excellent MRI enhancement in the tumor region. This SPIO-decorated MWNT composite encapsulated with antitumor drugs could potentially be useful for treatments, such as cancer therapy and MRI.

A novel temperature-responsive micelle for enhancing combination therapy.

A novel thermosensitive polymer p(N-isopropylacrylamide-co-poly[ethylene glycol] methyl ether acrylate)-block-poly(epsilon-caprolactone), p(NIPAAM-co-PEGMEA)-b-PCL, was synthesized and developed as nanomicelles. The hydrophobic heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin and the photosensitizer cyanine dye infrared-780 were loaded into the core of the micelles to achieve both chemotherapy and photothermal therapy simultaneously at the tumor site. The release of the drug could be controlled by varying the temperature due to the thermosensitive nature of the micelles. The micelles were less than 200 nm in size, and the drug encapsulation efficiency was >50%. The critical micelle concentrations were small enough to allow micelle stability upon dilution. Data from cell viability and animal experiments indicate that this combination treatment using photothermal therapy with chemotherapy had synergistic effects while decreasing side effects.

Targeting Colorectal Cancer Stem-Like Cells with Anti-CD133 Antibody-Conjugated SN-38 Nanoparticles.

Cancer stem-like cells play a key role in tumor development, and these cells are relevant to the failure of conventional chemotherapy. To achieve favorable therapy for colorectal cancer, PEG-PCL-based nanoparticles, which possess good biological compatibility, were fabricated as nanocarriers for the topoisomerase inhibitor, SN-38. For cancer stem cell therapy, CD133 (prominin-1) is a theoretical cancer stem-like cell (CSLC) marker for colorectal cancer and is a proposed therapeutic target. Cells with CD133 overexpression have demonstrated enhanced tumor-initiating ability and tumor relapse probability. To resolve the problem of chemotherapy failure, SN-38-loaded nanoparticles were conjugated with anti-CD133 antibody to target CD133-positive (CD133(+)) cells. In this study, anti-CD133 antibody-conjugated SN-38-loaded nanoparticles (CD133Ab-NPs-SN-38) efficiently bound to HCT116 cells, which overexpress CD133 glycoprotein. The cytotoxic effect of CD133Ab-NPs-SN-38 was greater than that of nontargeted nanoparticles (NPs-SN-38) in HCT116 cells. Furthermore, CD133Ab-NPs-SN-38 could target CD133(+) cells and inhibit colony formation compared with NPs-SN-38. In vivo studies in an HCT116 xenograft model revealed that CD133Ab-NPs-SN-38 suppressed tumor growth and retarded recurrence. A reduction in CD133 expression in HCT116 cells treated with CD133Ab-NPs-SN-38 was also observed in immunohistochemistry results. Therefore, this CD133-targeting nanoparticle delivery system could eliminate CD133-positive cells and is a potential cancer stem cell targeted therapy.

Combining the single-walled carbon nanotubes with low voltage electrical stimulation to improve accumulation of nanomedicines in tumor for effective cancer therapy.

Effective delivery of biomolecules or functional nanoparticles into target sites has always been the primary objective for cancer therapy. We demonstrated that by combining single-walled carbon nanotubes (SWNTs) with low-voltage (LV) electrical stimulation, biomolecule delivery can be effectively enhanced through reversible electroporation (EP). Clear pore formation in the cell membrane is observed due to LV (50V) pulse electrical stimulation amplified by SWNTs. The cell morphology remains intact and high cell viability is retained. This modality of SWNT + LV pulses can effectively transfer both small molecules and macromolecules into cells through reversible EP. The results of animal studies also suggest that treatment with LV pulses alone cannot increase vascular permeability in tumors unless after the injection of SWNTs. The nanoparticles can cross the permeable vasculature, which enhances their accumulation in the tumor tissue. Therefore, in cancer treatment, both SWNT + LV pulse treatment followed by the injection of LIPO-DOX® and SWNT/DOX + LV pulse treatment can increase tumor inhibition and delay tumor growth. This novel treatment modality applied in a human cancer xenograft model can provide a safe and effective therapy using various nanomedicines in cancer treatment.

In Vivo Effects of Free Form Astaxanthin Powder on Anti-Oxidation and Lipid Metabolism with High-Cholesterol Diet.

Astaxanthin extracted from Pomacea canaliculata eggs was made into free-form astaxanthin powder (FFAP) and its effects on lipid metabolism, liver function, antioxidants activities and astaxanthin absorption rate were investigated. 45 hamsters were split into 5 groups and fed with normal diet, high-cholesterol control (0.2% cholesterol), 1.6FFAP (control+1.6% FFAP), 3.2FFAP (control+3.2% FFAP) and 8.0FFAP (control+8.0% FFAP), respectively, for 6 weeks. FFAP diets significantly decreased the liver total cholesterol, triglyceride levels and increased liver fatty acids (C20:5n3; C22:6n3) compositions. It decreased plasma alanine aminotransferase and aspartate aminotransferase. In terms of anti-oxidative activities, we found 8.0 FFAP diet significantly decreased plasma and liver malonaldehyde (4.96±1.96 µg TEP eq./mL and 1.56±0.38 µg TEP eq./g liver) and liver 8-isoprostane levels (41.48±13.69 µg 8-ISOP/g liver). On the other hand, it significantly increased liver catalase activity (149.10±10.76 µmol/min/g liver), Vitamin C (2082.97±142.23 µg/g liver), Vitamin E (411.32±81.67 µg/g liver) contents, and glutathione levels (2.13±0.42 mg GSH eq./g liver). Furthermore, 80% of astaxanthin absorption rates in all FFAP diet groups suggest FFAP is an effective form in astaxanthin absorption. Finally, astaxanthin was found to re-distribute to the liver and eyes in a dose dependent manner. Taken together, our results suggested that the appropriate addition of FFAP into high cholesterol diets increases liver anti-oxidative activity and reduces the concentration of lipid peroxidase and therefore, it may be beneficial as a material in developing healthy food.

Traceable Self-Assembly of Laser-Triggered Cyanine-Based Micelle for Synergistic Therapeutic Effect.

To track nanocarriers, many researches adopt nanocarriers labeled with radiotracers or encapsulating near-infrared fluorescence (NIRF) dye. In this study, novel amphiphilic copolymers, methoxy poly(ethylene glycol) (mPEG)-cyanine-poly(ε-caprolactone) (PCL) (mPEG-Cy-PCL) are synthesized. mPEG-Cy-PCL are capable of performing NIRF imaging, photothermal therapy (PTT) on cancer cells and self-assembly nanocarriers. Cy-based micelles can encapsulate doxorubicin (Doxo@Cy-micelle) and achieve NIRF image-guided drug delivery. Doxo@Cy-micelles are nanosized micelles enhancing the accumulation of Doxo in tumor sites and decreasing side effects. Doxo@Cy-micelles exhibit an excellent PTT and synergistic chemotherapy of cancer via laser-triggered release of Doxo from micelles, eventually resulting in decreased cancer recurrence rates. The results show that Cy-based micelles are excellent nanocarriers for NIRF imaging and synergistic photothermal-chemotherapy of cancer.

Effects of water quality on dissolution of yerba mate extract powders.

Yerba mate tea is known as one of the most popular nonalcoholic beverages favoured by South Americans due to its nutrition facts and medicinal properties. The processing of yerba mate tea is found to affect the properties of its final forms. This study presents an investigation into the effects of water sources on the dissolution of yerba mate extract powders. Comparisons were conducted between yerba mate teas prepared by dissolving yerba mate extract powders into tap water and deionized water. Topics to be explored in this work are the major compositions and antioxidant activities, including total phenol content, reducing power, DPPH scavenging activity, and ABTS(+)• scavenging capacity. It is indicated that there is little difference for antioxidant activities and major constituents of yerba mate teas between both water sources. However, a deeper color is seen in the tap water case, resulting from the reaction between tannic acid and ions. This research finding can be treated as a way to benefit the yerba mate tea processing for applications.

Targeting colorectal cancer cells with single-walled carbon nanotubes conjugated to anticancer agent SN-38 and EGFR antibody.

In this study, single-walled carbon nanotubes (SWNTs) conjugated with antibody C225 were used to achieve targeted therapy against EGFR over-expressed colorectal cancer cells. In addition, the control release of the chemotherapeutic drug, 7-Ethyl-10-hydroxy-camptothecin (SN38), was studied. We used three different colorectal cancer cell lines, HCT116, HT29, and SW620, listed in the order of decreasing expression levels of EGFR. Our results showed that SWNT could use C225 to specifically bind to EGFR-expressed cells. The cellular uptakes of SWNT of EGFR over-expressed cells (HCT116 and HT29) were much higher than that of the negative control (SW620). We, next, demonstrated that receptor-mediated endocytosis was the primary cell entry route for SWNT. As a consequence, abundant amount of SN38 was released and EGFR over-expressed cells were killed. The drug control release process was studied by utilizing human carboxylesterase enzyme (hCE) that would break the bond linking SN38 and SWNT-carrier in cytoplasm. The intracellular SN38 release observed by confocal microscopy showed that SN38 actually dissociated from the SWNT-carrier first. SN38's entry to nucleus was then followed while the SWNT-carrier still remained in the cytoplasm. Overall, all these data suggested that SWNT could be a good carrier for targeting controlled release therapy.

Stability studies of ascorbic acid 2-glucoside in cosmetic lotion using surface response methodology.

Ascorbic acid 2-glucoside (AA-2G) has been widely used in cream and lotion types of cosmetic products. Thus, the degradation of AA-2G caused by the temperature change and pH variation was very critical for determining the bio-functionality of cosmetics. Response surface methodology (RSM) was introduced to study the influence of temperature and pH on the stability of AA-2G. The optimal condition of retaining AA-2G with the highest stability was determined to be 55.3°C and pH 6.4. The antioxidative activities of AA-2G including DPPH and ABTS free radical scavenging activities, metal chelating activity, and reducing ability were also determined. AA-2G was a good ascorbic acid derivative which could be used in cosmetic products as an active ingredient.

tert-Butyl 2-sulfanylidene-2,3-dihydro-1H-imidazole-1-carboxyl-ate.

In the title mol-ecule, C(8)H(12)N(2)O(2)S, the imidazole ring forms a dihedral angle of 5.9 (2)° with the mean plane of the carboxyl-ate group. In the crystal, mol-ecules are linked by pairs of N-H⋯S hydrogen bonds, forming inversion dimers.

Multimodal image-guided photothermal therapy mediated by 188Re-labeled micelles containing a cyanine-type photosensitizer.

Multifunctional micelles loaded with the near-infrared (NIR) dye and labeled with the radionuclide rhenium-188 ((188)Re) have been developed to provide multimodalities for NIR fluorescence and nuclear imaging and for photothermal therapy (PTT) of cancer. The NIR dye, IR-780 iodide, allowed the micelles to have dual functions in cancer NIR imaging and PTT. The (188)Re-labeled IR-780 micelles enabled imaging by NIR fluorescence and by microSPECT to guide the delivery of drugs and to monitor in real-time the tumor accumulation, intratumoral distribution, and kinetics of drug release, which serve as a basis of specific photothermal injury to the targeted tissue. We also investigated the biodistribution, generation of heat, and photothermal cancer ablation of IR-780 micelles of both in vitro and in vivo xenografts. Histopathology observed irreversible tissue damage, such as necrotic features, decreased cell proliferation, increased apoptosis of cells, and increased expression of heat shock proteins in the PTT-treated tumors. The (188)Re-labeled IR-780 micelles offer multifunctional modalities for NIR fluorescence and nuclear imaging and for PTT of cancer.