Impact of conjugation to different lipids on the lymphatic uptake and biodistribution of brush PEG polymers

作者：Mohammad Abdallah, Lihuan Lin, Ian K. Styles, Alexander Mörsdorf, James L. Grace, Gracia Gracia, Cornelia B. Landersdorfer, Cameron J. Nowell, John F. Quinn, Michael R. Whittaker, Natalie L. Trevaskis · 发表于：Journal of Controlled Release · 年份：2024 · DOI：10.1016/j.jconrel.2024.03.032 · 被引用次数：10 · 研究领域：Lymphatic System and Diseases、Advancements in Transdermal Drug Delivery、Immunotherapy and Immune Responses

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 polymer...