Thanks for the link Gustoes.
Gustoes wrote: https://www.mdpi.com/2072-6694/12/3/587/pdf
Abstract: The ruthenium-based photosensitizer (PS) TLD1433 has completed a phase I clinical trial for photodynamic therapy (PDT) treatment of bladder cancer. Here, we investigated a possible repurposing of this drug for treatment of conjunctival melanoma (CM). CM is a rare but often deadly ocular cancer. The efficacy of TLD1433 was tested on several cell lines from CM (CRMM1, CRMM2 and CM2005), uveal melanoma (OMM1, OMM2.5, MEL270), epidermoid carcinoma (A431) and cutaneous melanoma (A375). Using 15 min green light irradiation (21 mW/cm2, 19 J.cm−2, 520 nm), the highest phototherapeutic index (PI) was reached in CM cells, with cell death occurring via apoptosis and necrosis. The therapeutic potential of TLD1433 was hence further validated in zebrafish ectopic and newly-developed orthotopic CM models. Fluorescent CRMM1 and CRMM2 cells were injected into the circulation of zebrafish (ectopic model) or behind the eye (orthotopic model) and 24 h later, the engrafted embryos were treated with the maximally-tolerated dose of TLD1433. The drug was administrated in three ways, either by (i) incubating the fish in drugcontaining water (WA), or (ii) injecting the drug intravenously into the fish (IV), or (iii) injecting the drug retro-orbitally (RO) into the fish. Optimally, four consecutive PDT treatments were performed on engrafted embryos using 60 min drug-to-light intervals and 90 min green light irradiation (21 mW/cm2, 114 J.cm−2, 520 nm). This PDT protocol was not toxic to the fish. In the ectopic tumour model, both systemic administration by IV injection and RO injection of TLD1433 significantly inhibited growth of engrafted CRMM1 and CRMM2 cells. However, in the orthotopic model, tumour growth was only attenuated by localized RO injection of TLD1433. These data unequivocally prove that the zebrafish provides a fast vertebrate cancer model that can be used to test the administration regimen, host toxicity and anti-cancer efficacy of PDT drugs against CM. Based on our results, we suggest repurposing of TLD1433 for treatment of incurable CM and further testing in alternative pre-clinical models.
Developing new ocular PDT treatments often depends on a limited number of rabbit studies, due to lack of other animal models. To overcome this, we previously generated an ectopic CM model, and now developed an orthotopic CM model in zebrafish. Zebrafish xenograft models are particularly straightforward for testing compound toxicity and efficacy in vivo, as due to the small size and transparence of the embryo, one can examine on the one hand adverse effects on developing phenotypes or animal survival, and on the other hand tumour burden by fluorescence microscopy.
Recently, the McFarland and Lilge research groups have actively developed TLD1433 (Figure 1, left), a Ru-based PS. A phase Ib clinical trial for intravesical PDT treatment of non-muscle invasive bladder tumours using this PS was successfully completed in 2018, [22,29] and a much larger Phase 2 study is underway. The compound has a low cytotoxicity in the dark and an exceptionally high phototoxicity with light activation when tested on a wide range of human cancer cells [29]. Its activation in cells is optimal in the green domain of the spectrum (520 nm), and although the mechanism of cell death by light-activated TLD1433 is not completely clear, this PS generates 1O2 with near-to-unity quantum efficacy [22]. The outstanding type-II PDT properties of this compound involve initial population of metal-to-ligand charge transfer excited states, which, after intersystem crossing, lead to triplet intra-ligand (3IL) or intra-ligand charge-transfer excited states (3ILCT, Figure 1, right) that are very sensitive to oxygen and other excited state quenchers. These remarkable results led us to investigate a possible repurposing of TLD1433 for the PDT treatment of conjunctival melanoma (CM).
Last but not least, clinical PDT in intraocular melanoma has up to now been limited not only by the lack of clinically approved PS, but also by interferences by the ocular and tumour pigment with light absorption. Most approved PDT sensitizers are porphyrin compounds, which offer a quite narrow (~20 nm) excitation wavelength range. If the pigment of the tumour absorbs too much of that light, PDT activity may be compromised. TLD1433, like most Ru polypyridyl compounds, shows broad absorption bands (Δλ ~ 150 nm) between the blue and red regions of the spectrum, thereby allowing to fine-tune the excitation wavelength and optimise light absorption by the sensitizer vs. light absorption by the pigment [51]. These effects could not be tested here, as the CM and uveal melanoma cell lines have lost their pigments. Rutherrin, a new formulation of TLD1433 and transferrin, is now being proposed to improve the target specificity and water solubility of the PS [52–54].
Rutherrin was proven to cross the blood brain barrier (BBB) and is now under clinical investigation for glioblastoma multiforme (GBM) and non-small-cell lung cancer (NSCLC) [19].