Light can be used as an external trigger to precisely determine where and when a process is initiated as well as how much of the process is being consumed. Phototriggers are a type of photoresponsive functional group that undergo an irreversible photolysis reaction by selectively breaking a chemical bond, enabling three fundamental functions: the photoactivation of fluorescent and bioactive molecules; the photocleavable degradation of macromolecular materials; and the photorelease of drugs, active groups, or surface charges from carriers and interfaces. With the expanded applications of light-controlled technology, particularly in living systems, new challenges and improvements of phototriggers are required to fulfill the demands for better sensitivity, faster kinetics, and more-demanding biomedical applications. Here, improvements to several conventional phototriggers are highlighted, and their notable, representative biomedical applications and their challenges are discussed.

A novel photocontrolled thiol click chemistry based on spirothiopyran and maleimide is reported. Upon irradiation with λ=365 nm light, the spirothiopyran can isomerize to the open merocyanine form, a thiophenolate group, which can rapidly react with maleimide. The unreacted MC will readily isomerize back to the starting spirothiopyran, which can be repeatedly photoactivated as needed. Thus, this reversible photoactivated thiol confers spatiotemporal sequential control on the thiol–maleimide reaction using only one type of photochemical reaction. Polymer post-functionalization and hydrogel building with subsequent multipatterning using different maleimide molecules in a temporal sequential manner indicate that this photocontrolled Michael addition reaction can modulate the specific chemical events in a sequence.

Phototrigger-controlled drug-release devices (PDDs) can be conveniently manipulated by light to obtain on-demand release patterns, thereby affording an improved therapeutic efficacy. However, no example of the PDDs has been demonstrated beyond the cellular level to date. By loading 7-amino-coumarin derivative caged anticancer drug chlorambucil to yolk–shell structured nanocages possessing upconversion nanophosphors (UCNPs) as moveable core and silica as mesoporous shell, a near-infrared (NIR)-regulated PDD is successfully created. In vitro experiments demonstrate that drug release from the PDD could be triggered by continuous-wave 980 nm light in a controlled pattern. The PDD could be taken up by cancer cells and release the drug to kill cancer cells upon NIR irradiation. Further in vivo studies demonstrate that the PDD can effectively response the NIR stimuli in living tissue. This is the first example of successful NIR-regulated drug release in living animal model. Such achievement resolves the problem of low tissue penetration depth for traditional PDDs by adopting UCNPs as an NIR light switcher, which gives impetus to practical applications.

A novel photoconvertible fluorescent probe, which can be activated by intracellular thiols, has been synthesized. Such a molecular probe comprises three parts: a 7-aminocoumarin phototrigger, a thiol-removable energy acceptor, and a caged fluorescein scaffold with intracellular thiols reactivity as the fluorescent reporter. Extracellularly, the energy acceptor blocks the emission of the coumarin that regulates the photocleavage and photoactivation of the fluorescein. Intracelluarly, the high concentration of thiols releases the energy acceptor, thus activating the S1 state of the phototrigger, which emits coumarin blue fluorescence for pre-visualization and liberates the caged green-fluorescent fluorescein to highlight the specific cell upon illumination. Compared to traditional photoactivated organic dyes, the intracellular thiols activated probe requires double activations: one by intracellular thiols and the other by light activation. The dual activations restrict fluorescence precisely inside live cells and at the particular spatial region of light activation, thus a probe with precise spatial accuracy in live cells.

A new single-/two-photon sensitive monomer, (E)-5-(4-ethoxystyryl)−2-nitrobenzyl methacrylate (ENbMA), was synthesized and copolymerized with methyl methacrylate (MMA) to form a series of photosensitive copolymers P(ENbMA–MMA)s that were well characterized by ¹H NMR and GPC. The photochemical and photophysical properties of both photosensitive monomer and copolymers upon visible light irradiation were studied by UV–Vis, FTIR, and HPLC spectra, which confirmed that 5-(4-ethoxystyryl)-2-nitrobenzyl ester can be photolyzed effectively with generation of the corresponding 5-(4-ethoxystyryl)-2-nitrosobenzaldehyde and carboxylic acid groups. The successful photocleavage endowed the optimized copolymers with excellent micropatterning property due to the effective generation of alkaline-soluble carboxylic acid groups. Moreover, the high two-photon absorption cross-sections (over 20 GM at 800 nm) and the comparable photolysis upon two-photon NIR light irradiation of the chromophores provided the copolymers with significant application in two-photon microfabrication. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 130: 4099–4106, 2013