Quantitation of lymphatic transport mechanism and barrier influences on lymph node-resident leukocyte access to lymph-borne macromolecules and drug delivery systems

• Type of Material: Article
• Authors: Paul A Archer, Georgia Institute of Technology, Atlanta; Lauren F Sestito, Emory University; Margaret P Manspeaker, Georgia Institute of Technology, Atlanta; Meghan J O'Melia, Emory University; Nathan A Rohner, Georgia Institute of Technology, Atlanta; Alex Schudel, Georgia Institute of Technology, Atlanta; Yajun Mei, Georgia Institute of Technology, Atlanta; Susan N Thomas, Georgia Institute of Technology, Atlanta
• Language: English
• Date: 2021-12-01
• Publisher: Springer Verlag
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021, Controlled Release Society
• Final Published Version (URL): http://dx.doi.org/10.1007/s13346-021-01015-3
• Title of Journal or Parent Work: Drug Delivery and Translational Research
• Volume: 11
• Issue: 6
• Start Page: 2328
• End Page: 2343
• Grant/Funding Information: This work was supported by National Institutes of Health (NIH) Grants R01CA207619 (SNT), R01CA247484 (SNT), U01CA214354 (SNT), T32GM008433 (MJO, NAR), and T32EB006343 (LFS) and the Curci Foundation (SNT).; M.P.M. was supported by a National Science Foundation Graduate Research Fellowship. LFS and AS were American Heart Association Pre-doctoral Fellows.
• Keywords: transport barrier; lymphatic system; drug delivery; Lymph node; transport mechanism

Abstract

Lymph nodes (LNs) are tissues of the immune system that house leukocytes, making them targets of interest for a variety of therapeutic immunomodulation applications. However, achieving accumulation of a therapeutic in the LN does not guarantee equal access to all leukocyte subsets. LNs are structured to enable sampling of lymph draining from peripheral tissues in a highly spatiotemporally regulated fashion in order to facilitate optimal adaptive immune responses. This structure results in restricted nanoscale drug delivery carrier access to specific leukocyte targets within the LN parenchyma. Herein, a framework is presented to assess the manner in which lymph-derived macromolecules and particles are sampled in the LN to reveal new insights into how therapeutic strategies or drug delivery systems may be designed to improve access to dLN-resident leukocytes. This summary analysis of previous reports from our group assesses model nanoscale fluorescent tracer association with various leukocyte populations across relevant time periods post administration, studies the effects of bioactive molecule NO on access of lymph-borne solutes to dLN leukocytes, and illustrates the benefits to leukocyte access afforded by lymphatic-targeted multistage drug delivery systems. Results reveal trends consistent with the consensus view of how lymph is sampled by LN leukocytes resulting from tissue structural barriers that regulate inter-LN transport and demonstrate how novel, engineered delivery systems may be designed to overcome these barriers to unlock the therapeutic potential of LN-resident cells as drug delivery targets.