Effect of polymeric nanoparticle administration on the clearance activity of the mononuclear phagocyte system in mice

Abstract

We investigated the consequences of acute and subacute administration of mice with polyisobutylcyanoacrylate (PIBCA), polyisohexylcyanoacrylate (PIHCA), poly(D,L-lactic) acid (PLA), and polystyrene (PS) nanoparticles on the mononuclear phagocyte system phagocytic function. This was done by measuring the clearance rate of colloidal carbon. Single administration of PIBCA and PIHCA (but not PLA and PS) nanoparticles reduced carbon clearance in both a time- and dose-dependent fashion. Since clearance of preopsonized carbon was normal, it was assumed that PIBCA and PIHCA nanoparticles deplete opsonins specific for carbon recognition. A decrease in plasma fibronectin levels resulting from nanoparticle administration suggested its implication in their removal from blood. However, fibronectin does not seem to be responsible for PIBCA and PIHCA blockade. Phagocytic function was preserved after repeated treatment with nanoparticles, probably as a result of increased Kupffer cell phagocytic activity and the contribution of spleen macrophages. Neither toxicity nor effects due to nanoparticle hepatic accumulation were observed.

In VitroandIn VivoToxicity Study of Nanoparticles

“…However, the principal organs in which they are normally found are the spleen, liver and lymph nodes. Because of the architecture of these tissues, the spleen tends to be involved in clearing larger particles (>250 nm diameter) that have become trapped (Fernandez-Urrusuno et al, 1996). In contrast, the liver is more involved in clearing smaller particles, and the site-specific macrophages (Kupffer cells) will engulf nanoparticles (Fernandez-Urrusuno et al, 1997).…”

Targeted Delivery with Peptidomimetic Conjugated Self-Assembled Nanoparticles

“…The size, surface charge, surface hydrophilicity (contact angle), surface morphology, the sequence of amino acids of the conjugated peptide, and extent of conjugation of peptidomimetic NPs can significantly affect their immunogenicity and their clearance by the fixed macrophages of the mononuclear phagocytes system (MPS) (100)(101)(102). For phagocytosis, particles have to first make contact with the pseudopods of macrophages and be engulfed into the cytoplasm by lamellipods (103).…”

“…The pore cutoff size of most tumor models is 200-400 nm and NPs with diameter <200 nm are selectively taken up by tumor tissue (11,12). However, the association of cytotoxic drugs with NPs modifies the drug biodistribution profile, because untreated NPs are rapidly opsonized and massively cleared (the mean half-life of untreated NPs is 3-5 min after intravenous injection) by the fixed macrophages of the mononuclear phagocytes system (MPS) (100,101). It has been demonstrated that NPs with high curvature (50< diameter<200 nm) and surface modified with hydrophilic PEG polymers have prolonged half-life in the circulation system, leading to the development of long-circulating NPs for delivery of antitumor drugs (113)(114)(115)(116).…”

Colloidal drug carriers: achievements and perspectives

“…However, another group reported a temporary depletion of Kupffer cells, and hence the ability to clear bacteria, in rats, which was less marked when long-circulating liposomes (see below) were used [40]. A systematic study using unloaded nanoparticles confirmed a reversible decline in the phagocytic capacity of the liver after prolonging dosing, as well as a slight inflammatory response [41]. Thus, altered distribution may generate new types of toxicity and this must be borne in mind when developing carrier systems.…”