Focused ultrasound (FUS) exposure with the presence of microbubbles has been shown to transiently open the blood-brain barrier (BBB), and thus has potential to enhance the delivery of various kinds of therapeutic agents into brain tumors. The purpose of this study was to assess the preclinical therapeutic efficacy of FUS-BBB opening for enhanced temozolomide (TMZ) delivery in glioma treatment. FUS exposure with microbubbles was delivered to open the BBB of nude mice that were either normal or implanted with U87 human glioma cells. Different TMZ dose regimens were tested, ranging from 2.5 to 25 mg/kg. Plasma and brain samples were obtained at different time-points ranging from 0.5 to 4 hours, and the TMZ concentration within samples was quantitated via a developed LC-MS/MS procedure. Tumor progression was followed with T2-MRI, and animal survival and brain tissue histology were conducted. Results demonstrated that FUS-BBB opening caused the local TMZ accumulation in the brain to increase from 6.98 to 19 ng/mg. TMZ degradation time in the tumor core was found to increase from 1.02 to 1.56 hours. Improved tumor progression and animal survival were found at different TMZ doses (up to 15% and 30%, respectively). In conclusion, this study provides preclinical evidence that FUS-BBB opening increases the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting the potential for clinical application to improve current brain tumor treatment.

In clinical tumor therapy, chemotherapeutic routes have caused severe side effects; current delivery methods are unsatisfactory. Successful design of a remotely folate (FA)-grafted chitosan (CS)-coated magnetic nanoparticle (MNP) with low toxicity, has been achieved. A chemotherapeutic drug such as doxorubicin (DOX), is loaded in the MNP-based matrix (FA-grafted CS-DOX-_TPP-MNP), which is coated by an activated target tumor molecule of FA-grafted CS biopolymer with the inclusion of tripolyphosphate (TPP) as a linker. The resultant nano-complexes exhibited random aggregates (~240 nm) and zeta potential (−24.9 mV). In vivo experiments using athymic BALB/c nude mice with human glioblastoma U87 cells in a subcutaneous tumor model revealed that magnetic guidance of FA-grafted CS-DOX-_TPP-MNP, injected via the tail vein, significantly decreased tumor growth. This manuscript demonstrates the feasibility of magnetizing control of FA-grafted CS-DOX-_TPP-MNP to enhance the localization of drug release.

To date, knowing how to identify the location of chemotherapeutic agents in the human body after injection is still a challenge. Therefore, it is urgent to develop a drug delivery system with molecular imaging tracking ability to accurately understand the distribution, location, and concentration of a drug in living organisms. In this study, we developed bovine serum albumin (BSA)-based nanoparticles (NPs) with dual magnetic resonance (MR) and fluorescence imaging modalities (fluorescein isothiocyanate [FITC]-BSA-Gd/1,3-bis(2-chloroethyl)-1-nitrosourea [BCNU] NPs) to deliver BCNU for inhibition of brain tumor cells (MBR 261-2). These BSA-based NPs are water dispersible, stable, and biocompatible as confirmed by XTT cell viability assay. In vitro phantoms and in vivo MR and fluorescence imaging experiments show that the developed FITC-BSA-Gd/BCNU NPs enable dual MR and fluorescence imaging for monitoring cellular uptake and distribution in tumors. The T1 relaxivity (R1) of FITC-BSA-Gd/BCNU NPs was 3.25 mM^-1 s^-1, which was similar to that of the commercial T1 contrast agent (R1 =3.36 mM^-1 s^-1). The results indicate that this multifunctional drug delivery system has potential bioimaging tracking of chemotherapeutic agents ability in vitro and in vivo for cancer therapy.

Chemoresistance mechanisms of colorectal cancer remain largely elusive. We aim to compare the difference of chemotherapy responses between FOLFOX-resistant and wild-type colorectal cancer cells by proteomic profiling to suggest novel treatment targets. FOLFOX-resistant colorectal cancer cells DLD1-R and HCT116-R were developed by chronic exposure to progressive FOLFOX doses. Proteomic profiling of FOLFOX-resistant and wild-type cells under FOLFOX exposure were conducted by mass-spectrometry-based protein-analysis technology. Verification of selected KEGG pathways was conducted by Western blot. DLD1-R had significantly higher FOLFOX-chemoresistance (10.81 times) than its wild-type counterpart. A total of 309 and 90 differentially expressed proteins were identified in DLD1-R and HCT116-R, respectively. In terms of gene ontology molecular function, RNA binding and cadherin binding ranked first for DLD1 and HCT116 groups, respectively. For gene set enrichment analysis, ribosome pathway and DNA replication were significantly up-regulated and down-regulated in DLD1-R, respectively. The most significantly up-regulated pathway in HCT116-R was regulation of the actin cytoskeleton. Up-regulations in the ribosome pathway (DLD1-R) and actin cytoskeleton (HCT116-R) were verified by Western blot. There were several significantly altered signaling pathways in FOLFOX-resistant colorectal cancer cells under FOLFOX with notable up-regulations in the ribosomal process and actin cytoskeleton.

The July 2021 floods costed up to 200 lives and 30 billion euros of damages in Germany alone. The aftermath of this exceptional event was a wake-up call for questioning the ability of the hydrometeorological tools in providing timely and reliable flood forecasts, knowing that this kind of events will become more frequent due to global warming. For these events, we simulated the hourly streamflows of seven catchments in the west of Germany, by combining nine, partly polarimetric, radar-based rainfall products with two hydrological models: GR4H (Ficchì et al., 2019, 10.1016/j.jhydrol.2019.05.084), a bucket-style, lumped model, and ParFlow-CLM (Kollet and Maxwell, 2006, 10.1016/j.advwatres.2005.08.006), a distributed model that couples 3D sub-surface and overland flows. GR4H parameters were calibrated using more than 10 years of rainfall-runoff data, with emphasis on reproducing high flows, whereas ParFlow-CLM parameters were estimated based on landscape and soil properties. The key findings are as follows: (1) In comparison with estimates from rain gauges, all radar-based precipitation products underestimate the total precipitation depths for the 14th of July, with significant differences among the products. This is most likely due to strong coalescence processes below the height monitored by the radars. (2) The hydrographs simulated by GR4H and ParFlow-CLM are similar for 3 of the 7 catchments, whereas the differences in the remaining ones could be explained by the effect of human water management, not represented in ParFlow-CLM. (3) The ability to detect the exceedance of the 100-year flood highly depends on the precipitation product used, highlighting the need for reliable precipitation estimates to reproduce such exceptional events.