Light-Activatable Photocaged UNC2025 for Triggering TAM Kinase Inhibition in Bladder Cancer.

Photopharmacology is an emerging field that utilizes photo-responsive molecules to enable control over the activity of a drug using light. The aim is to limit the therapeutic action of a drug at the level of diseased tissues and organs. Considering the well-known implications of protein kinases in cancer and the therapeutic issues associated with protein kinase inhibitors, the photopharmacology is seen as an innovative and alternative solution with great potential in oncology. In this context, we developed the first photocaged TAM kinase inhibitors based on UNC2025, a first-in-class small molecule kinase inhibitor. These prodrugs showed good stability in biologically relevant buffer and rapid photorelease of the photoremovable protecting group upon UV-light irradiation (<10 min.). These light-activatable prodrugs led to a 16-fold decrease to a complete loss of kinase inhibition, depending on the protein and the position at which the coumarin-type phototrigger was introduced. The most promising candidate was the N,O-dicaged compound, showing the superiority of having two photolabile protecting groups on UNC2025 for being entirely inactive on TAM kinases. Under UV-light irradiation, the N,O-dicaged compound recovered its inhibitory potency in enzymatic assays and displayed excellent antiproliferative activity in RT112 cell lines.

Fully Automated Macro- and Microfluidic Production of [68Ga]Ga-Citrate on mAIO® and iMiDEVTM Modules.

68Ga-radionuclide has gained importance due to its availability via 68Ge/68Ga generator or cyclotron production, therefore increasing the number of 68Ga-based PET radiopharmaceuticals available in clinical practice. [68Ga]Ga-citrate PET has been shown to be prominent for detection of inflammation/infection of the musculoskeletal, gastrointestinal, respiratory, and cardiovascular systems. Automation and comparison between conventional and microfluidic production of [68Ga]Ga-citrate was performed using miniAllInOne® (Trasis) and iMiDEV™ (PMB-Alcen) synthetic modules. Fully automated procedures were elaborated for cGMP production of tracer. In order to facilitate the tracer approval as a radiopharmaceutical for clinical use, a new method for radiochemical identity determination by HPLC analysis to complement standard TLC radiochemical purity measurement was developed. The results showed higher radiochemical yields when using MCX cartridge on the conventional module mAIO®, while a PS-H+ cation exchanger was shown to be preferred for integration into the microfluidic cassette of iMiDEV™ module. In this study, the fully automated radiosynthesis of [68Ga]Ga-citrate using different synthesizers demonstrated reliable and reproducible radiochemical yields. In order to demonstrate the applicability of [68Ga]Ga-citrate, in vitro and in vivo studies were performed showing similar characteristics of the tracer obtained using macro- and microfluidic ways of production.