Metastatic cancers are prone to form metastasis at a distance and acquire drug resistance, which are very common clinically and major obstacles to successful chemotherapy. Besides the tumor itself, the lymphatic system is increasingly emerging as a new target for anticancer therapy because it is an important route of tumor metastasis. To specifically deliver drug to both highly metastatic tumor and its lymphatics, tumor- and tumor lymphatics-homing peptide (LyP-1) conjugated PEG-PCL micelles (LyP-1-PM) were first constructed. Artemisinin (ART), a natural product with potential anticancer and antilymphangiogenesis effects, was chosen as the model drug and associated into the micelles. Both PM and LyP-1-PM had similar physiochemical properties, about 30 nm in size with uniform distribution. Highly metastatic breast cancer MDA-MB-435S cells and lymphatic endothelial cells (LEC) were applied as cell models. Flow cytometry and confocal microscopy studies showed that LyP-1-PM exhibited its specificity to both cell lines evidenced by its higher cellular uptake than PM. LyP-1-PM-ART demonstrated higher inhibition effect than PM-ART against these two cell lines in cell apoptosis, cell cycle and cytotoxicity tests. Near-infrared imaging showed that LyP-1-PM was distributed more in orthotopic MDA-MB-435S tumor than PM. Further study by colocalization indicated that PM accumulated near blood vessels, while LyP-1-PM further homed to tumor lymphatic vessels. LyP-1-PM achieved higher antitumor efficacy than other ART formulations in vivo with low toxicity. Both in vitro and in vivo studies here proved that LyP-1 modification enhanced the specific delivery of ART or fluorescent probe loaded polymeric micelles to MDA-MB-435S and LEC. Therefore, LyP-1-PM might be promising in terms of specific delivery of therapeutic or imaging agents to both highly metastatic breast tumor and its lymphatics.
Successful cancer therapies aim to induce selective apoptosis in neoplastic cells. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered an attractive anticancer agent due to its tumor cell-specific cytotoxicity. However, earlier studies with recombinant TRAIL revealed many shortcomings, including a short half-life, off-target toxicity and existence of TRAIL-resistant tumor cells. In this study, we developed a novel engineering strategy for recombinant soluble TRAIL by redesigning its structure with the adenovirus knobless fiber motif to form a stable homotrimer with improved antitumor activity. The result is a highly stable fiber-TRAIL fusion protein that could form homotrimers similar to natural TRAIL. The recombinant fusion TRAIL developed here displayed high specific activity in both cell-based assays in vitro and animal tests in vivo. This construct will serve as a foundation for a new generation of recombinant proteins suitable for use in preclinical and clinical studies and for effective combination therapies to overcome tumor resistance to TRAIL.
We report a new method for large-scale production of GaMnN nanowires, by annealing manganese-gallium oxide nanowires in flowing ammonia at high temperature. Microstructure analysis indicates that the GaMnN nanowires have wurtzite GaN structure without Mn precipitates or Mn-related second phases. Magnetic measurements reveal that ferromagnetic ordering exists in the GaMnN nanowires, whose Curie temperature is above room temperature. A mean-field model based on the exchange coupling of the nondegenerate carrierlocalized impurity band, together with the consideration of the superexchange antiferromagnetic interaction, is used to explain the physical origin of the observed ferromagnetic ordering. Theoretical calculations indicate that the Curie temperature increases with the increase of the hole density and reveal a small ratio of the hole to the magnetic dopant density in the samples. The low ratio of hole to Mn concentration and the superexchange antiferromagnetic interaction lead to the very concave temperature dependence of the magnetization curve in contrast to conventional ferromagnetic M-T behaviour. The theoretical calculation is in agreement with the experimental data.Recently, diluted magnetic semiconductors (DMSs) have attracted considerable attention since they manifest both the spin and charge properties of the carriers, and much effort has been devoted to spintronics from the viewpoint of fundamental physics and potential applications. A high-Curie-temperature DMS above room temperature is the key for applications. A breakthrough theoretical work reported that some wide-bandgap semiconductors such as GaN and ZnO are the most promising candidates for achieving practical ferromagnetic ordering with T c above room temperature [1,2]. Much work has then focused on the Mnbased II-VI and III-V semiconductor materials, such as GaMnAs, InMnAs, GaMnN and
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