Ultrasound-Activated NIR Chemiluminescence for Deep Tissue and Tumor Foci Imaging.

Fluorescence imaging requires real-time external light excitation; however, it has the drawbacks of autofluorescence and shallower penetration depth, limiting its application in deep tissue imaging. At the same time, ultrasound (US) has high spatiotemporal resolution, deep penetrability, noninvasiveness, and precise localization of lesions; thus, it can be a promising alternative to light. However, US-activated luminescence has been rarely reported. Herein, an US-activated near-infrared (NIR) chemiluminescence (CL) molecule, namely, PNCL, is designed by protoporphyrin IX as a sonosensitizer moiety and a phenoxy-dioxetane precursor containing a dicyanomethyl chromone acceptor scaffold (NCL) as the US-responsive moiety. After therapeutic US radiation (1 MHz), the singlet oxygen (1O2), as an "intermediary", oxidizes the enol-ether bond of the NCL moiety and then emits NIR light via spontaneous decomposition. Combining the deep penetrability of US with a high signal-to-background ratio of NIR CL, the designed probe PNCL successfully realizes US-activated deep tissue imaging (∼20 mm) and selectively turns on signals in specific tumor foci. Bridging US chemistry with luminescence using an "intermediary" will provide new imaging methods for accurate cancer diagnosis.

Identification of metabolites of the novel anti-tumor drug candidate MDH-7 in rat urine by liquid chromatography coupled with triple quadrupole linear ion trap mass spectrometry.

RATIONALE: Our previous preliminary pharmacokinetic study demonstrated that the novel double pyrimidine tricyclic nucleoside MDH-7 in rats had a very short half-life (<30 min) after oral administration. As a result, the in vivo metabolic profile of MDH-7 should be investigated during early stages of drug development to better select drug candidates. METHODS: In this study, a rapid method was developed to identify the metabolites of MDH-7 in rat urine by means of ultra-performance liquid chromatography (UPLC) coupled with electrospray ionization mass spectrometry (ESI-MS) using a triple quadrupole linear ion trap instrument. MDH-7 and its metabolites were detected and characterized by the combined use of the multiple reaction monitoring-information-dependent acquisition-enhanced product ion (MRM-IDA-EPI) mode and the precursor scan information-dependent acquisition-enhanced product ion (PREC-IDA-EPI) mode. RESULTS: Ten novel metabolites of MDH-7 were identified and characterized in rat urine by LC/ESI-MS and collision-induced dissociation tandem mass spectrometry (CID-MS/MS) analyses. M1 was identified as 5-fluoro-N(4) -[(pentyloxy)carbonyl]cytosine; M2 and M3 were formed by hydroxylation products of M1. Metabolites M4-M10 were formed by a series of degradation reactions such as: deacetylation, hydroxylation, loss of the defluorocytosine base, oxidative-deamination, loss of the defluorouracil base, N-dealkylation and amide hydrolysis. CONCLUSIONS: Based on the profiles of the metabolites, possible metabolic pathways of MDH-7 in rats were proposed for the first time. This study provides new and available information on the metabolism of MDH-7 which is very useful to further understand its in vivo metabolic fate. Copyright © 2016 John Wiley & Sons, Ltd.