Fourier-transform ion-cyclotron resonance mass spectrometry (FT-ICR-MS) detection of oxidized cellular metabolites is described using isotopologic, carbonyl-selective derivatizing agents that integrate aminooxy functionality for carbonyl capture, quaternary nitrogen for electrospray enhancement, and a hydrophobic domain for sample cleanup. These modular structural features enable rapid, sensitive analysis of complex mixtures of metabolite-derivatives by FT-ICR-MS via continuous nanoelectrospray infusion. Specifically, this approach can be used to globally assess levels of low abundance and labile aldehyde and ketone metabolites quantitatively and in high throughput manner. These metabolites are often key and unique indicators of various biochemical pathways and their perturbations. Analysis of lung adenocarcinoma A549 cells established a profile of carbonyl metabolites spanning multiple structural classes. We also demonstrate a procedure for metabolite quantification using pyruvate as a model analyte.
Magnetic nanoparticle-supported lipid bilayers (SLBs) constructed around core-shell Fe3O4-SiO2 nanoparticles (SNPs) were prepared and evaluated as potential drug carriers. We describe how an oxime ether lipid can be mixed with SNPs to produce lipid-particle assemblies with highly positive ζ potential. To demonstrate the potential of the resultant cationic SLBs, the particles were loaded with either the anticancer drug doxorubicin or an amphiphilic analogue, prepared to facilitate integration into the supported lipid bilayer, and then examined in studies against MCF-7 breast cancer cells. The assemblies were rapidly internalized and exhibited higher toxicity than treatments with doxorubicin alone. The magnetic SLBs were also shown to increase the efficacy of unmodified doxorubicin.
Polymeric
micellar nanoparticles represent versatile and biocompatible
platforms for targeted drug delivery. However, tracking their biodistribution,
stability, and clearance profile in vivo is challenging. The goal
of this study was to prepare surface-modified micelles with peptide
GE11 for targeting the epidermal growth factor receptor (EGFR). In
vitro fluorescence studies demonstrated significantly higher internalization
of GE11 micelles into EGFR-expressing HCT116 colon cancer cells versus
EGFR-negative SW620 cells. Azo coupling chemistry of tyrosine residues
in the peptide backbone with aryl diazonium salts was used to label
the micelles with radionuclide 64Cu for positron emission
tomography (PET) imaging. In vivo analysis of 64Cu-labeled
micelles showed prolonged blood circulation and predominant hepatobiliary
clearance. The biodistribution profile of EGFR-targeting GE11 micelles
was compared with nontargeting HW12 micelles in HCT116 tumor-bearing
mice. PET revealed increasing tumor-to-muscle ratios for both micelles
over 48 h. Accumulation of GE11-containing micelles in HCT116 tumors
was higher compared to HW12-decorated micelles. Our data suggest that
the efficacy of image-guided therapies with micellar nanoparticles
could be enhanced by active targeting, as demonstrated with cancer
biomarker EGFR.
Aim
To evaluate the structure–activity relationship of oxime ether lipids (OELs) containing modifications in the hydrophobic domains (chain length, degree of unsaturation) and hydrophilic head groups (polar domain hydroxyl groups) toward complex formation with siRNA molecules and siRNA delivery efficiency of resulting complexes to a human breast cancer cell line (MDA-MB-231).
Materials & methods
Ability of lipoplex formation between oxime ether lipids with nucleic acids were examined using biophysical techniques. The potential of OELs to deliver nucleic acids and silence green fluorescent protein (GFP) gene was analyzed using MDA-MB-231 and MDA-MB-231/GFP cells, respectively.
Results & conclusion
Introduction of hydroxyl groups to the polar domain of the OELs and unsaturation into the hydrophobic domain favor higher transfection and gene silencing in a cell culture system.
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