Optical in vivo and ex vivo imaging of glioma cells migration via the cerebral vessels:Prospective clinical application of the beta2-adrenoreceptors blockade for glioma treatment

Malignant gliomas are highly invasive tumors that 1use the cerebral vessels for invasion due to high vascular fragility of the blood--brain barrier(BBB).On one hand,glioma is characterized by the BBB disruption,on the other hand,drug brain delivery via the BBB is a big challenge in glioma therapy.The limited information about vascular changes associated with glioma growth is a reason of slow progress in prevention of glioma development.Here,we present in vrivo and er vrivo study of the BBB disruption and glioma cells(GCs)migration in rats using fuorescence and confocal microscopy.We uncovered a local breach in the BBB in the main tumor mass but not within the border of normal and malignant cells,where the BBB was impermeable for high weight molecules.The migr ation of GCs were observed via the cerebral vessels with the intact BBB that was associated with macrophages infiltration.The mechanisms underlying glioma progression remain umknown but there is an evidence that the sympathetic nervous system(SNS)via activation of vascular beta2-adrenoreceptors(B2-ADRs)can play an important role in tumor metastasis.Our results clearly show an increase in the expression of vascular B2-ADRs and production of the beta arrestin-1-co-factor of B2-ADRs signaling pathway in rats with glioma.Pharmacological blockade of B2-ADRs reduces the BBB disruption,macrophages infiltration,GCs migration and increases survival rate.These data suggest that the blockade of B2-ADRs may be a novel adjuvant therapeutic strategy to reduce glioma progression and prevent metastasis。

Mechanisms of phototherapy of Alzheimer’s disease during sleep and wakefulness:the role of the meningeal lymphatics

With the increase in the aging population,the global number of people with Alzheimer’s disease(AD)progressively increased worldwide.The situation is aggravated by the fact that there is no the efective pharmacological therapy of AD.Photobiomodulation(PBM)is non-pharmacological approach that has shown very promising results in the therapy of AD in pilot clinical and animal studies.However,the mechanisms of therapeutic efects of PBM for AD are poorly understood.In this study on mice,we demonstrate that photodynamic efects of 5-aminolevulenic acid and laser 635 nm cause reduction of network of the meningeal lymphatic vessels(MLVs)leading to suppression of lymphatic removal of beta-amyloid(Aβ)from the right lateral ventricle and the hippocampus.Using the original protocol of PBM under electroencephalographic monitoring of wakefulness and sleep stages in non-anesthetized mice,we discover that the 7-day course of PBM during deep sleep vs.wakefulness provides better restoration of clearance of Aβfrom the ventricular system of the brain and the hippocampus.Our results shed light on the mechanism of PBM and show the stimulating efects of PBM on the brain lymphatic drainage that promotes transport of Aβvia the lymphatic pathway.The efects of PBM on the brain lymphatics in sleeping brain open a new niche in the study of restorative functions of sleep as well as it is an important informative platform for the development of innovative smart sleep technologies for the therapy of AD.

Plasmonic nanoparticles and nucleic acids hybrids for targeted gene delivery,bioimaging,and molecular recognition

Promising biomedical applications of hybrid materials composed of gold nanoparticles and nucleic acids have attracted strong interest from the nanobiotechnological community.The particular interest is owing to the robust and easy-to-make synthetic approaches,to the versatile optical and catalytic properties of gold nanoparticles combined with the molecular recognition and programmable properties of nucleic acids.The significant progress is made in the develop-ment of DNA-gold nanostructures and their applications,such as molecular recognition,cell and tissue bioimaging,targeted delivery of therapeutic agents,etc.This review is focused on the critical discussion of the recent applications of the gold nanoparticles-nucleic acids hybrids.The effect of particle size,surface,charge and thermal properties on the interactions with functional nucleic acids is discussed.For each of the above topics,the basic principles,recent advances,and current challenges are discussed.Emphasis is placed on the systematization of data over the theranostic systems on the basis of the gold nanoparticles-nucleic acids hybrids.Specifically,we start our discussion with observation of the recent data on interaction of various gold nano-particles with nucleic acids.Further we describe existing gene delivery systems,nucleic acids detection,and bioimaging technologies.Finally,we describe the phenomenon of the polymerase chain reaction improvement by gold nanoparticle additives and its potential underlying mechanisms.Lastly,we provide a short summary of reported data and outline the challenges and perspectives.

Blood–brain barrier and laser technology for drug brain delivery

Here,we discuss an important problem in medicine as development of efctive strategies for brain drug delivery.This problem is related to the blood-brain barrier(BBB),which is a“customs”controlling the entrance of different molecules from blood into the brain protecting the normal function of central nervous system(CNS).We show three interfaces of anatomical side of BBB and two functional types of BBB一physical and transporter barriers.Although this protective mechanism is essential for health of CNS,it also creates a hindrance to the entry of drugs into the brain.The BBB was discovered over 100 years ago but till now,there is no efective methods for brain drug delivery.There ane more than 70 approaches for overcoming BBB incuding physical,chenical and biological techniques but all of these tools have limitation to be widely used in clinical practice due to invasi venes,challenge in performing,very costly or lim-itation of drug concentration.Photodynamic therapy(PDT)is usual clinical method of surgical navigation for the resection of brain tumor and anti-cancer therapy.Nowadays,the application of PDT is considered as a potential promising tool for brain drug delivery via opening of BBB.Here,we show the first sucoessful experimental results in this field discussing the adventures and disadv antages of PDT-related BBB disruption as well as altematives to overcome these limitations and possi ble mechanisms with new pathways for brain clearance via gly mphatic and lymphatic systems.

Introduction to the special issue on surface-enhanced Raman spectroscopy and functionalized plasmonic nanoparticles for biomedical applications

Since its first discovery in 1974 from the enhanced Raman spectra of pyridine molecules on roughened silver surface,surface-enhanced Raman spectrosco-py(SERS)has garnered significant attention in the field of chemistry,biology,and medicine.With the sensitivity of down to single-molecule level and the intrinsic"fingerprint"spectrum,SERS enables the ultra-sensitive,specific,selective,and multi-plexing label-free analysis of a trace of molecules in aqueous biological environments,minus the inter-ference from water,white-light or tissue auto-fluorescence background.

Laser speckle imaging and wavelet analysis of cerebral blood flow associated with the opening of the blood–brain barrier by sound

The cerebral blood flow（CBF） alterations related to sound-induced opening of the blood–brain barrier（BBB） in adult mice are studied using laser speckle contrast imaging（LSCI） and wavelet analysis of vascular physiology.The results clearly show that the opening of the BBB is accompanied by the changes of venous but not microvessel circulation in the brain. The elevation of the BBB permeability is associated with the decrease of venous CBF and the increase of its complexity. These data suggest that the cerebral veins rather than microvessels are sensitive components of the CBF related to the opening BBB.

SERS-based lateral flow immunoassay of troponin I by using gapenhanced Raman tags

The lateral flow immuno assay (LFIA) has emerged as a powerful tool for rapid scree ning owing to its simplicity and flexibility for detection of various biomarkers. However, conventional LFIA strips have several disadvantages, including limits in quantitative analysis and low sensitivity. Here we developed a novel surface-e nhanced Rama n scatteri ng LFIA based on non spherical gap-e nhanced Raman tags (GERTs), with Raman molecules (RMs) embedded in a 1-nm gap between Au nanorod core and Au shell. Such tags have a strong and uniform surface-enhanced Rama n scattering (SERS) resp on se, an order of mag nitude higher than that of other comm on SERS tags such as Au nano rods, nano stars, Au nano shells with surface-adsorbed RMs, or spherical GERTs with embedded RMs. The feasibility of the tags was dem on strated by the semiqua ntitative and sen sitive detecti on of the heart disease biomarker cardiac tropo nin I (cTnI). GERTs were conjugated with mono clonal antibodies and used for LFIA in the same way as ordinary functionalized colloidal gold. The presenee of the target antigen, cTnI, was identified by Raman microscopy mapping of the test zone. With the SERS-based LFIA, the limit of cTnI detection was about 0.1 ng/mL. This value is within the diagnostic range of cTnI in the blood serum of patients with heart infarction and is 30 times lower than that of the colorimetric LFIA test using the same antibodies and either GERTs or colloidal gold as labels.

Au-nanocluster-loaded human serum albumin nanoparticles with enhanced cellular uptake for fluorescent imaging

Protein-directed fluorescent Au nanoclusters have been widely studied owing to their potential applications in sensing,imaging,and drug and gene delivery.However,the use of nanoclusters in drug delivery is limited by low cellular uptake.In this study,human serum albumin-directed Au nanoclusters served as building blocks to obtain protein nanoparticles by desolvation.The nanoparticles had a decent quantum yield(QY),high colloidal stability and low cytotoxicity,and they could be readily conjugated with biological molecules.The cellular uptake of the Au nanoclusters and nanocluster-loaded protein nanoparticles were studied by confocal fluorescence microscopy.Agglomeration of the protein-directed Au nanoclusters into 50–150-nm nanoparticles dramatically increased the cellular uptake.

Surface-enhanced Raman scattering inside Au@Ag core/shell nanorods

The design and synthesis of plasmonic nanoparticles with Raman-active molecules embedded inside them are of significant interest for sensing and imaging applications. However, direct synthesis of such nanostructures with controllable shape, size, and plasmonic properties remains extremely challenging. Here we report on the preparation of uniform Au@Ag core/sheU nanorods with controllable Ag shells of 1 to 25 nm in thickness. 1,4-Aminothiophenol （4-ATP） molecules, used as the Raman reporters, were located between the Au core and the Ag shell. Successful embedding of reporter molecules inside the core/shell nanoparticles was confirmed by the absence of selective oxidation of the amino groups, as measured by Raman spectroscopy. The dependence of Raman intensity on the location of the reporter molecules in the inside and outside of the nanorods was studied. The molecules in the interior showed strong and uniform Raman intensity, at least an order of magnitude higher than that of the molecules on the nanoparticle surface. In contrast to the usual surface-functionalized Raman tags, aggregation and clustering of nanoparticles with embedded molecules decreased the surface-enhanced Raman scattering （SERS） signal. The findings from this study provide the basis for a novel detection technique of low analyte concentration utilizing the high SERS response of molecules inside the core/shell metal nanostructures. As an example, we show robust SERS detection of thiram fungicide as low as 10-9 M in solutions.