Targeted Cancer Therapy Using Compounds Activated by Light

Abstract

Cancer chemotherapy is affected by a modest selectivity and toxic side effects of pharmacological interventions. Among novel approaches to overcome this limitation and to bring to therapy more potent and selective agents is the use of light for selective activation of anticancer compounds. In this review, we focus on the anticancer applications of two light-activated approaches still in the experimental phase: photoremovable protecting groups (“photocages”) and photoswitches. We describe the structural considerations behind the development of novel compounds and the plethora of assays used to confirm whether the photochemical and pharmacological properties are meeting the stringent criteria for an efficient in vivo light-dependent activation. Despite its immense potential, light activation brings many challenges, and the complexity of the task is very demanding. Currently, we are still deeply in the phase of pharmacological tools, but the vivid research and rapid development bring the light of hope for potential clinical use.

Biomimetic Photo-Switches Softening Model Lipid Membranes

“…24−26 In this framework, photoswitches may contribute to bypass one inherent problem of PDT, namely, the necessity to rely on the activation of 1 O 2 , which can be problematic due to the hypoxic conditions found in some solid tumors. 27, 28 A different strategy 29 relies on the accumulation of molecular switches into the cellular lipid membrane, followed by their light-induced conformational change, which results in the membrane destabilization and permeabilization, hence triggering cell death. To apply this strategy, however, it is necessary that the chemical properties of the switch permit the formation of stable and persistent aggregate with the biological macrostructure, a condition which can be met by the inclusion of hydrophobic groups to facilitate the penetration in the lipid core.…”

Recent Approaches to the Identification of Novel Microtubule-Targeting Agents

“…The design of both light-activated compounds and photopharmacological agents for targeted cancer therapies has recently been extensively reviewed with respect to their clinical potential ( Vickerman et al, 2021 ) as well as their use in photodynamic therapy ( Zhao et al, 2021 ) and in photopharmacology ( Dunkel and Ilaš, 2021 ). There are two different types of light-triggerable bioactive compounds: photocaged and photoswitchable.…”

Photoremovable Protecting Groups

“…Since the 1970s, a considerable effort has been dedicated both to the development of novel photoactivatable chemical probes and their applications in various experimental studies. Regarding the scope of PPG applications, the caged substrate could be as Encyclopedia 2022, 2 1227 simple as a proton or an inorganic species or ion (e.g., Ca 2+ [15], Zn 2+ [16], CO [17], NO [18], H 2 S [19]), it could be a small molecule (e.g., second messenger (such as inositol-1,4,5-triphosphate (IP 3 ) [20]), neurotransmitter (notably GABA and glutamate [21,22]), nucleotide [23], peptide [24], drug molecule [25] (such as antibiotics [26], analgesics [27] or anticancer agents [28]) or a more complex biomolecule (e.g., enzymes [29], RNA [30] or DNA [31]) (Figure 3).…”

“…Since the 1970s, a considerable effort has been dedicated both to the development of novel photoactivatable chemical probes and their applications in various experimental studies. Regarding the scope of PPG applications, the caged substrate could be as simple as a proton or an inorganic species or ion (e.g., Ca 2+ [15], Zn 2+ [16], CO [17], NO [18], H2S [19]), it could be a small molecule (e.g., second messenger (such as inositol-1,4,5-triphosphate (IP3) [20]), neurotransmitter (notably GABA and glutamate [21,22]), nucleotide [23], peptide [24], drug molecule [25] (such as antibiotics [26], analgesics [27] or anticancer agents [28]) or a more complex biomolecule (e.g., enzymes [29], RNA [30] or DNA [31]) (Figure 3). Examples of PPG applications for small molecules/inorganic species: (A) calcium caging with photoactivatable EGTA [32], (B) neurotransmitter glutamate caging with MNI [21], (C) caging the anticancer agent vemurafenib with a nitrobenzyl PPG [33], (D) a coumarin PPG-caged antibiotic agent [34], (E) a coumarin PPG-caged analgesic [27].…”