Photo-Uncaging of a Microtubule-Targeted Rigidin Analogue in Hypoxic Cancer Cells and in a Xenograft Mouse Model

Abstract

Marine alkaloid rigidins are cytotoxic compounds known to kill cancer cells at nanomolar concentrations by targeting the microtubule network. Here, a rigidin analogue containing a thioether group was "caged" by coordination of its thioether group to a photosensitive ruthenium complex. In the dark, the coordinated ruthenium fragment prevented the rigidin analogue from inhibiting tubulin polymerization and reduced its toxicity in 2D cancer cell line monolayers, 3D lung cancer tumor spheroids (A549), and a lung cancer tumor xenograft (A549) in nude mice. Photochemical activation of the prodrug upon green light irradiation led to the photosubstitution of the thioether ligand by water, thereby releasing the free rigidin analogue capable of inhibiting the polymerization of tubulin. In cancer cells, such photorelease was accompanied by a drastic reduction of cell growth, not only when the cells were grown in normoxia (21% O 2 ) but also remarkably in hypoxic conditions (1% O 2 ). In vivo, low toxicity was observed at a dose of 1 mg•kg −1 when the compound was injected intraperitoneally, and light activation of the compound in the tumor led to 30% tumor volume reduction, which represents the first demonstration of the safety and efficacy of ruthenium-based photoactivated chemotherapy compounds in a tumor xenograft.

Breaking the barrier: an osmium photosensitizer with unprecedented hypoxic phototoxicity for real world photodynamic therapy

“…41,[48][49][50][51][52][53][54] Likewise, relatively few systems have been tested for photodissociation in cell-free conditions under low oxygen conditions (i.e., 0-3%). 37,49,50,52,55 Performing experiments under hypoxic conditions is challenging due to a variety of factors such as the initial establishment of low oxygen tension or differences in cellular growth and metabolismif the cells can even grow at the desired oxygen level. A hypoxia chamber for cell incubation and processing is required to establish and maintain a low oxygen atmosphere, but many light devices do not t inside the chamber and/or result in excessive heating in the chamber.…”

Combination of chemotherapy and oxidative stress to enhance cancer cell apoptosis

“…By employing characteristic intracellular and surrounding environments of cancer cells, prodrugs that could be selectively activated by cancer cells have attracted increasing interests in the past few years. 14,15 Based on the unique microenvironment of cancer cells, a large number of prodrugs that respond to different stimuli, such as thiols, [16][17][18][19] acidic pH, 20,21 ROS, 13,22,23 enzymes, 24,25 hypoxia 26,27 and light, [28][29][30] have been disclosed with great success in the experimental treatment of various cancer cells. Among different types of prodrugs, exploiting the disul-de scaffold as a trigger unit has been widely adopted, [16][17][18][19]31,32 as cancer cells usually have a higher ability than normal cells to reduce the disulde bond due to the elevated level of antioxidant molecules, such as thioredoxin (Trx), thioredoxin reductase (TrxR) and reduced glutathione (GSH).…”

One‐ and Two‐Photon Phototherapeutic Effects of RuII Polypyridine Complexes in the Hypoxic Centre of Large Multicellular Tumor Spheroids and Tumor‐Bearing Mice**

“…Despite these benefits, studies of the antitumor effects of compounds in large MCTSs remain very rare. [9] To overcome this limitation and promote a better understanding of the biological effects of new compounds, there is an urgent need for in-depth studies of the ability of new compounds in large MCTSs. Ru(II) polypyridine complexes are gaining increasing attention as PDT PSs due to their attractive chemical and photophysical properties (e.g., high water solubility, chemical stability and photostability).…”