A nanoparticle-based nicotine vaccine and the influence of particle size on its immunogenicity and efficacy

Abstract

Traditional hapten-protein conjugate nicotine vaccines have shown less than desired immunological efficacy due to their poor recognition and internalization by immune cells. We developed a novel lipid-polymeric hybrid nanoparticle-based nicotine vaccine to enhance the immunogenicity of the conjugate vaccine, and studied the influence of particle size on its immunogenicity and pharmacokinetic efficacy. The results demonstrated that the nanovaccines, regardless of size, could induce a significantly stronger immune response against nicotine compared to the conjugate vaccine. Particularly, a significantly higher anti-nicotine antibody titer was achieved by the 100 compared to the 500 nm nanovaccine. In addition, both the 100 and 500 nm nanovaccines reduced the distribution of nicotine into the brain significantly. The 100 nm nanovaccine exhibited better pharmacokinetic efficacy than the 500 nm nanovaccine in the presence of alum adjuvant. These results suggest that a lipid-polymeric nanoparticle-based nicotine vaccine is a promising candidate to treat nicotine dependence.

Rationalization of a nanoparticle-based nicotine nanovaccine as an effective next-generation nicotine vaccine: A focus on hapten localization

“…[26, 32] In brief, 2.5 mg of lipid mixture consisting of different molar ratios of DOTAP, DSPE-PEG2000-maleimide, DSPE-PEG2000-amine, and CHOL, was evaporated to form a lipid film. The lipid film was hydrated with 0.01 M phosphate buffer saline (PBS) and sonicated for 2 min to form a liposome suspension.…”

“…[26] Specifically, the Nic-KLH conjugates used for preparing LPKN or LPNKN nanovaccines were synthesized by reacting 1.2 mg or 2.4 mg of Nic hapten with 5 mg of KLH. Hapten densities of Nic-KLH conjugates were estimated by a 2,4,6-trinitrobenzene sulfonic acid-based method as reported previously.…”

“…[26] In brief, an appropriate amount of Traut’s reagent was added into the Nic-KLH conjugates equivalent to 2 mg of KLH in 0.5 mL of PBS and reacted for 1 h to form thiolated Nic-KLH. The thiolated Nic-KLH equivalent to 1 mg of KLH was conjugated to 30 mg of lipid-polymeric hybrid NPs by reacting the thiolated Nic-KLH with maleimide groups in the lipid layer of NPs for 2 h. Unconjugated Nic-KLH was separated by centrifugation at 10,000 g , 4°C for 30 min, and quantified by the bicinchoninic acid assay.…”

“…[24–26] Particularly, lipid-polymeric hybrid nanoparticle (NP)-based nicotine nanovaccines were demonstrated to induce significantly higher immunogenicity over the conjugate vaccines and result in better pharmacokinetic efficacy in mice. [26, 27]…”

“…[29, 30] In our previous nanovaccine design, hapten was conjugated to the surface of protein antigens. [26] As the localization of haptens on vaccine NPs may potentially affect the recognition of antigens by immune cells, in this current work, we rationalized the design of a hybrid NP-based nicotine vaccine by studying the impact of hapten localization on its immunogenicity and pharmacokinetic efficacy. As shown in Scheme, three nanovaccines, which have haptens localized only on the carrier protein ( LPKN ), only on NP surface ( LPNK ), or on both ( LPNKN ), were synthesized.…”