Revealing Dynamics of Accumulation of Systemically Injected Liposomes in the Skin by Intravital Microscopy

Abstract

Accumulation 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.

Activity of Amphotericin B-Loaded Chitosan Nanoparticles against Experimental Cutaneous Leishmaniasis

“…Of greater relevance to this study, AmB liposomes with size < 100 nm showed extra-vasation at the inflammatory site of infection [ 22 ]. Additionally, small-sized nanoparticles have exhibited maximum deposition of their content in the skin dermis following topical application [ 43 ], and intravenously administered small nanoparticles have facilitated targeting of macrophages residing in the skin [ 43 , 44 , 45 , 46 ]. Small-sized nanoparticles (<100 nm) have also been reported to enable greater cell uptake, skin permeation and immune-targeting—all desirable properties in formulations for topical CL treatment [ 47 , 48 ].…”

The Interplay Between Blood Proteins, Complement, and Macrophages on Nanomedicine Performance and Responses

“…Furthermore, reactive macrophages may not necessarily reside in patients' lungs, and responses may arise from a subpopulation of Kupffer cells and/or splenic macrophages, or even other immune cells such as lung dendritic cells (Dams et al, 2000;Moghimi, 2018). Recently, we demonstrated that a significant fraction of intravenously injected liposomes, regardless of their composition, rapidly accumulate in F4/80 1 skin phagocytic cells (Griffin et al, 2017). Therefore, it is plausible that responsive skin macrophages could play a role in adverse cutaneous reactions as well as desensitization to nanomedicines.…”

Polymer Therapeutics: Biomarkers and New Approaches for Personalized Cancer Treatment

“…Interestingly, recently developed techniques detected free PEG or PEG-conjugates in tissues and plasma [ 168 , 169 ] and can be used to quantify pharmacokinetics and tissue distribution to identify at risk tissues before moving into first-in-man studies. Furthermore, a study from Griffin et al employed in vivo intravital microscopy to begin to understand the skin accumulation and toxicity of non-PEGylated and PEGylated liposomes after systemic injection into mice [ 170 ]. Studies such as this with PTs may uncover more on pharmacokinetics, aggregation, normal tissue toxicity and again, provide important information regarding future clinical application.…”