Calix[n]arene-based immunogens: A new non-proteic strategy for anti-cocaine vaccine

INTRODUCTION: Cocaine use disorder is a significant public health issue without a current specific approved treatment. Among different approaches to this disorder, it is possible to highlight a promising immunologic strategy in which an immunogenic agent may reduce the reinforcing effects of the drug if they are able to yield sufficient specific antibodies capable to bind cocaine and/or its psychoactive metabolites before entering into the brain. Several carriers have been investigated in the anti-cocaine vaccine development; however, they generally present a very complex chemical structure, which potentially hampers the proper assessment of the coupling efficiency between the hapten units and the protein structure. OBJECTIVES: The present study reports the design, synthesis and preclinical evaluation of two novel calix[n]arene-based anti-cocaine immunogens (herein named as V4N2 and V8N2) by the tethering of the hydrolysis-tolerant hapten GNE (15) on calix[4]arene and calix[8]arene moieties. METHODS: The preclinical assessment corresponded to the immunogenicity and dose–response evaluation of V4N2 and V8N2. The potential of the produced antibodies to reduce the passage of cocaine analogue through the blood–brain-barrier (BBB), modifying its biodistribution was also investigated. RESULTS: Both calix[n]arene-based immunogens elicited high titers of cocaine antibodies that modified the biodistribution of a cocaine radiolabeled analogue ((99m)Tc-TRODAT-1) and decreased cocaine-induced behavior, according to an animal model. CONCLUSION: The present results demonstrate the potential of V4N2 and V8N2 as immunogens for the treatment of cocaine use disorder.