ABSTRACT Glioblastoma (GBM) is the most complex and lethal adult primary brain cancer. Adequate drug diffusion and penetration are essential for treating GBM, but how the spatial heterogeneity in GBM impacts drug diffusion and transport is poorly understood. Herein, we report a new method, photoactivation of plasmonic nanovesicles (PANO), to measure molecular diffusion in the extracellular space of GBM. By examining three genetically engineered GBM mouse models that recapitulate key clinical features including angiogenic core and diffuse infiltration, we found that the tumor margin has the lowest diffusion coefficient (highest tortuosity) compared with the tumor core and surrounding brain tissue. Analysis of the cellular composition shows that the tortuosity in the GBM is strongly correlated with neuronal loss and astrocyte activation. Our all-optical measurement reveals the heterogeneous GBM microenvironment and highlights the tumor margin as a diffusion barrier for drug transport in the brain, with implications for therapeutic delivery.
Abstract Unconventional fluorescent polymers are attracting increasing attention because of their excellent biocompatibility and wide applications. However, these polymers typically exhibit weak long‐wavelength emission. Herein, three novel aliphatic linear polyphosphate esters are prepared via a one‐pot polycondensation reaction. Such polymers can generate strong blue, green, yellow, and red fluorescence under different excitations. Experimental and theoretical results showed that the cluster of C═C and phosphate ester groups attracted the negative charge of isolated functional groups, and the alkane chains and hydrogen atoms also provided a negative charge for spatial electronic communication. Then, intrinsic fluorescence arises from the charge‐transfer‐induced enhanced spatial electronic communication. Additionally, these polymers show potential applications in fluorescence film, ion detection, bacteria imaging, and visualization of the NaCl crystallization process. This work provides a universal design strategy for developing strong long‐wavelength emissive polymers and gains new insight into intrinsic emission mechanisms.
Abstract Glioblastoma multiforme (GBM) is the most prevalent malignant tumor in the central nervous system. It has diverse phenotypes, including diffuse single-cell infiltration in which the tumor cells co-opt the normal microvasculature, and the neovascularization of an expanding tumor mass. The blood-brain-tumor barrier (BBTB) is a significant obstacle to GBM treatment and restricts entry of most FDA-approved effective oncology drugs. Herein, we report that picosecond laser excitation of vascular-targeted plasmonic gold nanoparticles (AuNPs) can non-invasively and reversibly modulate the BBTB permeability (optoBBTB). OptoBBTB enhances the delivery of paclitaxel (Taxol) in two genetically engineered glioma models (GEMM) that span the spectrum of GBM phenotypes. OptoBBTB followed by Taxol delivery effectively suppresses tumor growth and prolongs the survival time of both GEMM. Moreover, our results raise the possibility that paclitaxel, which is amongst the most widely used oncology drugs because of its proven efficacy but has been abandoned for GBM following its failure to efficacy in early phase clinical trials due to poor blood-brain barrier (BBB) penetration, could now be reconsidered in combination with strategies to increase BBB permeability. In summary, optoBBTB is a novel and effective approach to increase the delivery of therapeutics with limited BBB permeability to treat neoplastic and non-neoplastic brain diseases.
Prospective observation of hemodynamic changes before and after the formation of atherosclerotic stenosis in the carotid artery is difficult. Thus, a vessel surface repairing method was used for retrospective hemodynamic study before and after atherosclerotic stenosis formation in carotid artery. The three-dimensional geometry of sixteen sinus atherosclerotic stenosis carotid arteries were repaired and restored as normal arteries. Computational fluid dynamics analysis was performed to estimate wall shear stress (WSS), velocity and vortex in atherosclerosis-free areas and sinus in stenosis-repaired carotid artery. The analysis was also performed in the stenotic segment and upstream and downstream of stenosis in stenotic carotid artery. Compared to the atherosclerosis-free areas in stenosis-repaired carotid artery, sinus presented significantly lower WSS (P < 0.05), lower velocity (P < 0.05) and apparent vortex. Compared to the sinus, the WSS in the upstream of stenosis was lower (P < 0.05), while in the downstream area was similar (P = 0.87), both upstream and downstream of stenosis demonstrated similar velocity to sinus (P = 0.76 and P = 0.36, respectively) and apparent vortex. Atherosclerosis-prone areas including normal carotid sinus and upstream and downstream of stenosis in stenotic carotid artery were subjected to lower WSS and velocity as well as apparent vortex, thereby might be associated with the formation and progress of atherosclerosis.
Purpose To noninvasively monitor carotid plaque vulnerability by exploring the relationship between pharmacokinetic parameters (PPs) of dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) and plaque types based on MRI‐modified American Heart Association (AHA) classification, as well as to assess the ability of PPs in discrimination between stable and vulnerable plaques suspected on MRI. Materials and Methods Of 70 consecutive patients with carotid plaques who volunteered for 3.0T MRI (3D time‐of‐flight [TOF], T 1 ‐weighted, T 2 ‐weighted, 3D magnetization‐prepared rapid acquisition gradient‐echo [MP‐RAGE] and DCE‐MRI), 66 participants were available for analysis. After plaque classification according to MRI‐modified AHA Lesion‐Type (LT), PPs ( K trans , k ep , v e , and v p ) of DCE‐MRI were measured. The Extended Tofts model was used for calculation of PPs. For participants with multiple carotid plaques, the plaque with the worst MRI‐modified AHA LT was chosen for analysis. Correlations between PPs and plaque types and the ability of these parameters to distinguish stable and vulnerable plaques suspected on MRI were assessed. Results Significant positive correlation between K trans and LT III to VI was found (ρ = 0.532, P < 0.001), as was the correlation between k ep and LT III to VI (ρ = 0.409, P < 0.001). Stable and vulnerable plaques suspected on MRI could potentially be distinguished by K trans (sensitivity 83%, specificity 100%) and k ep (sensitivity 77%, specificity 91%). Conclusion K trans and k ep from DCE‐MRI can provide quantitative information to monitor plaque vulnerability in vivo and differentiate vulnerable plaques suspected on MRI from stable ones. These two parameters could be adopted as imaging biomarkers for plaque characterization and risk stratification. Level of Evidence : 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:870–876
A double-mesoporous nanosystem was synthesized for treating as well as imaging cancer cells by using a simple and mild method. The mesoporous platinum (Pt) nanoparticles acting as a core show excellent photothermal effect under illumination with an 808 nm near infrared (NIR) laser. The mesoporous silica linked with a lanthanide (Gd) complex acting as a shell displays potential applications as a contrast agent for magnetic resonance imaging (MRI). The final mPt@mSiO2-GdDTPA nanosystems exhibit good biocompatibility in vitro and in vivo, when investigated by methyl thiazolyl tetrazolium assay and histological and serum biochemistry analysis. The investigation of the photothermal effect shows that the mPt@mSiO2-GdDTPA nanosystems exhibit an excellent photothermal therapy effect on HeLa cells and tumor-bearing mice. As theranostic agents, the nanosystems display a higher r1 value than the medical contrast agent magnevist and were successfully applied to in vivo MRI of Kunming mice. Therefore, the first systematic study on the photothermal effect of nanosystems based on mesoporous Pt nanoparticles does encourage the potential applications of metal nanoparticles and hybrid nanocomposites for cancer bioimaging and therapy.
Type 2 diabetes mellitus (T2DM) might aggravate the carotid plaque vulnerability, and increase the risk for ischemic stroke. Few studies reported the acute stroke subtype with carotid plaque characteristics in T2DM patients. This study aimed to investigate the association between carotid plaque characteristics and acute cerebral infarct (ACI) lesion features determined by MRI in T2DM patients. Patients with acute cerebrovascular syndrome in internal carotid artery territory were recruited. All patients were stratified into T2DM and non-T2DM groups and underwent both carotid and brain MRI scans. Ipsilateral carotid plaque morphological and compositional characteristics, intracranial and extracranial carotid artery stenosis were also determined. Stroke subtype based on the Trial of ORG 10172 in Acute Stroke Treatment classification and ACI lesion patterns were evaluated. Of the recruited 140 patients, 68 (48.6%) patients had T2DM (mean age 64.16 ± 11.38 years, 40 males). T2DM patients exhibited higher prevalence of carotid type IV–VI lesions, larger plaque burden as well as larger lipid-rich necrotic core (LRNC) compared with non-T2DM patients. Among the patients with carotid LRNC on symptomatic side, more concomitant large perforating artery infarct patterns and larger ACI size in the internal carotid artery territory were found in T2DM group than those in non-T2DM group. Carotid plaque with LRNC% > 22.0% was identified as an independent risk factor for the presence of ACI lesions confined to the carotid territory in T2DM patients, regardless of other risk factors. This study shows that more concomitant large perforating artery infarct patterns and larger ACI size in the internal carotid artery territory were found in the T2DM patients with ipsilateral carotid LRNC plaque than those in non-T2DM patients. Quantification of the carotid plaque characteristics, particularly the LRNC% by MRI has the potential usefulness for stroke risk stratification.
With the developing need for luminous materials with better performance, lanthanide-doped nanocrystals have been widely studied for their unique luminescence properties such as their narrow bandwidth emission, excellent chemical stability, and photostability, adjustable emission color, high signal-to-background ratio, deeper tissue penetration with less photo-damage, and low toxicity, etc., which triggered enthusiasm for research on the broad applications of lanthanide-doped nanocrystals in bioimaging, anti-counterfeiting, biosensing, and cancer diagnosis and treatment. Considerable progress has been made in the past few decades, but low upconversion luminescence efficiency has been a hindrance in achieving further progress. It is necessary to summarize the recently relevant literature and find solutions to improve the efficiency. The latest experimental and theoretical studies related to the deliberate design of rare earth luminescent nanocrystals have, however, shown the development of metal ion-doped approaches to enhance the luminescent intensity. Host lattice manipulation can enhance the luminescence through increasing the asymmetry, which improves the probability of electric dipole transition; and the energy transfer modulation offers a reduced cross-relaxation pathway to improve the efficiency of the energy transfer. Based on the mechanisms of host lattice manipulation and energy transfer modulation, a wide range of enhancements at all wavelengths or even within a particular wavelength have been accomplished with an enhancement of up to a hundred times. In this mini review, we present the strategy of metal ion-doped lanthanide nanocrystals to cope with the issue of enhancing luminescence, overview the advantages and tricky challenges in boosting the luminescence, and provide a potential trend of future study in this field.
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