Responsive CEST MRI biosensors offer good sensitivity and excellent specificity for detection of biomarkers with great potential for clinical translation. We report the application of fosfosal, a phosphorylated form of salicylic acid, for the detection of alkaline phosphatase (AP) enzyme. We detected conversion of fosfosal to salicylic acid in the presence of the enzyme by CEST MRI. Importantly the technique was able to detect AP enzyme expressed in cells in the presence of other cell components, which improves specificity. Various isoforms of the enzyme showed different Michaelis–Menten kinetics and yet these kinetics studies indicated very efficient catalytic rates. Our results with the fosfosal biosensor encourage further in vivo studies.
Objectives-This research study sought to improve the treatment of pancreatic cancer by improving the drug delivery of a promising AKT/PDK1 inhibitor, PHT-427, in poly(lactic-coglycolic) acid (PLGA) nanoparticles.Methods-PHT-427 was encapsulated in single-emulsion and double-emulsion PLGA nanoparticles . The drug release rate was evaluated to assess the effect of the second PLGA layer of DE-PLGA-427. Ex vivo cryo-imaging and drug extraction from ex vivo organs was used to assess the whole body biodistribution in an orthotopic model of MiaPaCa-2 pancreatic cancer. Anatomical MRI was used to noninvasively assess the effects of four weeks of nanoparticle-drug treatment on tumor size, and diffusion-weighted MRI longitudinally assessed changes in tumor cellularity.Results-DE-PLGA-427 showed delayed drug release and longer drug retention in the pancreas relative to SE-PLGA-427. Diffusion-weighted MRI indicated a consistent decrease in cellularity
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Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript during drug treatment with both types of drug-loaded nanoparticles. Both SE-and DE-PLGA-427 showed a 6-fold and 4-fold reduction in tumor volume relative to untreated tumors, and an elimination of primary pancreatic tumor in 68% of the mice.Conclusions-These results indicated that the PLGA nanoparticles improved drug delivery of PHT-427 to pancreatic tumors, which improved the treatment of Mia PaCa-2 pancreatic cancer.
A responsive magnetic resonance (MRI) contrast agent has been developed that can detect the enzyme activity of DT-diaphorase. The agent produced different chemical exchange saturation transfer (CEST) MRI signals before and after incubation with the enzyme, NADH, and GSH at different pH values whereas it showed good stability in a reducing environment without enzyme.
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