Nanodrug delivery: Strategies to circumvent nanoparticle trafficking by Kupffer cells in the liver

Kupffer cells (KCs) are resident macrophages of the liver purposefully attached to sinusoidal endothelial cells in the sinusoidal domain of the liver to offer a first line of innate immunity. KCs uptake decreases nanoparticle delivery to liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), and hepatocytes. Thus, liver accumulation is one of the major problems with intravenously administered nanoparticles. Strategies such as PEGylation, transient clearance of KCs, surface modification of nanoparticles, including charge, and saturation of the KCs phagocytic response seem to be promising strategies to reduce nanoparticle trafficking in the liver. Transient depletion of KCs, decreasing nanoparticle uptake by KCs and saturation of the phagocytic response of KCs by non-toxic nanoparticles often increase nanoparticle delivery to liver cells like LSECs, HSCs, hepatocytes and other target tissues. KCs depletion by clodronate liposomes and PEGylation improves tumour delivery of various drug conjugated metallic and metal oxide nanoparticles up to several folds and improves their bioavailability in circulation. Though these strategies have led to decreased liver accumulation and an increased blood half-life, KCs depletion strategies are not well-characterized for their safety. KCs play a pivotal role in innate immunity and their transient depletion may reduce the integrity of the immune system. Therefore, studies are warranted on the concurrent effect of KCs depletion on the innate immunity of the body.