Targeting Dysfunctional Vascular Endothelial Cells Using Immunoliposomes Under Flow Conditions

Mahsa Kheradmandi; Ian Ackers; Monica M Burdick; Ramiro Malgor; Amir M Farnoud

doi:10.1007/s12195-020-00616-1

Targeting Dysfunctional Vascular Endothelial Cells Using Immunoliposomes Under Flow Conditions

Cell Mol Bioeng. 2020 May 4;13(3):189-199. doi: 10.1007/s12195-020-00616-1. eCollection 2020 Jun.

Authors

Mahsa Kheradmandi¹, Ian Ackers^{2

3}, Monica M Burdick^{1

3}, Ramiro Malgor^{2

3}, Amir M Farnoud^{1

3}

Affiliations

¹ Department of Chemical and Biomolecular Engineering, Ohio University, 161 Stocker Center, Athens, OH 45701 USA.
² Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701 USA.
³ Translational Biomedical Science Program, Ohio University, Athens, OH 45701 USA.

Abstract

Introduction: Atherosclerosis (ATH), the build up of fat in the arteries, is a principal cause of heart attack and stroke. Drug instability and lack of target specificity are major drawbacks of current clinical therapeutics. These undesirable effects can be eliminated by site-specific drug delivery. The endothelial surface over ATH lesions has been shown to overexpress vascular cell adhesion molecule1 (VCAM1), which can be used for targeted therapy.

Methods: Here, we report the synthesis, characterization, and development of anti VCAM1-functionalized liposomes to target cells overexpressing VCAM1 under static and flow conditions. Liposomes were composed of dioleoyl-phosphatidylcholine, sphingomyelin, cholesterol, and distearoyl-phosphatidylethanolamine-polyethylene glycol-cyanur (31.67:31.67:31.67:5 mol%). VCAM1 expression in endothelial cells was induced by lipopolysaccharide (LPS) treatment.

Results: Characterization study revealed that liposomes were negatively charged (- 7.7 ± 2.6 mV) with an average diameter of 201.3 ± 3.3 nm. Liposomes showed no toxicity toward THP-1 derived macrophages and endothelial cells. Liposomes were able to target both fixed and non-fixed endothelial cells, in vitro, with significantly higher localization observed in non-fixed conditions. To mimic biological and physiologically-relevant conditions, liposome targeting was also examined under flow (4 dyn/cm²) with or without erythrocytes (40% v/v hematocrit). Liposomes were able to target LPS-treated endothelial cells under dynamic culture, in the presence or absence of erythrocytes, although targeting efficiency was five-fold lower in flow compared to static conditions.

Conclusions: This liposomal delivery system showed a significant improvement in localization on dysfunctional endothelium after surface functionalization. We conclude that VCAM1-functionalized liposomes can target and potentially deliver therapeutic compounds to ATH regions.

Keywords: Atherosclerosis; Cell adhesion molecules; Drug delivery; Endothelium; Nanomedicine.

Abstract

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