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 drug-containing 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.

In vivo data are rare but essential for establishing the clinical potential of ruthenium-based photoactivated chemotherapy (PACT) compounds, a new family of phototherapeutic drugs that are activated via ligand photosubstitution....

Cell‐specific drug delivery remains a major unmet challenge for cancer nanomedicines. Here, light‐triggered, cell‐specific delivery of liposome‐encapsulated doxorubicin to xenograft human cancer cells in live zebrafish embryos is demonstrated. This method relies on light‐triggered dePEGylation of liposome surfaces to reveal underlying targeting functionality. To demonstrate general applicability of this method, light‐triggered, MDA‐MB‐231 breast cancer cell specific targeting in vivo (embryonic zebrafish) is shown using both clinically relevant, folate‐liposomes, as well as an experimental liposome‐cell fusion system. In the case of liposome‐cell fusion, the delivery of liposomal doxorubicin direct to the cytosol of target cancer cells results in enhanced cytotoxicity, compared to doxorubicin delivery via either folate‐liposomes or free doxorubicin, as well as a significant reduction in xenograft cancer cell burden within the embryonic fish.

Diffuse idiopathic skeletal hyperostosis (DISH) is a noninflammatory skeletal disease characterized by the progressive ectopic ossification and calcification of ligaments and enthuses. However, specific pathogenesis remains unknown. Bone marrow mesenchymal stem cells (BMSCs) are a major source of osteoblasts and play vital roles in bone metabolism and ectopic osteogenesis. However, it is unclear whether BMSCs are involved in ectopic calcification and ossification in DISH. The current study aimed to explore the osteogenic differentiation abilities of BMSCs from DISH patients (DISH-BMSCs). Our results showed that DISH-BMSCs exhibited stronger osteogenic differentiation abilities than normal control (NC)-BMSCs. Human cytokine array kit analysis showed significantly increased secretion of Galectin-3 in DISH-BMSCs. Furthermore, Galectin-3 downregulation inhibited the increased osteogenic differentiation ability of DISH-BMSCs, whereas exogenous Galectin-3 significantly enhanced the osteogenic differentiation ability of NC-BMSCs. Notably, the increased Galectin-3 in DISH-BMSCs enhanced the expression of β-catenin as well as TCF-4, whereas attenuation of Wnt/β-catenin signaling partially alleviated Galectin-3-induced osteogenic differentiation and activity in DISH-BMSCs. In addition, our results noted that Galectin-3 interacted with β-catenin and enhanced its nuclear accumulation. Further in vivo studies showed that exogenous Galectin-3 enhanced ectopic bone formation in the Achilles tendon in trauma-induced rats by activating Wnt/βcatenin signaling. The current study indicated that enhanced osteogenic differentiation of DISH-BMSCs was mainly attributed to the increased secretion of Galectin-3 by DISH-BMSCs, which enhanced β-catenin expression and its nuclear accumulation. Our study helps illuminate the mechanisms of pathological osteogenesis and sheds light on the possible development of potential therapeutic strategies for DISH treatment.