Gilesbanke6360
The possibility to conjugate tumor-targeted cytotoxic nanoparticles and conventional antitumoral drugs in single pharmacological entities would open a wide spectrum of opportunities in nanomedical oncology. This principle has been explored here by using CXCR4-targeted self-assembling protein nanoparticles based on two potent microbial toxins, the exotoxin A from Pseudomonas aeruginosa and the diphtheria toxin from Corynebacterium diphtheriae, to which oligo-floxuridine and monomethyl auristatin E respectively have been chemically coupled. The resulting multifunctional hybrid nanoconjugates, with a hydrodynamic size of around 50 nm, are stable and internalize target cells with a biological impact. Although the chemical conjugation minimizes the cytotoxic activity of the protein partner in the complexes, the concept of drug combination proposed here is fully feasible and highly promising when considering multiple drug treatments aimed to higher effectiveness or when facing the therapy of cancers with acquired resistance to classical drugs.The repair of tendon injuries is often compromised by post-operative peritendinous adhesions. Placing a physical barrier at the interface between the tendon and the surrounding tissue could potentially solve this problem by reducing adhesion formation. At present, no such system is available for routine use in clinical practice. Here, we propose the development of a bilayer membrane combining a nanofibrous poly(ε-caprolactone) (PCL) electrospun mesh with a layer of self-assembling peptide hydrogel (SAPH) laden with type-B synoviocytes. This bilayer membrane would act as an anti-adhesion system capable of restoring tendon lubrication, while assisting with synovial sheath regeneration. The PCL mesh showed adequate mechanical properties (Young's modulus=19±4 MPa, ultimate tensile stress=9.6±1.7 MPa, failure load=0.5±0.1 N), indicating that the membrane is easy to handle and capable to withstand the frictional forces generated on the tendon's surface during movement (~0.3 N). Morphological analysis confirmed the generation of a mesh with nanosized PCL fibres and small pores ( less then 3 μm), which prevented fibroblast infiltration to impede extrinsic healing but still allowing diffusion of nutrients and waste. Rheological tests showed that incorporation of SAPH layer allows good lubrication properties when the membrane is articulated against porcine tendon or hypodermis, suggesting that restoration of tendon gliding is possible upon implantation. Moreover, viability and metabolic activity tests indicated that the SAPH was conducive to rabbit synoviocyte growth and proliferation over 28 days of 3D culture, sustaining cell production of specific matrix components, particularly hyaluronic acid. Synoviocyte-laden peptide hydrogel promoted a sustained endogenous production of hyaluronic acid, providing an anti-friction layer that potentially restores the tendon gliding environment.Complex liposomes were assembled with 1,2-distearoyl-sn-glycero-3-phosphocholine, dihexadecyl phosphate (DHDP), cholesterol and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphate (PA) to act as drug carriers for resveratrol (RES) and epigallocatechin gallate (EGCG). The liposomes were modified with leptin (Lep) on the surface to cross the blood-brain barrier (BBB) and to rescue degenerated dopaminergic neurons. The activity of RES and EGCG against neurotoxicity was investigated using an in vitro neurodegenerative model established by SH-SY5Y cells with an insult of 1-methyl-4-phenylpyridinium (MPP+). The results indicated that increasing the mole percentage of DHDP and PA increased the particle size and absolute zeta potential value, and improved the entrapment efficiency of RES and EGCG; however, this increase reduced the release rate of RES and EGCG and the grafting efficiency of Lep. The ability of Lep/RES-EGCG-PA-liposomes to cross the BBB was found to be higher than that of non-modified liposomes. Further, the addition of PA and Lep into liposomes enhanced cell viability and target efficiency. The immunofluorescence results demonstrated that the conjugation of Lep with liposomes enabled the docking of HBMECs and SH-SY5Y cells via Lep receptor, and enhanced their ability to permeate the BBB and cellular uptake. Immunofluorescence and western blot analysis also revealed that RES and EGCG encapsulated into liposomes could be a neural defensive strategy by reducing the apoptosis promotor protein Bcl-2 associated X protein and α-synuclein, and enhancement in the apoptosis inhibitor protein B cell lymphoma 2, tyrosine hydroxylase, and the dopamine transporter. Hence, Lep-PA-liposomes can be an excellent choice of potential delivery system for PD treatment.Nepenthes pitcher plants capture prey with leaves specialised as pitfall traps. Insects are trapped when they 'aquaplane' on the pitcher rim (peristome), a surface structured with macroscopic and microscopic radial ridges. What is the functional significance of this hierarchical surface topography? Here, we use insect pad friction measurements, photolithography, wetting experiments and physical modelling to demonstrate that the ridges enhance the trap's efficacy by satisfying two functional demands on prey capture Macroscopic ridges restrict lateral but enhance radial spreading of water, thereby creating continuous slippery tracks which facilitate prey capture when little water is present. Microscopic ridges, in turn, ensure that the water film between insect pad and peristome remains stable, causing insects to aquaplane. In combination, the hierarchical ridge structure hence renders the peristome wettable, and water films continuous, so avoiding the need for a strongly hydrophilic surface chemistry, which would compromise resistance to desiccation and attract detrimental contamination.This study examined the effect of matching musical emotion and the mood of the listener on working memory and free recall in normal aging. Memory measures were taken at baseline in healthy young and older participants, and, following a happy or sad mood induction, again after exposure to both mood-matching and -mismatching music in a counterbalanced repeated measures design. Compared to baseline, [i] recall was greater following mood-matching than mood-mismatching music in both groups, and was reduced following mood-mismatching music in older adults, [ii] working memory was greater in the mood-matching condition, but did not differ from baseline in the mismatching condition. The results have significant implications for the increasingly popular forms of intervention involving music used with older populations experiencing cognitive decline.
Currently, the reference method of brown adipose tissue (BAT) imaging is
F-fluorodeoxyglucose positron emission tomography ([
F]FDG PET). BAT imaging by [
F]FDG PET requires additional stimulation process, which is inconvenient and hard to be standardized. The translocator protein 18kDa (TSPO) PET has been found to be effective for visualization of BAT. Herein, we evaluated the feasibility of [
F]fluoromethyl-PBR28-d
([
F]fmPBR28-d
), a TSPO PET tracer, for interscapular BAT imaging in comparison with [
F]FDG PET.
C57BL/6 mice were used for the [
F]fmPBR28-d
and [
F]FDG PET imaging. [
F]fmPBR28-d
PET was performed in the thermoneutral condition (n=5) and after cold exposure (4°C for 4h) on the next day using the same mice. [
F]FDG PET was performed in the thermoneutral and cold exposure conditions with the same method with [
F]fmPBR28-d
PET. Ex vivo biodistribution study of [
F]fmPBR28-d
was performed in ten C57BL/6 mice (5 thermoneutral, 5 cold exposure). TSPO immunohistochemistryd a higher BAT to background ratio than [
F]FDG PET. Also, we found that [
F]fmPBR28-d
PET uptake and TSPO expression of BAT increased under cold exposure condition. Further works are warranted to assess the clinical significance of TSPO PET uptake in BAT.
[18F]FmPBR28-d2 PET demonstrated prominent interscapular BAT uptakes regardless of additional stimulation, and showed a higher BAT to background ratio than [18F]FDG PET. Also, we found that [18F]fmPBR28-d2 PET uptake and TSPO expression of BAT increased under cold exposure condition. Further works are warranted to assess the clinical significance of TSPO PET uptake in BAT.
The deposition of islet amyloid composed of amylin aggregates is related to β-cell mass dysfunction in type 2 diabetes mellitus (T2DM), and it may be involved in the development and progression of T2DM. In this study, we newly designed, synthesized, and evaluated a radiogallium-labeled pyridyl benzofuran derivative ([
Ga]GPBF) as an amylin imaging probe.
An in vitro competitive inhibition assay was performed to determine the binding affinity for amylin aggregates. An in vitro autoradiographic study was carried out using pancreatic sections from a T2DM patient. A biodistribution of [
Ga]GPBF in normal mice was evaluated. Finally, we carried out ex vivo autoradiography using mouse transplanted with amylin aggregates.
GPBF exhibited binding affinity for amylin aggregates in vitro. In addition, [
Ga]GPBF clearly labeled islet amyloids in in vitro autoradiography of a T2DM pancreatic section. In a biodistribution study using normal mice, [
Ga]GPBF showed initial uptake into the pancreas, but non-specific accumulation in the liver, spleen, and pancreas was also observed. Furthermore, an ex vivo autoradiogram demonstrated that [
Ga]GPBF bound to amylin aggregates in the pancreas of the amylin aggregate-transplanted mice.
These results provide useful insights into the development of radiogallium labeled probes that target amylin aggregates in the T2DM pancreas.
These results provide useful insights into the development of radiogallium labeled probes that target amylin aggregates in the T2DM pancreas.
The epidermal growth factor receptor (EGFR) has emerged as an attractive target in the treatment of various cancers. Radiolabeled small molecules, antibodies, and peptides that specifically target EGFR are promising probes for tumor imaging to guide personalized treatment with EGFR-targeted drugs. This study aimed to radiolabel GE11 (an EGFR-specific targeting peptide) with 18-fluorine to develop a new EGFR-targeting positron emission tomography (PET) probe, [
F]FP-Lys-GE11, for imaging tumors overexpressing EGFR.
[
F]FP-Lys-GE11 was produced by radiolabeling a GE11 peptide with the prosthetic group 4-nitrophenyl-2-[
F]fluoropropionate ([
F]NFP). Stability in PBS and mice serum, affinity for A431 cell line, U87 and PC-3 cells uptake and blocking studies, and biodistribution of [
F]FP-Lys-GE11 were determined. 2h dynamic and static PET scans of probe for tumor-bearing mice normal and inhibition uptake were performed.
[
F]FP-Lys-GE11 was stable in PBS and mice serum. The Kd and Bmax values of probe for A431 were 42.43±3.75nM and 3383±81.73 CPM, respectively. Nazartinib mw In cell uptake and blocking experiments, a significant reduction in radioactivity accumulation (over 4-fold) was observed by blocking U87 and PC-3 cells with unlabeled peptide. PET imaging of U87 and PC-3 tumor-bearing mice revealed clear tumor imaging (tumor radioactivity accumulation was 3.48±0.44 and 3.68±0.76%ID/g respectively, tumor-to-muscle ratio was 3.45±0.43 and 3.64±0.76 respectively). Blocking imaging revealed that the U87 tumor uptake was significantly inhibited (2.21±0.41%ID/g). The biodistribution and dynamic PET imaging showed that [
F]FP-Lys-GE11 was mainly excreted by the kidneys and the rest was excreted through the bile and intestines.
The current results showed that [
F]FP-Lys-GE11was a good radiolabeled peptide probe for EGFR overexpression tumor's imaging.
The current results showed that [18F]FP-Lys-GE11was a good radiolabeled peptide probe for EGFR overexpression tumor's imaging.
