Abstract
Cells of the immune system were proposed for use as Trojan horse for tumour-specific drug delivery. The efficacy of such cell-based drug delivery depends on the site-specific cell homing. This present study was aimed to investigate the potential of leucocytes for intratumoural site-specific enrichment using a locoregional application route in experimental liver tumours. Human neutrophils were isolated from peripheral blood and directly labelled with calcein AM or loaded with doxorubicin. The neutrophil loading and release of doxorubicin and the migration and adhesion to ICAM-1 were analysed in vitro. Macrophages were isolated and activated in vitro. Leucocyte plugging and the distribution pattern in the liver microvasculature were studied ex vivo, and the efficacy of leucocyte plugging in tumour blood vessels was analysed in vivo after superselective intra-arterial injection in mouse liver tumour models. Neutrophils were characterised by the high dose-dependent uptake and rapid release of doxorubicin. Doxorubicin loading did not affect neutrophil migration function. Neutrophil plugging in liver microvasculature was very high (> 90%), both after ex vivo perfusion and after injection in vivo. However, neutrophils as well as activated macrophages plugged insufficiently in tumour blood vessels and passed through the tumour microvasculture with a very low sequestration rate in vivo. Neutrophils possess several properties to function as potentially effective drug carriers; however, the tumour site-specific drug delivery after selective locoregional injection was observed to be insufficient owing to low intratumoural microvascular plugging.Graphical abstract
Highlights
Cells belonging to the immune system, such as neutrophils [1], monocytes [2], dendritic cells [3, 4], macrophages [5] and lymphocytes [6] can serve as carriers to transport drugs to disease sites
The present study investigated the role of neutrophilbased locoregional drug delivery as a potential Trojan horse for the treatment of liver tumours
peripheral blood mononuclear cells (PBMCs) were treated with 100 ng/ mL granulocyte–macrophage colony-stimulating factor (GM-CSF, GenScript, Piscataway, USA) for 48 h and for 5 days thereafter with 100 ng/mL GM-CSF, 50 ng/ mL human recombinant γ-interferon (Affymetrix eBioscience, Wien, Austria), and 10 ng/mL lipopolysaccharides (Sigma-Aldrich, Taufkirchen, Germany) in phenol red RPMI-1640 medium supplemented with 10% foetal calf serum (FCS, CCPro, Oberdorla, Germany), 2 mM L-glutamine, 20 U/mL penicillin, 0.1 mg/mL streptomycin (CCPro), 1 mM sodium pyruvate, and 0.05 mM 2-mercaptoethanol (Thermo, Waltham, MA, USA)
Summary
Cells belonging to the immune system, such as neutrophils [1], monocytes [2], dendritic cells [3, 4], macrophages [5] and lymphocytes [6] can serve as carriers to transport drugs to disease sites These cells may potentially score over conventional routes of administration, because they prolong the half-life of the drug that they deliver and lower drug immunogenicity [7]. Neutrophils constitute 50–70% of circulating leucocytes and represent the largest group of inflammatory cells in human blood [12]. They circulate freely in the blood but are rapidly activated by inflammatory signals [13]. They show chemotaxis and can migrate and extravasate to inflammatory tissue sites to defend the body against pathogenic microorganisms [14]
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