Codelivery of CuS and DOX into Deep Tumors with Size and Charge-Switchable PAMAM Dendrimers for Chemo-photothermal Therapy.

Accurate targeting of therapeutic agents to specific tumor tissues, especially via deep tumor penetration, has been an effective strategy in cancer treatments. Here, we described a flexible nanoplatform, pH-responsive zwitterionic acylsulfonamide betaine-functionalized fourth-generation PAMAM dendrimers (G4-AB), which presented multiple advantages for chemo-photothermal therapy, including template synthesis of ultrasmall copper sulfide (CuS) nanoparticles and further encapsulation of doxorubicin (DOX) (G4-AB-DOX/CuS), long-circulating performance by a relatively large size and zwitterionic surface in a physiological environment, combined size shrinkage, and charge conversions via pH-responsive behavior in an acidic tumor microenvironment (TME). Accordingly, high tumor penetration and positive cell uptake for CuS and DOX have been determined, which triggered an excellent combination treatment under near-infrared irradiation in comparison to the monochemotherapy system and irresponsive chemo-photothermal system. Our study represented great promise in constructing multifunctional carriers for the effective delivery of photothermal nanoparticles and drugs in chemo-photothermal therapy.

Targeting of miR-150 on Gli1 gene to inhibit proliferation and cell cycle of esophageal carcinoma EC9706.

OBJECTIVE: Glioma-associated oncogene homolog 1 (Gli1) in Hedgehog signal pathway regulates Cyclin D1 expression, cell cycle or proliferation modulation. Esophageal cancer patients had significantly elevated Gli1 expression, which is related with survival and prognosis. It has been demonstrated that the level of miR-150 was decreased in esophageal cancer patients compared to normal control. As a complementary relationship exists between miR-150 and 3'-UTR of Gli1, this study investigated if miR-150 played a role in regulating Gli1 expression, and proliferation or cell cycle of esophageal cancer cells. PATIENTS AND METHODS: Esophageal squamous cell carcinoma (ESCC) patients from our hospital were recruited to collect tumor and adjacent tissues for miR-150 and Gli1 expression. Esophageal carcinoma cell line EC9706 and normal esophageal epithelial cell line HEEC were compared for expression of miR-150, Gli1 and Cyclin D1. Dual luciferase reporter gene assay examined the targeted relationship between miR-150 and 3'-UTR of Gli1. In vitro cultured EC9706 cells were treated with miR-150 mimic, si-Gli1 or the combination of miR-150 mimic and si-Gli1, respectively, to check their gene expression, cell cycle and proliferation. RESULTS: ESCC tissues had significantly higher Gli1 expression and lower miR-150 expression. EC9706 cell also had higher Gli1 expression than that in HEEC, whilst miR-150 was down-regulated. Via targeting 3'-UTR of Gli1 gene, miR-150 inhibited its expression. Transfection of miR-150 mimic, si-Gli1 or the combination of miR-150 mimic and si-Gli1, respectively, remarkably decreased expression of Gli1 and Cyclin D1 expression in EC9706 cells, whose cell cycle arresting at G0/G1 phase was enhanced with weakened proliferation. CONCLUSIONS: MiR-150 can induce G0/G1 cell cycle arresting and weaken proliferation of esophageal carcinoma cells via targeted inhibition on Gli1 and downstream expression of Cyclin D1.

Effects of vitexin on the pharmacokinetics and mRNA expression of CYP isozymes in rats.

In traditional therapy with Chinese medicine, vitexin has several pharmacological properties, including antinociceptive, antispasmodic, antioxidant, antimyeloperoxidase, and α-glucosidase inhibitory activities. Recently, vitexin was shown to protect the heart against ischemia/reperfusion injury in an in vitro model by inhibiting apoptosis. The purpose of this study was to find out whether vitexin influences the effect on rat cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C11, and CYP3A1) by using cocktail probe drugs in vivo; the influence on the levels of CYP mRNA was also studied. A cocktail solution at a dose of 5 mL/kg, which contained phenacetin (10 mg/kg), tolbutamide (1 mg/kg), and midazolam (5 mg/kg), was given as oral administration to rats treated with short or long period of intravenous vitexin via the caudal vein. Blood samples were collected at a series of time points, and the concentrations of probe drugs in plasma were determined by HPLC-mass spectrometry (MS)/MS. The corresponding pharmacokinetic parameters were calculated by the software of DAS 2.0. In addition, real-time reverse transcription-polymerase chain reaction was performed to determine the effects of vitexin on the mRNA expression of CYP1A2, CYP2C11, and CYP3A1 in rat liver. Treatment with short or long period of vitexin had no effects on rat CYP1A2. However, CYP3A1 enzyme activity was inhibited by vitexin in a concentration-dependent and time-dependent manner. Furthermore, CYP2C11 enzyme activity was induced after short period treatment but inhibited after long period of vitexin treatment. The mRNA expression results were in accordance with the pharmacokinetic results. In conclusion, vitexin can either inhibit or induce activities of CYP2C11 and CYP3A1. Therefore, caution is needed when vitexin is co-administered with some CYP2C11 or CYP3A1 substrates in clinic, which may result in treatment failure and herb-drug interactions.