Biomaterials 27 (2006) 136–144 The effect of methoxy-PEG chain length and molecular architecture on lymph node targeting of immuno-PEG liposomes S.M. Moghimi à Molecular Targeting and Polymer Toxicology Group, School of Pharmacy, University of Brighton, Brighton BN2 4GJ, UK Received 8 March 2005; accepted 27 May 2005 Available online 12 July 2005 Abstract The rate of drainage and lymphatic distribution of subcutaneously injected liposomes is controlled by inclusion of methoxypoly(ethyleneglycol), mPEG-phospholipid into the liposomal bilayer. The effect is most dramatic with liposomes containing 15 mol% mPEG-lipid, with an average PEG molecular mass of 350 Da. These vesicles are drained rapidly from the injection site into the initial lymphatics when compared to unmodified liposomes, and are retained more favourably by the scavengers of the regional lymph node. Liposomes decorated with longer surface mPEG chains (6.7 mol% of mPEG 2000 -lipid) exhibit faster drainage rates than vesicles having 15 mol% mPEG 350 -lipid in their lipid bilayer, but their lymph node retention is very poor. The lymph node retention of rapidly drained PEG-bearing vesicles was increased dramatically following conjugation of a non- specific IgG to the distal end of PEG, using a functionalized PEG 2000 lipid. Adjusting the molecular architecture of surface mPEG and IgG-PEG chains to a ‘‘nearly overlapped mushroom’’ regime further enhanced target recognition of immuno-PEG 2000 liposomes without compromising their drainage rate from the interstitium. The lymph node retention of these vesicles was further optimized by enriching their lipid bilayer with 20mol% phosphatidylserine. These approaches have established important compositional and structural variables that control lymphatic targeting of immuno-PEG liposomes and their application in experimental medicine and biology is discussed. r 2005 Elsevier Ltd. All rights reserved. Keywords: Steric stabilization; Stealth liposomes; Macrophage; Antibody conjugation; Fc receptor; Lymphatic system; Phosphatidylserine; Poly(ethyleneglycol) 1. Introduction Liposomes are promising carriers for delivery of therapeutic and medical imaging agents to the lymphatic microvessels and their associated lymph nodes when administered interstitially [1]. In lymphatic capillaries, numerous endothelial cells overlap extensively at their margins. Following interstitial injection, many of the overlapped endothelial cells are separated and thus passageways are provided between the interstitium and lymphatic lumen (patent junctions) and liposomes are conveyed to the nodes via the afferent lymph [1]. In lymph nodes, macrophages of medullary sinuses and paracortex are mainly responsible for particle capture from the lymph [2,3]. In addition, liposome uptake by littoral and reticular cells as well as polymorphonuclear granulocytes has also been reported [3,4]. However, the size and surface characteristics of interstitially injected particles can influence their passage into the initial lymphatic system and localization among the lymph node elements [1,2,5–9]. Generally, smaller the particle size, faster the lymphatic uptake. Also depending on their surface characteristics, such as the extent of surface hydrophobicity/hydrophilicity, small sized particles may even aggregate at the injection site and/or interact with the ground substance of interstitium [1,2]. These events will retard particle movement into the lymphatic ARTICLE IN PRESS www.elsevier.com/locate/biomaterials 0142-9612/$-see front matter r 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.biomaterials.2005.05.082 à Tel.: +441273642063; fax: +441273679333. E-mail address: s.m.moghimi@brighton.ac.uk.