Hypoxia-Activated and Indomethacin-Mediated Theranostic Prodrug Releasing Drug On-Demand for Tumor Imaging and Therapy.

A smart theranostic prodrug IMC-FDU-TZBC-NO2, releasing active drug on-demand based on hypoxia-activated and indomethacin-mediated, for solid tumor imaging and efficient therapy was designed. This prodrug was constructed by conjugating chemotherapy drug 5-fluoro-2-deoxyuridine (FDU), targeting moiety indomethacin (IMC), and the hypoxic trigger 4-nitrobenzyl group to a fluorescent dye precursor, which was mediated by IMC and activated by NTR under hypoxic conditions. The fluorescent dye IMC-TZBCM was generated and FDU was released at the same time in tumor cells. The rates and amounts of FDU release and IMC-TZBCM generation were regulated by hypoxia status, and increased with increasing degree of hypoxia. Nevertheless, it is "locked" in normal cells. It combined the advantages of tumor targeting, diagnosis, and chemotherapy functions, showed excellent targeting ability to cancer cells, excellent stability in physiological conditions, high cellular uptake efficiency, and on-demand drug release behavior. The in vitro and in vivo assays demonstrated that IMC-FDU-TZBC-NO2 exhibits enhanced anticancer potency and low side effects. The novel targeted theranostic prodrug activated by hypoxia shows a great potential in cancer therapy.

Hypoxia-Activated Anticancer Prodrug for Bioimaging, Tracking Drug Release, and Anticancer Application.

A novel anticancer theranostic prodrug, FDU-DB-NO2, specifically activated by hypoxia for selective two-photon imaging hypoxia status, real-time tracking drug release, and solid tumor therapy was designed. The devised prodrug consists of an anticancer drug floxuridine (FDU), a fluorescence dye precursor 4'-(diethylamino)-1,1'-biphenyl-2-carboxylate (DB), and a hypoxic trigger 4-nitrobenzyl group. In normal cells, FDU-DB-NO2 is "locked". Whereas in tumor cells, the prodrug is "unlocked" by hypoxia and results in fluorescent dye 7-(diethylamino)coumarin (CM) generation along with FDU release. The amounts and rates of CM formation and FDU release were controlled by hypoxic status and increased with the decreasing of the O2 concentration. The hypoxic status, distribution of oxygen, and amount of FDU release in tumor cells, spheroids, and tumor tissue could be visualized by fluorescence. FDU-DB-NO2 showed high cytotoxicity against hypoxic MCF-7 and MCG-803 cell lines and no cytotoxicity against normoxic BRL-3A cells and exhibited effective inhibition on tumor growth of MCF-7-cell-inoculated xenograft nude mice. This strategy may provide a promising platform for selective two-photon imaging hypoxia status, real-time tracking drug release, and personalized solid tumor treatment.

A measles outbreak in a middle school with high vaccination coverage and evidence of prior immunity among cases, Beijing, P.R. China.

BACKGROUND: Age-appropriate receipt of ≥ 2 measles-containing vaccine (MCV) doses has been considered evidence of immunity against measles. Transmission of measles is rarely reported among such persons. METHODS: We report a measles outbreak in a middle school in Beijing that has high coverage with ≥ 2 documented MCV doses. History of previous measles and documentation of MCV receipt were collected for all individuals. Cases were identified by active surveillance and confirmed by laboratory tests. Measles immunoglobulin G (IgG) titers and clinical presentations were obtained for each case. RESULTS: Of 1331 individuals without a prior history of measles, 1172 (88.1% [95%CI:86.4-91.5%]) and 1078 (81.0% [95%CI:78.9-83.1%]) had age-appropriate receipt of ≥ 2 MCV doses by domestic and U.S. CDC/ACIP criteria, respectively. Thirteen measles cases occurred in the outbreak. The index case and 3 secondary cases were students. The 9 tertiary cases included 2 teachers and 7 students. All 11 student cases received ≥ 2 age-appropriate MCV doses by Chinese domestic criteria; 8 were age-appropriately vaccinated by U.S. CDC/ACIP criteria. Measles IgG was detected during the acute phase of measles for all but 2 cases -the first case and 1 tertiary case. Among students with age-appropriate receipt of ≥ 2 MCV doses, the length of time since the last MCV was significantly associated with risk of measles: for the 1172 students, the risk was 4.6 [OR5.6;95%CI:1.4-22.9] and 5.5 [OR6.5;95%CI:1.4-29.8] times higher when the last MCV dose was 5-9 years and ≥ 10 years prior, respectively, compared with <5 years prior; for the 1078 students, the risk was 4.1 [OR5.1;95%CI:1.3-20.7] times higher when the last MCV dose was 5-9 years prior compared with <5 years prior. CONCLUSIONS: This is the first report from China showing measles transmission among persons with prior evidence of immunity. Secondary vaccine failure may have played an important role in measles transmission. Further laboratory surveillance is needed to assess the persistence of vaccine-induced immunity of domestically-produced MCV in China.