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

A novel upconverting nanotheranostic agent, UCNP-CA_E-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 (CA_E, a UV-photo trigger and a fluorescence dye precursor), and a 4-nitrobenzyl group (a hypoxic trigger). In addition, FDU was modified by CA_E, and CA_E was modified by the 4-nitrobenzyl group; moreover, CA_E was conjugated to UCNPs by covalent bonds to form a novel UCNP-CA_E-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-CA_E-FDU/NO₂ catalyzed by over-expression of nitroreductase (NTR), 1,6-rearrangement-elimination, the photo-isomerization of UCNP-CA_E-FDU caused by absorption of NIR irradiation and emission at 365 nm of UCNP-CA_E-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-CA_E-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-CA_E-FDU/NO₂ endow it with great potential applications for precise imaging of tumour cells and personalized solid tumour treatment.