Mitochondria-Targeted Photoactivatable Real-Time Monitoring of a Controlled Drug Delivery Platform

Abstract

The current anticancer therapies are limited by their lack of controlled spatiotemporal release at the target site of action. We report a novel drug delivery platform that provides on-demand, real-time, organelle-specific drug release and monitoring upon photoactivation. The system is comprised of a model anticancer drug doxorubicin, an alkyltriphenylphosphonium moiety to target mitochondria in cancer cells, and a hydroxycinnamate photoactivatable linker that is covalently attached to the drug and mitochondria-targeting moieties such that it can be phototriggered by either UV (one-photon) or NIR (two-photon) light to form a fluorescent coumarin product and facilitate the release of drug payload. The extent of drug release is quantified by the fluorescence intensity of the coumarin formed. Further, the photoactivatable prodrug accumulates in the mitochondria and shows light-triggered temporally controlled cell death. In the future, our platform can be tuned for any biological application of interest, offering immense value in biomedicine.

Recent advances in self-immolative linkers and their applications in polymeric reporting systems

“…Sasmal et al have recently reported drug delivery platform 216 based upon a key cinnamate photoactivation. 218 In the same way as Mosey and Floreancig (Scheme 7), Sasmal et al have employed Murphy's triphenylphosphonium directing group to target the mitochondria of the relevant cell type, and the success of this approach was evident in the fluorescence microscopy studies following treatment of HeLa cells with 216 (92% of cellular uptake into the mitochondria within 2 h). Use of one (365 nm) or two-photon irradiation (700 nm) 219 of 216 proved successful in releasing the doxorubicin reporter group.…”

“…An alternative platform for effective intramolecular cyclisation systems have been realised by the trimethyl-lock linkers, these take advantage of a Thorpe-Ingold effect in tandem with repulsion from an adjacent aromatic methyl group: recently, these have been thoroughly reviewed by Klahn. [220][221][222][223] Jullien and Schmidt have reported valuable kinetic data of their rates of cyclisation, utilising a photoactivatable self-immolative system 217 that, upon trigger activation, results in a 6-exo-trigcyclisation (218), favoured by steric hindrance, resulting in lactonization of the linker to give 219 in ca. 3 minutes liberating the fluorescent reporter 220 (Scheme 49).…”

“…Scheme Dal Corso and Gennari's dual triggered SIE for camptothecin delivery 202. 39 Scheme Drug delivery platforms 215 and 216 based around photoisomerism of cinnamate linkers 217,218.…”

Photoremovable Protecting Groups

“…Additionally, cell-or site-selective targeting units could be integrated into the construct. Singh et al developed a mitochondria-targeting system (using an alkyltriphenylphosphonium (TPP) targeting moiety) with an o-hydroxycinnamate PPG, releasing doxorubicin upon light irradiation [58] (Figure 8). Although the o-hydroxycinnamate PPG itself is not In the former case, upon TP excitation the TP-absorbing unit donates an electron to the pyridinium PPG unit (* referring to the photoexcited state), leading to a photochemical reaction and the release of the cargo [8].…”

“…Additionally, cell-or site-selective targeting units could be integrated into the construct. Singh et al developed a mitochondria-targeting system (using an alkyltriphenylphosphonium (TPP) targeting moiety) with an o-hydroxycinnamate PPG, releasing doxorubicin upon light irradiation [58] (Figure 8). Although the o-hydroxycinnamate PPG itself is not fluorescent, upon its photoinduced isomerization and cyclization a fluorescent coumarin derivative is formed, that could be exploited for the real-time monitoring of the release process.…”