Cholesterol-directed nanoparticle assemblies based on single amino acid peptide mutations activate cellular uptake and decrease tumor volume.

Peptide drugs have been difficult to translate into effective therapies due to their low in vivo stability. Here, we report a strategy to develop peptide-based therapeutic nanoparticles by screening a peptide library differing by single-site amino acid mutations of lysine-modified cholesterol. Certain cholesterol-modified peptides are found to promote and stabilize peptide α-helix formation, resulting in selectively cell-permeable peptides. One cholesterol-modified peptide self-assembles into stable nanoparticles with considerable α-helix propensity stabilized by intermolecular van der Waals interactions between inter-peptide cholesterol molecules, and shows 68.3% stability after incubation with serum for 16 h. The nanoparticles in turn interact with cell membrane cholesterols that are disproportionately present in cancer cell membranes, inducing lipid raft-mediated endocytosis and cancer cell death. Our results introduce a strategy to identify peptide nanoparticles that can effectively reduce tumor volumes when administered to in in vivo mice models. Our results also provide a simple platform for developing peptide-based anticancer drugs

Mesenchymal stem cells as carriers and amplifiers in CRAd delivery to tumors

<p>Abstract</p> <p>Background</p> <p>Mesenchymal stem cells (MSCs) have been considered to be the attractive vehicles for delivering therapeutic agents toward various tumor diseases. This study was to explore the distribution pattern, kinetic delivery of adenovirus, and therapeutic efficacy of the MSC loading of E1A mutant conditionally replicative adenovirus Adv-Stat3(-) which selectively replicated and expressed high levels of anti-sense Stat3 complementary DNA in breast cancer and melanoma cells.</p> <p>Methods</p> <p>We assessed the release ability of conditionally replicative adenovirus (CRAd) from MSC using crystal violet staining, TCID₅₀assay, and quantitative PCR. In vitro killing competence of MSCs carrying Adv-Stat3(-) toward breast cancer and melanoma was performed using co-culture system of transwell plates. We examined tumor tropism of MSC by Prussian blue staining and immunofluorescence. In vivo killing competence of MSCs carrying Adv-Stat3(-) toward breast tumor was analyzed by comparison of tumor volumes and survival periods.</p> <p>Results</p> <p>Adv-Stat3(-) amplified in MSCs and were released 4 days after infection. MSCs carrying Adv-Stat3(-) caused viral amplification, depletion of Stat3 and its downstream proteins, and led to significant apoptosis in breast cancer and melanoma cell lines. In vivo experiments confirmed the preferential localization of MSCs in the tumor periphery 24 hours after tail vein injection, and this localization was mainly detected in the tumor parenchyma after 72 hours. Intravenous injection of MSCs carrying Adv-Stat3(-) suppressed the Stat3 pathway, down-regulated Ki67 expression, and recruited CD11b-positive cells in the local tumor, inhibiting tumor growth and increasing the survival of tumor-bearing mice.</p> <p>Conclusions</p> <p>These results indicate that MSCs migrate to the tumor site in a time-dependent manner and could be an effective platform for the targeted delivery of CRAd and the amplification of tumor killing effects.</p

Simulation of mud invasion and analysis of resistivity profile in sandstone formation module

To investigate the dynamic invasion process of drilling fluid, the parameters of the physical model in laboratory were optimized based on numerical simulation and a physical simulation system for mud invasion in undisturbed zone was developed. Then, the experiment of fresh water invasion in sandstone formation was conducted to measure the radial resistivity and mudcake parameters over time, and a mudcake porosity and permeability calculation model with the invasion time was proposed based on the measurement. Finally, the numerical simulation results were compared and calibrated with the physical simulation results to find out the regularity of drilling fluid invasion under formation conditions. The results show that the mudcake forms quickly and the porosity and permeability of the mudcake decrease sharply after the beginning of drilling fluid invasion, and the invasion process is mainly controlled by the mudcake after a certain period. The mudcake parameters model developed in this study can depict the changes of mudcake parameters during the invasion process. The characteristics of radial resistivity profile under mud invasion are affected by sandstone physical properties, mudcake parameters and formation water salinity. Key words: mud invasion, physical modeling, numerical simulation, mudcake, resistivity, porosity, permeabilit

Modification of Iron-Tailings Concrete with Biochar and Basalt Fiber for Sustainability

Currently, less than 15% of waste iron tailings are utilized. Iron tailings can be used as fine aggregate in concrete, but this kind of concrete has no coarse aggregate, resulting in low strength. Additionally, iron tailings contain some heavy metals, which will cause environmental pollution if improperly treated. In this study, the mechanical properties, sulfate resistance, and pore structure distribution of basalt fiber-biochar-concrete (PFB) were studied. Where basalt is to enhance the mechanical properties of samples, and biochar is to adsorb heavy metals in iron tailings, to prepare environmentally friendly materials. Unconfined compressive strength (UCS) test, flexural strength (FS), sulfate immersion test, leaching behavior, and mercury intrusion porosimetry (MIP) test were used to study the performance of the samples, and X-ray diffraction (XRD), Fourier transform infrared spectrometer (FTIR), and scanning electron microscope (SEM) was used to characterize the samples, explaining the change mechanism of the macroscopic test. The results show that the compressive strength of PFB increased by 2.5% but the flexural strength increased by 12%. The basalt and biochar improve the pore size distribution of samples, that is, the pore size greater than 10 nm is reduced while the pore size between 2 and 6 nm is increased. Biochar can effectively adsorb heavy metals of Cu, Zn, Pb, and Cd, and their leaching concentration is reduced by 50–70%. Basalt fiber improves the mixing performance of concrete, while biochar with a small particle size fills the micro pores in concrete; this paper provides a new idea of sustainability for the preparation of environmentally friendly materials and the utilization of waste iron tailings

A Probe for the Detection of Hypoxic Cancer Cells.

Hypoxia is a common feature of tumor cells. Nitroreductase (NTR), a common biomarker of hypoxia, has been widely used to evaluate the extent of tumor hypoxia. In this study, three fluorescent probes (FBN-1-3) were synthesized to monitor the extent of hypoxia in cancer cells in real time. FBN-1-3 were composed of a fluorescein analogue and one of three different aromatic nitro groups. Of these probes, FBN-1 showed excellent sensitivity and selectivity in detecting hypoxia via a reduction in O2 concentration. Confocal fluorescence imaging and flow cytometry demonstrated that HepG-2, A549, and SKOV-3 cells incubated with FBN-1 under reduced oxygen conditions showed significantly enhanced fluorescence. A mouse HepG-2 tumor model confirmed that FBN-1 responds rapidly to NTR and can be used to evaluate the degree of tumor hypoxia. The changes in intra- and extracellular NTR in tumor cells were also concurrently monitored, which did not reveal a link between NTR concentration and degree of hypoxia. Our work provides a functional probe for tumor hypoxia, and our results suggest the fluorescent response of our probe is due to a decrease in O2 concentration, and not NTR concentration

Near-Infrared Fluorogenic Probes with Polarity-Sensitive Emission for in Vivo Imaging of an Ovarian Cancer Biomarker

Lysophosphatidic acid (LPA, cutoff values ≥ 1.5 μM) is an effective biomarker for early stage ovarian cancer. The development of selective probes for LPA detection is therefore critical for early clinical diagnosis. Although current methods have been developed for the detection of LPA in solution, they cannot be used for tracking LPA in vivo. Here, we report a near-infrared (NIR) fluorescent probe that can selectively respond to LPA based on polarity-sensitive emission at a very low detection limit of 0.5 μM in situ. This probe exhibits a marked increase of fluorescence at 720 nm upon binding to LPA, allowing the direct visualization of LPA in vitro and in vivo without interference from other biomolecules. Moreover, the probe containing two arginine-glycine-aspartic acid units can be efficiently taken up by cancer cells based on an α_vβ₃ integrin receptor targeting mechanism. It also exhibits excellent biocompatibility and high pH stability in live cells and in vivo. Confocal laser scanning microscopy and flow cytometric imaging of SKOV-3 cells have confirmed that our probe can be used to image LPA in live cells. In particular, its NIR turn-on fluorescence can be used to effectively monitor LPA imaging in a SKOV-3 tumor-bearing mouse model. Our probe may pave the way for the detection of cancer-related biomarkers and even for early stage cancer diagnosis