Therapeutic outcome for the treatment of glioma was often limited due to low permeability of delivery systems across the blood-brain barrier (BBB) and poor penetration into the tumor tissue. In order to overcome these hurdles, we developed the dual-targeting doxorubicin liposomes conjugated with cell-penetrating peptide (TAT) and transferrin (T7) (DOX-T7-TAT-LIP) for transporting drugs across the BBB, then targeting brain glioma, and penetrating into the tumor. The dual-targeting effects were evaluated by both in vitro and in vivo experiments. In vitro cellular uptake and three-dimensional tumor spheroid penetration studies demonstrated that the system could not only target endothelial and tumor monolayer cells but also penetrate tumor to reach the core of the tumor spheroids and inhibit the growth of the tumor spheroids. In vivo imaging further demonstrated that T7-TAT-LIP provided the highest tumor distribution. The median survival time of tumor-bearing mice after administering DOX-T7-TAT-LIP was significantly longer than those of the single-ligand doxorubicin liposomes and free doxorubicin. In conclusion, the dual-ligand liposomes comodified with T7 and TAT possessed strong capability of synergistic targeted delivery of payload into tumor cells both in vitro and in vivo, and they were able to improve the therapeutic efficacy of brain glioma in animals.

Purpose To translate a recombinant peptide containing the amino-terminal fragment (ATF) of urokinase plasminogen activator receptor-targeted magnetic iron oxide (IO) nanoparticles (uPAR-targeted human ATF-IONPs) into clinical applications, we conducted a pilot study to evaluate the toxicity and pharmacokinetics of this nanoparticle in normal rhesus monkeys. Methods We assessed the changes in the following: magnetic resonance imaging (MRI) signals from pretreatment stage to 14 days posttreatment, serum iron concentrations from 5 minutes posttreatment to 12 weeks posttreatment, routine blood examination and serum chemistry analysis results from pretreatment stage to 12 weeks after administration, and results of staining of the liver with Perls’ Prussian Blue and hematoxylin–eosin at 24 hours and 3 months posttreatment in two rhesus monkeys following an intravenous administration of the targeted nanoparticles either with a polyethylene glycol (ATF-PEG-IONP) or without a PEG (ATF-IONP) coating. Results The levels of alkaline phosphatase, alanine transaminase, and direct bilirubin in the two monkeys increased immediately after the administration of the IONPs but returned to normal within 20 days and stayed within the normal reference range 3 months after the injection. The creatinine levels of the two monkeys stayed within the normal range during the study. In addition, red blood cells, white blood cells, hemoglobin level, and platelets remained normal during the 3 months of the study. Conclusion All of the results suggest that a transient injury in terms of normal organ functions, but no microscopic necrotic lesions, was observed at a systemic delivery dose of 5 mg/kg of iron equivalent concentration in the acute phase, and that no chronic toxicity was found 3 months after the injection. Therefore, we conclude that uPAR-targeted IONPs have the potential to be used as receptor-targeted MRI contrasts as well as theranostic agents for the detection and treatment of human cancers in future studies.

Objective Evaluation of the efficacy of adeno‐associated virus 2 mediated gene transfer of vascular endothelial growth factor Trap (AAV2‐VEGF‐Trap) alone or combination with paclitaxel in a mouse model of triple‐negative breast cancer (TNBC) using diffusion‐weighted magnetic resonance imaging (DW‐MRI) and in vivo fluorescence imaging. Materials and Methods Xenografted TNBC tumors were established by subcutaneous injection of MDA‐MB‐231 cells into nude mice. Tumors were treated with AAV2‐VEGF‐Trap, paclitaxel, AAV2‐VEGF‐Trap combined with paclitaxel and control. A 7.0‐Tesla magnetic resonance (MR) was used to obtain the apparent diffusion coefficient (ADC) values and ΔADC values. In vivo fluorescence imaging coupled with the optical imaging probe AngioSense680 EX was acquired to obtain average luminous intensity values. Immunohistochemical staining of tumor Ki‐67 and vascular endothelial cell marker antigen (CD31) were used to evaluate the effects on tumor proliferation and angiogenesis. Results The combination of AAV2‐VEGF‐Trap with paclitaxel exhibited greater tumor growth inhibition compared with the other groups. The ADC values in the paclitaxel group and the AAV2‐VEGF‐Trap in combination with paclitaxel group were significant greater compared with the control group, and the ΔADC values of all treatment groups were significantly increased compared with the control group on the 14th day after administration. Decreased microvessel density and luminous intensity in the treatment groups that contain AAV2‐VEGF‐Trap were observed. Reduced proliferation activity was noted in groups that contained paclitaxel. Conclusion AAV2‐VEGF‐Trap inhibits TNBC growth though inhibiting tumor neovascularization with a single intravenous injection, and AAV2‐VEGF‐Trap exhibits a synergistic effect when used in combination with paclitaxel for TNBC neoadjuvant therapy. In vivo fluorescence imaging can detect the anti‐angiogenesis effect of AAV2‐VEGF‐Trap early and noninvasively. DW‐MRI can longitudinally monitor the neoadjuvant efficacy of TNBC.

This study investigated the effect of a lotic environment on morphological characteristics and energy metabolism in juvenile grass carp Ctenopharyngodon idella. The fish were stocked in the lotic environment and forced to swim for 12 h per day for 4 weeks at three water current velocities of 0.5, 2, and 4 body length s−1 (Bl s−1). The control fish were stocked in the lentic environment with water current velocities of 0 Bl s−1. The results showed that lotic environment significantly increased body weight, body length, and condition factor of grass carp. The first principal component (PC1) characterized by measured overall body size suggested that fish in a lotic environment had body stoutness and wider tail stalk. Standard metabolic rate (SMR), maximum metabolic rate (MMR), and aerobic swimming performance (Ucrit) were elevated with the increased water flow and positively correlated with PC1. The 4 Bl s−1 group showed significantly decreased contents of serum glucose and muscular glycogen, and a significantly increased level of serum lactic acid. The mRNA expression levels of AMP-activated protein kinase-phosphorylate PPAR γ coactivator 1 α-nuclear respiratory factor 1 (AMPK-PGC1α-NRF1) pathway-related genes were significantly upregulated in red muscle of grass carp in the lotic environment. Water flow environment at 4 Bl s−1 significantly increased ratios of metabolic enzymes (lactate dehydrogenase/citrate synthase) and cytochrome c oxidase/citrate synthase) in the muscle. The relationship between morphological characteristics and metabolic capacity suggested that the body size of grass carp in a lotic environment was shaped to promote energy metabolism. The study identified the evidence of the mechanism and relationship of the trade-off between energy and morphology in grass carp.

In this work, the performance of medium-pressure UV/peracetic acid (MPUV/PAA/H2O2) was explored on removing reactive black 5 (RB5), aniline (ANL), and polyvinyl alcohol (PVA), three typical refractory contaminants in printing and dyeing wastewater, compared with MPUV/H2O2. MPUV/PAA/H2O2 showed 75.0, 44.9, and 57.7% removals of RB5, ANL, and PVA, respectively, within 5 min. The removal of RB5 increased from 68.98 to 91.2%, with pH increasing from 6 to 9, while the removals of ANL and PVA were much less pH-dependent. Quenching experiment results indicated that UV photolysis and radical (i.e., •OH and R-C•) oxidation contributed to RB5 removal, while PAA showed high activity in the oxidation of ANL. For PVA, •OH oxidation and UV photolysis were likely the main mechanisms. The coexisting natural organic matter had a negative effect on the degradation of RB5 and PVA. In addition, MPUV/PAA/H2O2 could effectively degrade those pollutants without increasing the toxicity. This work provides a theoretical reference for the utilization of MPUV/PAA/H2O2 in removing structurally diverse refractory contaminants from printing and dyeing wastewater.