Core/Shell Structured Fe3O4@TiO2-DNM Nanospheres as Multifunctional Anticancer Platform: Chemotherapy and Photodynamic Therapy Research.

The dose-dependent toxicity and low specificity against cancerous cells have restricted the clinical use of daunomycin (DNM). Titanium dioxide (TiO2) has been wildly used as an inorganic photodynamic therapy (PDT) agent and drug carrier. To facilitate the targeted drug delivery and combined therapy, in the present study, TiO2-coated Fe3O4 nanoparticles (Fe3O4@TiO2 NPs) were employed to load DNM and the drug-loaded Fe3O4@TiO2-DNM Nps exhibited smart pH-controlled releasing and satisfactory cytotoxicity as well as photocytotocity. The combination of prussian blue staining and fluorescence methods evidenced the effortless cell internalization of the fabricated Fe3O4@TiO2-DNM Nps for the cancer cells. The cell cycle status experiments indicated that the as-prepared nanospheres arrested the S and G2/M periods of the cancer cell proliferation in the dark, and further induced the apoptosis under the irradiation of ultraviolet light. The cell apoptotic results revealed that the apoptosis induced by the Fe3O4@TiO2-DNM Nps was in the early stage. The constructed Fe3O4@TiO2-DNM NPs have been endowed with multifunctions that allow them to selectively deliver combinatorial therapeutic payload and exhibit integrated therapeutic effectiveness to tumors.

Expression and prognostic value of soluble CD97 and its ligand CD55 in intrahepatic cholangiocarcinoma.

The incidence rate of intrahepatic cholangiocarcinoma is rising, and treatment options are limited. Therefore, new biological markers of intrahepatic cholangiocarcinoma are needed. Immunohistochemistry and enzyme-linked immunosorbent assay were applied to analyze the expressions of CD97, CD55, and soluble CD97 in 71 patients with intrahepatic cholangiocarcinoma and 10 patients with hepatolithiasis. CD97 and CD55 were not expressed in hepatolithiatic tissues, but positive expression was observed in 76.1% (54/71) and 70.4% (50/71) of intrahepatic cholangiocarcinoma patients. The univariate analyses indicated that the positive expressions of CD97 and CD55 were related to short intrahepatic cholangiocarcinoma survival of patients (both p = 0.001). Furthermore, CD97 and CD55 expressions and biliary soluble CD97 levels were significantly associated with histological grade (p = 0.004, 0.002, and 0.012, respectively), lymph node metastases (p = 0.020, 0.038, and 0.001, respectively), and venous invasion (p = 0.003, 0.002, and 0.001, respectively). The multivariate analyses indicated that lymph node metastases (hazard ratio: 2.407, p = 0.003), positive CD55 expression (hazard ratio: 4.096, p = 0.003), and biliary soluble CD97 levels (hazard ratio: 2.434, p = 0.002) were independent risk factors for the intrahepatic cholangiocarcinoma survival. The receiver operating characteristic (ROC) curve analysis indicated that when the cutoff values of biliary soluble CD97 were 1.15 U/mL, the diagnostic value for predicting lymph node metastasis had a sensitivity of 87.5% and a specificity of 51.3%. For intrahepatic cholangiocarcinoma patient death within 60 months at a cutoff value of 0.940 U/mL, the diagnostic value sensitivity was 89.3% and the specificity was 93.3%. Biliary soluble CD97 may be a new biological marker for early diagnosis, prediction of lymph node metastasis and poor prognosis, and discovery of a therapeutic target.

Serum vascular endothelial growth factors C and D as forecast tools for patients with gallbladder carcinoma.

Gallbladder carcinoma (GBC) is the most common cancer of the biliary tract. Lymph node metastasis (LNM) is the major diffusion route of GBC and is a prognosis factor. The aim of study was to assess the potential of the serum VEGF-C and VEGF-D (sVEGF-C/D) levels to predict the presence of LNM and the survival of GBC patients. The preoperative sVEGF-C/D levels of 31 patients with GBC, 10 patients with cholesterol polyps, and 10 healthy volunteers were measured by enzyme-linked immunoadsorbent assay (ELISA). The sVEGF-C/D levels of patients with GBC were significantly higher than those of people with healthy gallbladders (p < 0.001 and p = 0.001, respectively) and cholesterol polyp (p = 0.032 and p = 0.004, respectively). In GBC, the sVEGF-C levels were associated with LNM (p = 0.011), distant metastasis (p = 0.018), and stage (p = 0.045), but the sVEGF-D levels had a significant association with the tumor depth (p = 0.001), LNM (p = 0.001), distant metastasis (p = 0.047), and stage (p = 0.002). The sVEGF-C/D diagnostic values for the presence of GBC were sensitivity of 71.0 and 74.2 % and specificity of 80.0 and 85.0 %, respectively. With respect to the diagnosis of LNM, the diagnostic values of sVEGF-C/D were as follows: sensitivity 81.2 and 87.5 % and specificity 73.3 and 80.0 %, respectively. The mean survival time with high sVEGF-C was significantly shorter than that with low sVEGF-C (p < 0.001), which was also true for low sVEGF-D (p = 0.032). The preoperative sVEGF-C/D levels might be reliable biomarkers for the presence of disease and LNM in patients with GBC. The sVEGF-C/D levels may be prognosis factors that can predict a poor outcome for GBC patients.

Calcium carbonate end-capped, folate-mediated Fe3O4@mSiO2 core-shell nanocarriers as targeted controlled-release drug delivery system.

Magnetic mesoporous silica nanospheres (MMSN) were prepared and the surface was modified with cancer cell-specific ligand folic acid. Calcium carbonate was then employed as acid-activated gatekeepers to cap the mesopores of the MMSN, namely, MMSN-FA-CaCO3. The formation of the MMSN-FA-CaCO3 was proved by several characterization techniques, viz. transmission electron microscopy, zeta potential measurement, Fourier transform infrared spectroscopy, BET surface area measurement, and UV-Vis spectroscopy. Daunomycin was successfully loaded in the MMSN-FA-CaCO3 and the system exhibited sensitive pH stimuli-responsive release characteristics under blood or tumor microenvironment. Cellular uptake by folate receptor (FR)-overexpressing HeLa cells of the MMSN-FA-CaCO3 was higher than that by non-folated-conjugated ones. Intracellular-uptake studies revealed preferential uptake of these nanoparticles into FR-positive [FR(+)] HeLa than FR-negative [FR(-)]A549 cell lines. DAPI stain experiment showed high apoptotic rate of MMSN-FA-DNM-CaCO3 to HeLa cells. The present data suggest that the CaCO3 coating and folic acid modification of MMSN are able to create a targeted, pH-sensitive template for drug delivery system with application in cancer therapy.

Shedding lights on the flexible-armed porphyrins: Human telomeric G4 DNA interaction and cell photocytotoxicity research.

DNA polymorphism exerts a fascination on a large scientific community. Without crystallographic structural data, clarification of the binding modes between G-quadruplex (G4) and ligand (complex) is a challenging job. In the present work, three porphyrin compounds with different flexible carbon chains (arms) were designed, synthesized and characterized. Their binding, folding and stabilizing abilities to human telomeric G4 DNA structures were comparatively researched. Positive charges at the end of the flexible carbon chains seem to be favorable for the DNA-porphyrin interactions, which were evidenced by the spectral results and further confirmed by the molecular docking calculations. Biological function analysis demonstrated that these porphyrins show no substantial inhibition to Hela, A549 and BEL 7402 cancer cell lines under dark while exhibit broad inhibition under visible light. This significantly enhanced photocytotoxicity relative to the dark control is an essential property of photochemotherapeutic agents. The feature of the flexible arms emerges as critical influencing factors in the cell photocytotoxicity. Moreover, an ROS-mediated mitochondrial dysfunction pathway was suggested for the cell apoptosis induced by these flexible-armed porphyrins. It is found that the porphyrins with positive charges located at the end of the flexible arms represent an exciting opportunity for photochemotherapeutic anti-cancer drug design.

Daunomycin-loaded superparamagnetic iron oxide nanoparticles: Preparation, magnetic targeting, cell cytotoxicity, and protein delivery research.

The clinical use of daunomycin is restricted by dose-dependent toxicity and low specificity against cancer cells. In the present study, modified superparamagnetic iron oxide nanoparticles were employed to load daunomycin and the drug-loaded nanospheres exhibited satisfactory size and smart pH-responsive release. The cellular uptake efficiency, targeted cell accumulation, and cell cytotoxicity experimental results proved that the superparamagnetic iron oxide nanoparticle-loading process brings high drug targeting without decreasing the cytotoxicity of daunomycin. Moreover, a new concern for the evaluation of nanophase drug delivery's effects was considered, with monitoring the interactions between human serum albumin and the drug-loaded nanospheres. Results from the multispectroscopic techniques and molecular modeling calculation elucidate that the drug delivery has detectable deleterious effects on the frame conformation of protein, which may affect its physiological function.