Molecular Design of Squalene/Squalane Countertypes via the Controlled Oligomerization of Isoprene and Evaluation of Vaccine Adjuvant Applications

Adlington, Kevin; El harfi, Jaouad; Li, Jianing; Carmichael, Kim; Guderian, Jeffrey A.; Fox, Christopher B.; Irvine, Derek

Abstract

The potential to replace shark-derived squalene in vaccine adjuvant applications with synthetic squalene/poly(isoprene) oligomers, synthesized by the controlled oligomerization of isoprene is demonstrated. Following on from our previous work regarding the synthesis of poly(isoprene) oligomers, we demonstrate the ability to tune the molecular weight of the synthetic poly(isoprene) material beyond that of natural squalene, while retaining a final backbone structure that contained a minimum of 75% of 1,4 addition product and an acceptable polydispersity. The synthesis was successfully scaled from the 2 g to the 40 g scale both in the bulk (i.e., solvent free) and with the aid of additional solvent by utilizing catalytic chain transfer polymerization (CCTP) as the control method, such that the target molecular weight, acceptable dispersity levels, and the desired level of 1,4 addition in the backbone structure and an acceptable yield (?60%) are achieved. Moreover, the stability and in vitro bioactivity of nanoemulsion adjuvant formulations manufactured with the synthetic poly(isoprene) material are evaluated in comparison to emulsions made with shark-derived squalene. Emulsions containing the synthetic poly(isoprene) achieved smaller particle size and equivalent or enhanced bioactivity (stimulation of cytokine production in human whole blood) compared to corresponding shark squalene emulsions. However, as opposed to the shark squalene-based emulsions, the poly(isoprene) emulsions demonstrated reduced long-term size stability and induced hemolysis at high concentrations. Finally, we demonstrate that the synthetic oligomeric poly(isoprene) material could successfully be hydrogenated such that >95% of the double bonds were successfully removed to give a representative poly(isoprene)-derived squalane mimic.

• Journal Article Type: Article
• Acceptance Date: Nov 23, 2015
• Online Publication Date: Dec 11, 2015
• Publication Date: Dec 11, 2015
• Deposit Date: Aug 30, 2018
• Print ISSN: 1525-7797
• Electronic ISSN: 1526-4602
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 17
• Issue: 1
• Pages: 165-172
• DOI: https://doi.org/10.1021/acs.biomac.5b01285
• Public URL: http://www.scopus.com/inward/record.url?eid=2-s2.0-84954191172&partnerID=40&md5=466207fb806058ac7f6afbff0fe155e8
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.biomac.5b01285