Artesunate Exhibits Synergy With Cisplatin and Cytotoxicity for Upper Tract and Bladder Urothelial Carcinoma Cells.

BACKGROUND/AIM: Urothelial carcinoma (UC) may arise from the urothelium of the upper tract and the bladder. Cisplatin-based therapy remains the gold standard for UC treatment. The poor 5-year survival rate of UC patients creates an urgent need to develop new drugs for advanced UC therapy. Artesunate (ART), a traditional Chinese medicine for treating malaria, is a potential anticancer agent, but its antigrowth effects on upper tract and bladder UC have not been investigated. MATERIALS AND METHODS: The antigrowth effect of ART in HT 1376 (bladder UC cells) and BFTC 909 [upper tract urothelial carcinoma (UTUC) cells] was determined by the CCK-8 assay. Flow cytometric analysis was used to evaluate the cell cycle distribution and apoptosis. The cell cycle, apoptosis, and autophagy-related protein expression were analyzed by western blotting. The efficacy of combination treatment with cisplatin was determined by the Calcusyn software. RESULTS: ART induced HT 1376 and BFTC 909 cell death in a concentration- and time-dependent manner, inducing G2/M cell-cycle arrest. ART induced apoptosis and redox imbalance in HT 1376 and BFTC 909 cells. Application of the reactive oxygen species (ROS) scavenger, N-acetyl-L-cysteine (NAC), attenuated cell death in ART-treated UC cells. BFTC 909 cells show a better response after ART treatment. CONCLUSION: ART may be a candidate drug for treating UTUC and bladder UC while increasing the therapeutic effect of cisplatin.

Advances in Magnetic Nanoparticle-Mediated Cancer Immune-Theranostics.

Cancer immunotherapy is a cutting-edge strategy that eliminates cancer cells by amplifying the host's immune system. However, the low response rate and risks of inducing systemic toxicity have raised uncertainty in the treatment. Magnetic nanoparticles (MNPs) as a versatile theranostic tool can be used to target delivery of multiple immunotherapeutics and monitor cell/tissue responses. These capabilities enable the real-time characterization of the factors that contribute to immunoactivity so that future treatments can be optimized. The magnetic properties of MNPs further allow the implementation of magnetic navigation and magnetic hyperthermia for boosting the efficacy of immunotherapy. The multimodal approach opens an avenue to induce robust immune responses, minimize safety issues, and monitor immune activities simultaneously. Thus, the object of this review is to provide an overview of the burgeoning fields and to highlight novel technologies for next-generation immunotherapy. The review further correlates the properties of MNPs with the latest treatment strategies to explore the crosstalk between magnetic nanomaterials and the immune system. This comprehensive review of MNP-derived immunotherapy covers the obstacles and opportunities for future development and clinical translation.

Circulating tumor-cell-targeting Au-nanocage-mediated bimodal phototherapeutic properties enriched by magnetic nanocores.

Metastasis resulting from circulating tumor cells (CTCs) is associated with 90% of all cancer mortality. To disrupt cancer dissemination, therapeutic targeting of CTCs by extracorporeal photodynamic therapy (PDT) has emerged; however, it still remains impractical due to its limited therapeutic window. Herein, we developed a photosensitive and magnetic targeted core-satellite nanomedicine (TCSN) to augment the light-induced damage to the targeted cells. The magnetic nanocore (MNC) with multiple iron oxide nanoparticles stabilized using thiolated polyvinyl alcohol can magnetize the CTCs to achieve magnetic enrichment under a magnetic field. Multiple gold nanocage (AuNC) satellites were conjugated on the MNC to facilitate bimodal photothermal therapy and PDT. Adjusting the thiol content in the MNC allows manipulating the AuNC density on TCSNs, which has been found to demonstrate a density-dependent bimodal phototherapeutic effect under laser irradiation at 808 and 940 nm. Moreover, with the immobilization of anti-epithelial cell adhesion molecule (anti-EpCAM), TCSN exhibited an enhanced affinity toward EpCAM-expressing 4T1 cells. We demonstrate that TCSN-labeled 4T1 cells can be isolated and photo-eradicated in a microfluidic channel with a dynamic flow. Our studies showed that TCSN with the complementary properties of MNC and AuNCs can largely augment the therapeutic window by magnetic enrichment and bimodal phototherapy, serving as an advanced extracorporeal strategy to remove CTCs.

Rhodiolae Kirliowii Radix et Rhizoma and Crataegus pinnatifida Fructus Extracts Effectively Inhibit BK Virus and JC Virus Infection of Host Cells.

The human polyomaviruses BK (BKPyV) and JC (JCPyV) are ubiquitous pathogens long associated with severe disease in immunocompromised individuals. BKPyV causes polyomavirus-associated nephropathy and hemorrhagic cystitis, whereas JCPyV is the causative agent of the fatal demyelinating disease progressive multifocal leukoencephalopathy. No effective therapies targeting these viruses are currently available. The goal of this study was to identify Chinese medicinal herbs with antiviral activity against BKPyV and JCPyV. We screened extracts of Chinese medicinal herbs for the ability to inhibit hemagglutination by BKPyV and JCPyV virus-like particles (VLPs) and the ability to inhibit BKPyV and JCPyV binding and infection of host cells. Two of the 40 herbal extracts screened, Rhodiolae Kirliowii Radix et Rhizoma and Crataegus pinnatifida Fructus, had hemagglutination inhibition activity on BKPyV and JCPyV VLPs and further inhibited infection of the cells by BKPyV and JCPyV, as evidenced by reduced expression of viral proteins in BKPyV-infected and JCPyV-infected cells after treatment with Rhodiolae Kirliowii Radix et Rhizoma or Crataegus pinnatifida Fructus extract. The results in this work show that both Rhodiolae Kirliowii Radix et Rhizoma and Crataegus pinnatifida Fructus may be sources of potential antiviral compounds for treating BKPyV and JCPyV infections.

Magnetic hyperthermia enhance the treatment efficacy of peri-implant osteomyelitis.

BACKGROUND: When bacteria colony persist within a biofilm, suitable drugs are not yet available for the eradication of biofilm-producing bacteria. The aim of this study is to study the effect of magnetic nano-particles-induced hyperthermia on destroying biofilm and promoting bactericidal effects of antibiotics in the treatment of osteomyelitis. METHODS: Sixty 12-weeks-old male Wistar rats were used. A metallic 18G needle was implanted into the bone marrow cavity of distal femur after the injection of Methicillin-sensitive Staphylococcus aureus (MSSA). All animals were divided into 5 different treatment modalities. The microbiological evaluation, scanning electron microscope examination, radiographic examination and then micro-CT evaluation of peri-implant bone resorption were analyzed. RESULTS: The pathomorphological characteristics of biofilm formation were completed after 40-days induction of osteomyelitis. The inserted implants can be heated upto 75 °C by magnetic heating without any significant thermal damage on the surrounding tissue. We also demonstrated that systemic administration of vancomycin [VC (i.m.)] could not eradicate the bacteria; but, local administration of vancomycin into the femoral canal and the presence of magnetic nanoparticles hyperthermia did enhance the eradication of bacteria in a biofilm-based colony. In these two groups, the percent bone volume (BV/TV: %) was significantly higher than that of the positive control. CONCLUSIONS: For the treatment of chronic osteomyelitis, we developed a new modality to improve antibiotic efficacy; the protection effect of biofilms on bacteria could be destroyed by magnetic nanoparticles-induced hyperthermia and therapeutic effect of systemic antibiotics could be enhanced.

Sodium Dodecyl Sulfate-Modified Doxorubicin-Loaded Chitosan-Lipid Nanocarrier with Multi Polysaccharide-Lecithin Nanoarchitecture for Augmented Bioavailability and Stability of Oral Administration In Vitro and In Vivo.

For oral anti-cancer drug delivery, a new chitosan-lipid nanoparticle with sodium dodecyl sulfate modification was designed and synthesized using a double emulsification. TEM examination showed that the DOX-loaded nanoparticles, termed D-PL/TG NPs, exhibited a unique core-shell configuration composed of multiple amphiphilic chitosan-lecithin reverse micelles as the core and a triglyceride shell as a physical barrier to improve the encapsulation efficiency and reduce the drug leakage. In addition, the D-PL/TG NPs with sodium dodecyl sulfate modification on the surface have enhanced stability in the GI tract and increased oral bioavailability of doxorubicin. In vitro transport studies performed on Caco-2 monolayers indicated that the D-PL/TG NPs enhanced the permeability of DOX in the Caco-2 monolayers by altering the transport pathway from passive diffusion to transcytosis. The in vivo intestinal absorption assay suggested that the D-PL/TG NPs were preferentially absorbed through the specialized membranous epithelial cells (M cells) of the Peyer's patches, resulting in a significant improvement (8-fold) in oral bioavailability compared to that of free DOX. The experimental outcomes in this work demonstrate that the D-PL/TG NPs provide an exciting opportunity for advances in the oral administration of drugs with poor bioavailability that are usually used in treating tough and chronic diseases.

Functionalized graphene nanocomposites for enhancing photothermal therapy in tumor treatment.

Graphene and its derivatives have unique physical and chemical properties that make them promising vehicles for photothermal therapy (PTT)-based cancer treatment. With intrinsic near-infrared (NIR) absorption properties, graphene-based nanomaterials can be used for PTT and other therapeutics, particularly in combination therapy, to provide successful thermal ablation of cancer cells. In the recent years, advances in graphene-based PTT have produced efficient and efficacious tumor inhibition via nanomaterial structural design and different functionalizations of graphene-derived nanocomposites. Graphene-based nanosystems exhibit multifunctional properties that are useful for PTT applications including enhancement of multimodalities, guided imaging, enhanced chemotherapy and low-power efficient PTT for optimum therapeutic efficiency. Therefore, in this review, we address critical issues and future aspects of PTT-based combination therapy.

A theranostic nrGO@MSN-ION nanocarrier developed to enhance the combination effect of sonodynamic therapy and ultrasound hyperthermia for treating tumor.

Sonodynamic therapy (SDT), which induces activation of sonosensitizers in cancer cells through ultrasound irradiation, has emerged as an alternative and promising noninvasive therapeutic approach to kill both superficial and deep parts of tumors. In this study, mesoporous silica (MSN) grown on reduced graphene oxide nanosheet (nrGO) capped with Rose Bengal (RB)-PEG-conjugated iron-oxide nanoparticles (IONs), nrGO@MSN-ION-PEG-RB, was strategically designed to have targeted functionality and therapeutic efficacy under magnetic guiding and focused ultrasound (FUS) irradiation, respectively. The singlet oxygen produced by ultrasound-activated RB and the ultrasound-induced heating effect was enhanced by rGO and IONs, which improved the cytotoxic effect in cancer cells. In an animal experiment, we demonstrated that the combination of sonodynamic/hyperthermia therapy with magnetic guidance using this nanocomposite therapeutic agent can produce remarkable efficacious therapy in tumor growth inhibition. Furthermore, the combination effect induced by FUS irradiation produces significant damage to both superficial and deep parts of the targeted tumor.

A High-Sensitivity and Low-Power Theranostic Nanosystem for Cell SERS Imaging and Selectively Photothermal Therapy Using Anti-EGFR-Conjugated Reduced Graphene Oxide/Mesoporous Silica/AuNPs Nanosheets.

A high-sensitivity and low-power theranostic nanosystem that combines with synergistic photothermal therapy and surface-enhanced Raman scattering (SERS) mapping is constructed by mesoporous silica self-assembly on the reduced graphene oxide (rGO) nanosheets with nanogap-aligned gold nanoparticles (AuNPs) encapsulated and arranged inside the nanochannels of the mesoporous silica layer. Rhodamine 6G (R6G) as a Raman reporter is then encapsulated into the nanochannels and anti-epidermal growth factor receptor (EGFR) is conjugated on the nanocomposite surface, defined as anti-EGFR-PEG-rGO@CPSS-Au-R6G, where PEG is polyethylene glycol and CPSS is carbon porous silica nanosheets. SERS spectra results show that rGO@CPSS-Au-R6G enhances 5 × 10(6) magnification of the Raman signals and thus can be applied in the noninvasive cell tracking. Furthermore, it displays high sensitivity (detection limits: 10(-8) m R6G solution) due to the "hot spots" effects by the arrangements of AuNPs in the nanochannels of mesoporous silica. The highly selective targeting of overexpressing EGFR lung cancer cells (A549) is observed in the anti-EGFR-PEG-rGO@CPSS-Au-R6G, in contrast to normal cells (MRC-5). High photothermal therapy efficiency with a low power density (0.5 W cm(-2) ) of near-infrared laser can be achieved because of the synergistic effect by conjugated AuNPs and rGO nanosheets. These results demonstrate that the anti-EGFR-PEG-rGO@CPSS-Au-R6G is an excellent new theranostic nanosystem with cell targeting, cell tracking, and photothermal therapy capabilities.

Dual-Targeting Lactoferrin-Conjugated Polymerized Magnetic Polydiacetylene-Assembled Nanocarriers with Self-Responsive Fluorescence/Magnetic Resonance Imaging for In Vivo Brain Tumor Therapy.

Maintaining a high concentration of therapeutic agents in the brain is difficult due to the restrictions of the blood-brain barrier (BBB) and rapid removal from blood circulation. To enable controlled drug release and enhance the blood-brain barrier (BBB)-crossing efficiency for brain tumor therapy, a new dual-targeting magnetic polydiacetylene nanocarriers (PDNCs) delivery system modified with lactoferrin (Lf) is developed. The PDNCs are synthesized using the ultraviolet (UV) cross-linkable 10,12-pentacosadiynoic acid (PCDA) monomers through spontaneous assembling onto the surface of superparamagnetic iron oxide (SPIO) nanoparticles to form micelles-polymerized structures. The results demonstrate that PDNCs will reduce the drug leakage and further control the drug release, and display self-responsive fluorescence upon intracellular uptake for cell trafficking and imaging-guided tumor treatment. The magnetic Lf-modified PDNCs with magnetic resonance imaging (MRI) and dual-targeting ability can enhance the transportation of the PDNCs across the BBB for tracking and targeting gliomas. An enhanced therapeutic efficiency can be obtained using Lf-Cur (Curcumin)-PDNCs by improving the retention time of the encapsulated Cur and producing fourfold higher Cur amounts in the brain compared to free Cur. Animal studies also confirm that Lf targeting and controlled release act synergistically to significantly suppress tumors in orthotopic brain-bearing rats.

Magnetic core-shell nanocapsules with dual-targeting capabilities and co-delivery of multiple drugs to treat brain gliomas.

Lactoferrin (Lf)-tethered magnetic double emulsion nanocapsules (Lf-MDCs) are assembled from polyvinyl alcohol (PVA), polyacrylic acid (PAA), and iron oxide (IO) nanoparticles. The core-shell nanostructure of the Lf-MDCs (particle diameters from 100 to 150 nm) can simultaneously accommodate a hydrophilic drug, doxorubicin (Dox), and a hydrophobic drug, curcumin (Cur), in the core and shell, respectively, of the nanocapsules for an efficient drug delivery system. The release patterns of the two drugs can be regulated by manipulating the surface charges and drug-loading ratios, providing the capability for a stepwise adjuvant release to treat cancer cells. The results demonstrate that the dual (Dox+Cur)-drug-loaded nanocapsule can be effectively delivered into RG2 glioma cells to enhance the cytotoxicity against the cells through a synergistic effect. The combined targeting, i.e., magnetic guidance and incorporation of Lf ligands, of these Lf-MDCs results in significantly elevated cellular uptake in the RG2 cells that overexpress the Lf receptor. Interestingly, an intravenous injection of the co-delivered chemotherapeutics follows by magnetic targeting in brain tumor-bearing mice not only achieve high accumulation at the targeted site but also more efficiently suppress cancer growth in vivo than does the delivery of either drug alone.

Polysaccharide-lecithin reverse micelles with enzyme-degradable triglyceride shell for overcoming tumor multidrug resistance.

A newly-designed drug carrier with enzyme-triggered release behavior and the ability to circumvent multidrug resistance was successfully developed. By optimizing the ratio of lecithin and polysaccharide in reverse micelles, encapsulation efficiency and encapsulation stability can be significantly improved.

A novel multifunctional nano-platform with enhanced anti-cancer and photoacoustic imaging modalities using gold-nanorod-filled silica nanobeads.

The novel nano-seaurchin structure is characteristic of high-density and well-dispersed gold nanorods in one mesoporous silica nanobead. This nanoplatform provided increased photothermal stability, stable photoacoustic signal and highly efficient hyperthermia effect both in vitro and in vivo, indicating a powerful theranostic modality.

Core-shell nanocapsules stabilized by single-component polymer and nanoparticles for magneto-chemotherapy/hyperthermia with multiple drugs.

Iron-oxide-containing double emulsion capsules carrying both hydrophilic and hydrophobic therapeutic molecules can deliver drugs and energy on demand in vivo. Magneto-chemotherapy/hyperthermia involves a burst-like release of hydrophilic doxorubicin and hydrophobic paclitaxel, remotely triggered by a high frequency magnetic field, which also releases energy via internalized iron oxide nanoparticles, all contributing to cell kill.

Synthesis, characterization, and CO(2) adsorptive behavior of mesoporous AlOOH-supported layered hydroxides.

A novel CO(2) solid sorbent was prepared by synthesizing and modifying AlOOH-supported CaAl layered double hydroxides (CaAl LDHs), which were prepared by using mesoporous alumina (γ-Al(2)O(3)) and calcium chloride (CaCl(2)) in a hydrothermal urea reaction. The nanostructured CaAl LDHs with nanosized platelets (3-30 nm) formed and dispersed inside the crystalline framework of mesoporous AlOOH (boehmite). By calcination of AlOOH-supported LDHs at 700 °C, the mesoporous CaAl metal oxides exhibited ordered hexagonal mesoporous arrays or uniform nanotubes with a large surface area of 273 m(2) g(-1) , a narrow pore size distribution of 6.2 nm, and highly crystalline frameworks. The crystal structure of the calcined mesoporous CaAl metal oxides was multiphasic, consisting of CaO/Ca(OH)(2), Al(2)O(3), and CaAlO mixed oxides. The mesoporous metal oxides were used as a solid sorbent for CO(2) adsorption at high temperatures and displayed a maximum CO(2) capture capacity (≈45 wt %) of the sorbent at 650 °C. Furthermore, it was demonstrated that the mesoporous CaAl oxides showed a more rapid adsorption rate (for 1-2 min) and longer cycle life (weight change retention: 80 % for 30 cycles) of the sorbent because of the greater surface area and increased number of activated sites in the mesostructures. A simple model for the formation mechanism of mesoporous metal oxides is tentatively proposed to account for the synergetic effect of CaAl LDHs on the adsorption of CO(2) at high temperature.

Quantum-dot-tagged reduced graphene oxide nanocomposites for bright fluorescence bioimaging and photothermal therapy monitored in situ.

Quantum-dot-tagged reduced graphene oxide (QD-rGO) nanocomposites (left) internalized into targeted tumor cells display bright fluorescence from the QDs (right); by absorbing NIR radiation incident on the rGO and converting it into heat, they also cause simultaneous cell death and fluorescence reduction (bottom). The nanocomposite is thus capable of tumor imaging, photothermal therapy and in situ monitoring of treatment in progress.

Drug release behavior of chitosan-montmorillonite nanocomposite hydrogels following electrostimulation.

Nanocomposites hydrogel (nanohydrogel) composed of chitosan (CS) and montmorillonite (MMT) were prepared and systematically studied for drug release behavior following electrostimulation. The deterioration of the responsiveness and reversibility of CS upon repeated on-off electrostimulation switching operations are major limitations for clinical applications, as it suffers from too much structural instability for the precise control of the release of drug upon cyclic electrostimulation. To overcome these limitations, an inorganic phase, MMT, was incorporated in the CS matrix to enhance the anti-fatigue property and corresponding long-term stable release kinetics. X-ray diffraction analysis and time-dependent optical absorbance showed that the MMT incorporated into the nanohydrogel exhibited an exfoliated nanostructure. The exfoliated silica nanosheets are able to act as cross-linkers to form a network structure between the CS and MMT, and this difference in the cross-linking density strongly affects the release of vitamin B(12) under electrostimulation. With a lower MMT concentration (1 wt.%), the release kinetics of vitamin B(12) from the nanohydrogel shows a pseudo-zero-order release, and the release mechanism was changed from a diffusion-controlled mode to a swelling-controlled mode under electrostimulation. Further increasing the MMT content reduced both the diffusion exponent n and the responsiveness of the nanohydrogel to electrostimulation. In addition, a consecutively repeated "on" and "off" operation shows that the electroresponsiveness of the nanohydrogel with higher MMT concentrations was reduced, but its anti-fatigue behavior was considerably improved. In this work, the nanohydrogel with 2 wt.% MMT achieved a mechanically reliable and practically desirable pulsatile release profile and excellent anti-fatigue behavior, compared with that of the pure CS.

Biofunctional ZnO nanorod arrays grown on flexible substrates.

A square pattern of thioctic acid self-assembled ZnO nanorod arrays was grown on a large 4-in. thermoplastic polyurethane (TPU) flexible substrate via an in situ soluthermal process at low temperature (348 K). With the addition of dimercaptosuccinic acid (DMSA), the surface chemistry forms a disordered ZnO phase, and the morphology of the ZnO-DMSA nanorods changes with various DMSA addition times. As evidenced by the Zn2p3/2, C1s, O1s, S2p, and N-1s scans of X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD), DMSA and proteins were conjugated on the single crystalline ZnO nanorods. The photoluminescence (PL) spectra indicated that the optical properties of ZnO nanorod arrays were changed while the DMSA was inserted, and proteins were conjugated. Furthermore, a control test found that the ZnO nanorods show a significant improvement in sensitive characterization over the ZnO film. As another proteins (e.g., human serum albumin, HSA) were bound onto the ZnO-bovine serum albumin (BSA) nanorod arrays, an enhanced ultraviolet emission intensity was detected. On the basis of these results, one might be expected to conjugate specific biomolecules on the biofunctional ZnO nanorod arrays to detect the complementary biomolecules by PL detecting.