PMID- 34571191 OWN - NLM STAT- MEDLINE DCOM- 20220404 LR - 20220405 IS - 1873-3441 (Electronic) IS - 0939-6411 (Linking) VI - 172 DP - 2022 Mar TI - Association of a vaccine adjuvant with endogenous HDL increases lymph uptake and dendritic cell activation. PG - 240-252 LID - S0939-6411(21)00236-8 [pii] LID - 10.1016/j.ejpb.2021.09.004 [doi] AB - Vaccines are a powerful health intervention but there is still an unmet need for effective preventative and therapeutic vaccines for many diseases such as cancer and infections. Interstitial (e.g. subcutaneous (SC)) injection in nano-sized carriers such as high density lipoproteins (HDLs) can improve the access of vaccine subunit antigens or adjuvants to target immune cells in the lymphatics and potentiate vaccination responses such as cytotoxic T lymphocyte (CTL) responses (Kuai et al., 2016, 2018; Qian et al., 2016). Here we examined how cholesterol conjugation to the vaccine adjuvant CpG, and incorporation into HDL, changes lymphatic absorption and association with, and processing by, dendritic cells (DCs), ultimately influencing adjuvant efficacy. We investigated the lymphatic disposition of cholesterol conjugated CpG incorporated into HDL (HDL(Chol-CpG-Cy5)) relative to free cholesterol conjugated CpG (Chol-CpG-Cy5) and unconjugated CpG (free CpG-Cy5) after SC administration in rats and mice. HDL (Chol-CpG-Cy5) and Chol-CpG-Cy5 differentially altered CpG absorption into lymph vs. blood, but surprisingly resulted in similarly higher LN accumulation relative to free CpG. The mechanism of access of Chol-CpG-Cy5 into lymph might be partly due to association with endogenous HDL at the injection site followed by transport into lymph in association with the HDL. To measure CpG association with and processing by DCs and the strength of the immune response, mice were vaccinated with free ovalbumin (OVA) co-administered with the different CpG constructs. There were significant changes in DC activation that were reflective of the trend in LN accumulation at 24 h post-vaccination. However, T cell responses at 24 h and 7 days post-vaccination were not significantly different across the CpG groups although the response was less variable for Chol-CpG-Cy5 compared to free CpG Cy5 and also HDL(Chol-CpG-Cy5) - despite similar LN accumulation with the latter. Overall, our data indicate that cholesterol conjugation and incorporation into HDL increases adjuvant lymph disposition and DC activation. CI - Copyright (c) 2021 Elsevier B.V. All rights reserved. FAU - Gracia, Gracia AU - Gracia G AD - Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia. FAU - Cao, Enyuan AU - Cao E AD - Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia. FAU - Kochappan, Ruby AU - Kochappan R AD - Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia. FAU - Porter, Christopher J H AU - Porter CJH AD - Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia. FAU - Johnston, Angus P R AU - Johnston APR AD - Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia. FAU - Trevaskis, Natalie L AU - Trevaskis NL AD - Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Australia. Electronic address: Natalie.Trevaskis@monash.edu. LA - eng PT - Journal Article DEP - 20210924 PL - Netherlands TA - Eur J Pharm Biopharm JT - European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V JID - 9109778 RN - 0 (Adjuvants, Immunologic) RN - 0 (Adjuvants, Vaccine) RN - 0 (Antigens) RN - 0 (Oligodeoxyribonucleotides) RN - 9006-59-1 (Ovalbumin) SB - IM MH - *Adjuvants, Immunologic MH - *Adjuvants, Vaccine MH - Animals MH - Antigens MH - Dendritic Cells MH - Mice MH - Mice, Inbred C57BL MH - Oligodeoxyribonucleotides MH - Ovalbumin MH - Rats OTO - NOTNLM OT - Adjuvant OT - Delivery OT - HDL OT - Lymph OT - Lymph node OT - Vaccination EDAT- 2021/09/28 06:00 MHDA- 2022/04/05 06:00 CRDT- 2021/09/27 20:14 PHST- 2021/04/30 00:00 [received] PHST- 2021/09/02 00:00 [revised] PHST- 2021/09/11 00:00 [accepted] PHST- 2021/09/28 06:00 [pubmed] PHST- 2022/04/05 06:00 [medline] PHST- 2021/09/27 20:14 [entrez] AID - S0939-6411(21)00236-8 [pii] AID - 10.1016/j.ejpb.2021.09.004 [doi] PST - ppublish SO - Eur J Pharm Biopharm. 2022 Mar;172:240-252. doi: 10.1016/j.ejpb.2021.09.004. Epub 2021 Sep 24.