PMID- 38513730 OWN - NLM STAT- Publisher LR - 20240327 IS - 1873-4995 (Electronic) IS - 0168-3659 (Linking) VI - 369 DP - 2024 Mar 26 TI - Impact of conjugation to different lipids on the lymphatic uptake and biodistribution of brush PEG polymers. PG - 146-162 LID - S0168-3659(24)00185-8 [pii] LID - 10.1016/j.jconrel.2024.03.032 [doi] AB - Delivery to peripheral lymphatics can be achieved following interstitial administration of nano-sized delivery systems (nanoparticles, liposomes, dendrimers etc) or molecules that hitchhike on endogenous nano-sized carriers (such as albumin). The published work concerning the hitchhiking approach has mostly focussed on the lymphatic uptake of vaccines conjugated directly to albumin binding moieties (ABMs such as lipids, Evans blue dye derivatives or peptides) and their subsequent trafficking into draining lymph nodes. The mechanisms underpinning access and transport of these constructs into lymph fluid, including potential interaction with other endogenous nanocarriers such as lipoproteins, have largely been ignored. Recently, we described a series of brush polyethylene glycol (PEG) polymers containing end terminal short-chain or medium-chain hydrocarbon tails (1C2 or 1C12, respectively), cholesterol moiety (Cho), or medium-chain or long-chain diacylglycerols (2C12 or 2C18, respectively). We evaluated the association of these materials with albumin and lipoprotein in rat plasma, and their intravenous (IV) and subcutaneous (SC) pharmacokinetic profiles. Here we fully detail the association of this suite of polymers with albumin and lipoproteins in rat lymph, which is expected to facilitate lymph transport of the materials from the SC injection site. Additionally, we characterise the thoracic lymph uptake, tissue and lymph node biodistribution of the lipidated brush PEG polymers following SC administration to thoracic lymph cannulated rats. All polymers had moderate lymphatic uptake in rats following SC dosing with the lymph uptake higher for 1C2-PEG, 2C12-PEG and 2C18-PEG (5.8%, 5.9% and 6.7% dose in lymph, respectively) compared with 1C12-PEG and Cho-PEG (both 1.5% dose in lymph). The enhanced lymph uptake of 1C2-PEG, 2C12-PEG and 2C18-PEG appeared related to their association profile with different lipoproteins. The five polymers displayed different biodistribution patterns in major organs and tissues in mice. All polymers reached immune cells deep within the inguinal lymph nodes of mice following SC dosing. The ability to access these immune cells suggests the potential of the polymers as platforms for the delivery of vaccines and immunotherapies. Future studies will focus on evaluating the lymphatic targeting and therapeutic potential of drug or vaccine-loaded polymers in pre-clinical disease models. CI - Copyright (c) 2024 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Abdallah, Mohammad AU - Abdallah M AD - Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. FAU - Lin, Lihuan AU - Lin L AD - Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. FAU - Styles, Ian K AU - Styles IK AD - Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. FAU - Morsdorf, Alexander AU - Morsdorf A AD - Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. FAU - Grace, James L AU - Grace JL AD - Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. FAU - Gracia, Gracia AU - Gracia G AD - Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. FAU - Landersdorfer, Cornelia B AU - Landersdorfer CB AD - Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. FAU - Nowell, Cameron J AU - Nowell CJ AD - Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia. FAU - Quinn, John F AU - Quinn JF AD - Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; Department of Chemical Engineering, Faculty of Engineering, Monash University, Clayton, VIC, Australia. FAU - Whittaker, Michael R AU - Whittaker MR AD - Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. Electronic address: michael.whittaker@monash.edu. FAU - Trevaskis, Natalie L AU - Trevaskis NL AD - Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. Electronic address: natalie.trevaskis@monash.edu. LA - eng PT - Journal Article DEP - 20240326 PL - Netherlands TA - J Control Release JT - Journal of controlled release : official journal of the Controlled Release Society JID - 8607908 SB - IM OTO - NOTNLM OT - Albumin-hitchhiking OT - Brush PEG OT - Immunotherapy OT - Lipid OT - Lipoproteins OT - Lymph OT - Polyethylene glycol OT - Vaccine COIS- Declaration of competing interest None. EDAT- 2024/03/22 00:44 MHDA- 2024/03/22 00:44 CRDT- 2024/03/21 20:24 PHST- 2024/01/03 00:00 [received] PHST- 2024/02/28 00:00 [revised] PHST- 2024/03/16 00:00 [accepted] PHST- 2024/03/22 00:44 [pubmed] PHST- 2024/03/22 00:44 [medline] PHST- 2024/03/21 20:24 [entrez] AID - S0168-3659(24)00185-8 [pii] AID - 10.1016/j.jconrel.2024.03.032 [doi] PST - aheadofprint SO - J Control Release. 2024 Mar 26;369:146-162. doi: 10.1016/j.jconrel.2024.03.032.