![]() The controlled release of drugs using nanoparticle-based delivery vehicles is a promising strategy to improve the safety and efficacy of chemotherapy. ![]() , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología Collectively, this work establishes HMBP monophosphonate ProPAgens as ideal candidates for further investigation as novel cancer immunotherapeutic agents. Additionally, a combination of in silico and in vitro enzymatic assays demonstrated the metabolism of these phosphonamidates to release the unmasked PAg monophosphonate species. ![]() ![]() These prodrugs showed excellent stability in human serum (t1/2 > 12 h) and potent activation of VÎ☹/VÎ♂ T-cells (EC50 ranging from 5 fM to 73 nM), which translated into sub-nanomolar γδ T-cell-mediated eradication of bladder cancer cells in vitro. In this work, we report a novel and short Grubbs olefin metathesis-mediated synthesis of methylene and difluoromethylene monophosphonate derivatives of the PAg (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBP) as well as their aryloxy diester phosphonamidate prodrugs, termed ProPAgens. The presence of the pyrophosphate group in these PAgs has limited their drug-like properties because of its instability and polar nature. VÎ☹/VÎ♂ T-cells are activated by pyrophosphate-containing small molecules known as phosphoantigens (PAgs).
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