Αρχειοθήκη ιστολογίου

Παρασκευή 22 Σεπτεμβρίου 2017

Targeting Phosphatidylserine with Calcium-dependent Protein-Drug Conjugates for the Treatment of Cancer

In response to cellular stress, phosphatidylserine (PS) is exposed on the outer membrane leaflet of tumor blood vessels and cancer cells, motivating the development of PS-specific therapies. The generation of drug-conjugated PS-targeting agents represents an unexplored therapeutic approach, for which anti-tumor effects are critically dependent on efficient internalization and lysosomal delivery of the cytotoxic drug. In the current study, we have generated PS-targeting agents by fusing PS-binding domains to a human IgG1-derived Fc fragment. The tumor localization and pharmacokinetics of several PS-specific Fc fusions have been analyzed in mice and demonstrate that Fc-Syt1, a fusion containing the synaptotagmin 1 C2A domain, effectively targets tumor tissue. Conjugation of Fc-Syt1 to the cytotoxic drug, monomethyl auristatin E, results in a protein-drug conjugate (PDC) that is internalized into target cells and, due to the Ca²⁺-dependence of PS binding, dissociates from PS in early endosomes. The released PDC is efficiently delivered to lysosomes and has potent anti-tumor effects in mouse xenograft tumor models. Interestingly, whilst an engineered, tetravalent Fc-Syt1 fusion shows increased binding to target cells, this higher avidity variant demonstrates reduced persistence and therapeutic effects compared with bivalent Fc-Syt1. Collectively, these studies show that finely tuned, Ca²⁺-switched PS-targeting agents can be therapeutically efficacious.



from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yxBZGS

Δεν υπάρχουν σχόλια:

Δημοσίευση σχολίου