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.

An upconverting nanotheranostic agent activated by hypoxia combined with NIR irradiation for selective hypoxia imaging and tumour therapy.

A novel upconverting nanotheranostic agent, UCNP-CAE-FDU/NO2, activated by both hypoxia (internal stimuli) and NIR irradiation (external stimuli) was designed and synthesized for simultaneous imaging and chemotherapy of solid tumours. The devised theranostic agent consists of an active drug, floxuridine (FDU), upconverting nanoparticles (UCNP: NaYF4:Yb3+/Tm3+, multifunctional carriers for upconverting 980 nm NIR light to 365 nm UV light and tumour-targeted drug delivery), (E)-o-hydroxycinnamic acid (CAE, a UV-photo trigger and a fluorescence dye precursor), and a 4-nitrobenzyl group (a hypoxic trigger). In addition, FDU was modified by CAE, and CAE was modified by the 4-nitrobenzyl group; moreover, CAE was conjugated to UCNPs by covalent bonds to form a novel UCNP-CAE-FDU/NO2 platform. In normal cells, the platform is "locked", whereas in tumour cells, hypoxia combined with NIR illumination (980 nm) "unlocks" the platform, based on a series of reactions including the reduction of UCNP-CAE-FDU/NO2 catalyzed by over-expression of nitroreductase (NTR), 1,6-rearrangement-elimination, the photo-isomerization of UCNP-CAE-FDU caused by absorption of NIR irradiation and emission at 365 nm of UCNP-CAE-FDU/NO2, and intramolecular esterification, which initiate the fluorescent dye in conjugation with UCNP (UCNP-CM) formation and FDU release with high spatio-temporal control. The amounts of FDU and UCNP-CM released can be accurately tuned by controlling the NIR illumination time. UCNP-CAE-FDU/NO2 showed excellent selectivity for hypoxic cells, exhibited high cytotoxicity against cancer cells and almost no cytotoxicity to normal cells, presented significant inhibition of tumour growth in vivo, and displayed sensitive detection of the hypoxic status and the amount of FDU released. The excellent properties of UCNP-CAE-FDU/NO2 endow it with great potential applications for precise imaging of tumour cells and personalized solid tumour treatment.