Breaking photoswitch activation depth limit using ionising radiation stimuli adapted to clinical application

Abstract

Electromagnetic radiation-triggered therapeutic effect has attracted a great interest over the last 50 years. However, translation to clinical applications of photoactive molecular systems developed to date is dramatically limited, mainly because their activation requires excitation by low-energy photons from the ultraviolet to near infra-red range, preventing any activation deeper than few millimetres under the skin. Herein we conceive a strategy for photosensitive-system activation potentially adapted to biological tissues without any restriction in depth. High-energy stimuli, such as those employed for radiotherapy, are used to carry energy while molecular activation is provided by local energy conversion. This concept is applied to azobenzene, one of the most established photoswitches, to build a radioswitch. The radiation-responsive molecular system developed is used to trigger cytotoxic effect on cancer cells upon gamma-ray irradiation. This breakthrough activation concept is expected to expand the scope of applications of photosensitive systems and paves the way towards the development of original therapeutic approaches.

Stimuli-activatable nanomedicine meets cancer theranostics

“…Besides, the release/activation modes, such as immediately activated, sustainedly activated, progressively activated, and pulsatively activated, could be explored for optimized design of various nanostructures for the activatable nanomedicine. H2O2-activatable ferrocene: hydrophobic to hydrophilic transformation [74] H2O2-sensitive phenylboronic acid [75] Enzyme MMP2-cleavable peptide PLGIAG [76] Caspase 3/7-cleavage DEVD peptide (Asp-Glu-Val-Asp) [27] Cathepsin B-cleavage GFLG tetrapeptide (Gly-Phe-Leu-Gly) [77] GGT-cleavage γ-glutamyl moieties [78] Hypoxia A cleavable p-nitrobenzyl group by nitroreductase [79] Azobenzenes (AZO): reduction [ Light-cleavable coumarin ester [84] US pMEMA: poly(methoxyethyl methacrylate) [85] Indirect breakage of thioketal bonds with the aid of a sonosensitizer [86] Cleavage of ACVA C-N bonds [87] Ionizing radiation Reduction of N-oxide [88] Diselenid bond: cleavage [89] Geometrical structure transformation: cis-GdAzo to trans-GdAzo [90] Thermal Poly(N-isopropylacrylamide) (PNIPAAm) [91] Poly[(N-N-diethyl)acrylamide] (pDEA) [92] Dipalmitoyl phosphatidylcholine (DPPC): gel to liquid-crystalline phase transition [93] MMP2: matrix metalloproteinase 2; GGT: gamma-glutamyl transpeptidase; US: ultrasound; ACVA: 4,4'-Azobis(4-cyanovaleric acid).…”

Molecular Machines For The Control Of Transmembrane Transport

“…Photoswitches for lipid membrane disruption. Top: structure of DSPC lipid 24 , UV-responsive azoPC 25 , red-light-responsive red-azoPC 26 , and ionizing-radiation-responsive gadolinium complex 27 . Bottom: schematic of phototriggered release of cargo from a lipid compartment.…”

“…A gadolinium−azobenzene conjugate 27 has recently been reported, which can be switched with ionizing radiation. 133 The lanthanide initially absorbs highenergy photons and mediated switching through energy transfer to the azobenzene core. This radio-switch amphiphile demonstrated ionizing radiation could induce molecular rearrangement of the azobenzene to disrupt cellular membranes and trigger a cytotoxic effect.…”

“…Trauner and co-workers introduced the tetra-chloroazobenzene phospholipid 26 which has been shown to mediate the photocontrolled release of doxorubicin from distearoylphosphatidylcholine (DSPC)/cholesterol vesicles with 630 nm/465 nm light in vivo in zebrafish embryos. , Encapsulating lanthanide upconversion nanoparticles within the lumen of vesicles is another method that has been shown to enable long-wavelength photoswitching of azobenzene photolipids. , These nanoparticles absorb 980 nm near-infrared photons and re-emit shorter wavelengths of light, including UV (∼360 nm) and blue (∼450 nm), which was shown to isomerize the azobenzene, releasing doxorubicin. A gadolinium–azobenzene conjugate 27 has recently been reported, which can be switched with ionizing radiation . The lanthanide initially absorbs high-energy photons and mediated switching through energy transfer to the azobenzene core.…”

Photoswitchable luminescent lanthanide complexes controlled and interrogated by four orthogonal wavelengths of light

“…43–46 However, there are only two reports of kinetically stable 47 photoswitchable lanthanide complexes, and in these systems the azobenzene moieties have not been optimised, exhibiting inefficient photoisomerisation upon excitation with UV light, and a short thermal half-life for the Z isomer. 48,49…”