Polymer-based vaccines for substance use disorders: Targeting ketamine and methamphetamine with protein-free hyperbranched polyethyleneimine carriers

Substance use disorders (SUDs) present a critical global health challenge, as current treatment options often prove insufficient, particularly for substances like ketamine and methamphetamine. In this study, we developed a novel immunotherapeutic strategy utilizing protein-free, polymer-based vaccines, with hyperbranched polyethylenimine (Hb-PEI) as a carrier to enhance immune specificity and remove the production of non-specific antibodies. Haptens for ketamine and methamphetamine were covalently conjugated to the Hb-PEI carrier, along with the Toll-like receptor (TLR) 7/8 agonist 1V209, to stimulate targeted humoral immune responses. Our results demonstrated that vaccines produced specific antibodies capable of effectively neutralizing ketamine- and methamphetamine-induced effects, such as conditioned place preference (CPP) and ketamine-induced analgesia. Notably, the immune response persisted for 95-112 days, demonstrating the vaccines' long-lasting efficacy. In contrast, no antibodies were generated when the adjuvant 1V209 was physically combined with the hapten, underscoring the importance of synergistic vaccine components. Additionally, the polymer-based approach exhibited excellent biocompatibility, without generating non-specific antibodies or causing adverse health effects. These findings highlight the potential of Hb-PEI-based vaccines as a promising platform for treating SUDs, offering a new pathway for clinical applications in combating drug addiction.