Low Efficiency of Leucocyte Plugging-Based Drug Delivery To Cancer In Mice

Background: Cells of immune system were proposed for use as Trojan horse for tumor-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 intratumoral site-specific enrichment using locoregional application route in experimental liver tumors. Methods: Human neutrophils were isolated from peripheral blood and directly labeled with calcein AM or loaded with doxorubicin. The neutrophil loading and release of doxorubicin, migration and adhesion to ICAM-1 were analyzed in vitro. Macrophages were isolated and activated in vitro. Leucocyte plugging and distribution pattern in the liver microvasculature were studied ex vivo and the efficacy of leucocyte plugging in tumor blood vessels were analyzed in vivo after superselective intra-arterial injection in mouse liver tumor models. Results: Neutrophils were characterized 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 tumor blood vessels and passed through the tumor microvasculture with a very low sequestration rate in vivo. Conclusions: 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.