Department of Pharmacology & Toxicology and ⊥Center for Addiction Research, and ‡Sealy Center for Vaccine Development, University of Texas Medical Branch , 301 University Blvd, Galveston, Texas 77555, United States.
ACS Chem Neurosci. 2016 May 18;7(5):546-52. doi: 10.1021/acschemneuro.5b00345. Epub 2016 Mar 8.
The development of anti-cocaine vaccines that counteract the rewarding effects of the drug are currently being investigated as adjunct therapies for prevention of relapse in abstinent users. However, cocaine is weakly immunogenic and requires conjugation to carrier proteins and coadministration with strong adjuvants, which carry the risk of local reactogenicity and systemic toxicity. Here we report synthetic and multivalent self-assembling peptide nanofibers as adjuvant-free carriers for cocaine vaccines. A novel cocaine hapten modified at the P3 site was conjugated to the N-terminus of an amphipathic self-assembling domain KFE8. In aqueous buffers the cocaine-KFE8 conjugate assembled into β-sheet rich nanofibers, which raised anti-cocaine antibodies without the need for added adjuvants in mice. Vaccinated mice were treated with cocaine and a significant negative correlation was observed between antibody levels and cocaine-evoked hyperactivity. These totally synthetic and multivalent nanofibers with well-defined chemical composition represent the first generation of adjuvant-free cocaine vaccines.
目前，人们正在研究抗可卡因疫苗，以对抗该药物的奖赏效应，作为预防戒毒者复吸的辅助疗法。然而，可卡因的免疫原性较弱，需要与载体蛋白缀合，并与强佐剂共同给药，这会带来局部反应原性和全身毒性的风险。在这里，我们报告了作为无佐剂载体的合成和多价自组装肽纳米纤维用于可卡因疫苗。一种在 P3 位修饰的新型可卡因半抗原与两亲自组装结构域 KFE8 的 N 端缀合。在水性缓冲液中，可卡因-KFE8 缀合物组装成富含β-折叠的纳米纤维，在不添加额外佐剂的情况下在小鼠中引发抗可卡因抗体。用可卡因对免疫接种的小鼠进行处理，观察到抗体水平与可卡因引起的过度活动之间存在显著的负相关。这些具有明确化学组成的完全合成和多价纳米纤维代表了第一代无佐剂可卡因疫苗。
