Reference data

TitleRevealing Dynamics of Accumulation of Systemically Injected Liposomes in the Skin by Intravital Microscopy
AuthorJames I. Griffin†§, Guankui Wang†‡§, Weston J. Smith†‡§, Vivian P. Vu†§, Robert Scheinman‡§, Dominik Stitch∥, Radu Moldovan∥, Seyed Moein Moghimi‡⊥# , and Dmitri Simberg*†‡§
Affiliation(s)†Translational Bio-Nanosciences Laboratory, ‡Colorado Center for Nanomedicine and Nanosafety, and §Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado 80045, United States ∥ Advanced Light Microscopy Core Facility, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, United States ⊥ School of Pharmacy, The Faculty of Medical Sciences, Newcastle University, King George VI Building, Newcastle upon Tyne NE1 7RU, U.K. # Division of Stratified Medicine, Biomarkers & Therapeutics, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE1 7RU, U.K.
Keyworddoxorubicin; extravasation; liposomes; near-infrared fluorescence; PEG; skin
AbstractAccumulation of intravenously injected cytotoxic liposomes in the skin induces serious toxicity. We used single time point and longitudinal intravital microscopy to understand skin accumulation dynamics of non-PEGylated and PEGylated liposomes after systemic injection into mice. Non-PEGylated egg phosphatidylcholine (PC) liposomes showed short circulation half-life (1.3 h) and immediate aggregation in the blood, with some aggregates lodging in skin microvasculature soon after the injection. At 24 h, and more prominently at 48 h postinjection, liposomes appeared in dermal and subdermal cells. PEGylated egg PC liposomes showed long circulation half-life (22 h) and no aggregation in the blood. PEGylated liposomes started to accumulate in the skin microvasculature as soon as 5 min after the injection. Within 3 h postinjection, PEGylated liposomes accumulated in extravascular cells in the dermis and subdermis. Liposomes were present in the skin for at least 7 days postinjection. A regulatory approved PEGylated liposomal doxorubicin (LipoDox) and empty liposomes of the same composition as LipoDox showed similar skin distribution as PEGylated egg PC liposomes, suggesting that this phenomenon is relevant to liposomes of different lipid composition. Decorating liposomes with shorter PEGs (350 or 700) in addition to PEG 2000 did not decrease the deposition. Outside the capillaries, liposomes partially colocalized with CD45-, F4/80+ cells. The accumulation of liposomes was not due to prior neutrophil/platelet binding and transport across endothelium. Moreover, our studies have excluded a role of complement in the skin accumulation of liposomes. Further understanding of mechanisms of this important phenomenon can improve the safety of liposomal nanocarriers.


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