Nanoparticle clearance is governed by Th1/Th2 immunity and strain background

Abstract

Extended circulation of nanoparticles in blood is essential for most clinical applications. Nanoparticles are rapidly cleared by cells of the mononuclear phagocyte system (MPS). Approaches such as grafting polyethylene glycol onto particles (PEGylation) extend circulation times; however, these particles are still cleared, and the processes involved in this clearance remain poorly understood. Here, we present an intravital microscopybased assay for the quantification of nanoparticle clearance, allowing us to determine the effect of mouse strain and immune system function on particle clearance. We demonstrate that mouse strains that are prone to Th1 immune responses clear nanoparticles at a slower rate than Th2-prone mice. Using depletion strategies, we show that both granulocytes and macrophages participate in the enhanced clearance observed in Th2-prone mice. Macrophages isolated from Th1 strains took up fewer particles in vitro than macrophages from Th2 strains. Treating macrophages from Th1 strains with cytokines to differentiate them into M2 macrophages increased the amount of particle uptake. Conversely, treating macrophages from Th2 strains with cytokines to differentiate them into M1 macrophages decreased their particle uptake. Moreover, these results were confirmed in human monocyte-derived macrophages, suggesting that global immune regulation has a significant impact on nanoparticle clearance in humans. IntroductionThe potential clinical applications of nanoparticles and nanoformulations have been investigated for more than 30 years. Nanoparticle approaches have the potential to revolutionize drug delivery by allowing for the encapsulation of drugs with poor solubility or stability in a stable carrier particle. In addition, targeting nanoparticles to specific pathological sites may allow an increased effective dose of drug at the needed site, while decreasing systemic drug exposure, and therefore side effects. However, to date, only 2 nanoformulations for cancer treatment have been approved for clinical use (liposomal doxorubicin [Doxil] and protein-bound paclitaxel [Abraxane]) (1-3). One major obstacle for the use of nanoparticles in vivo is rapid clearance by the cells of the reticuloendothelial system (RES)/mononuclear phagocyte system (MPS) (4-7). In addition to rapid clearance, variable activity of the MPS among patients leads to widely variable pharmacokinetics of nanoformulations in the clinic, reducing the efficacy of both approved and future experimental nanoformulations (8).

The influence of surface charge on serum protein interaction and cellular uptake: studies with dendritic polyglycerols and dendritic polyglycerol-coated gold nanoparticles

“…4,5 Often the use of NPs in medicine is hampered by the fast binding of plasma proteins to their surfaces (opsonization), leading to quick clearance of the circulating NPs by the reticuloendothelial system, which is also called the mononuclear phagocytic system. [6][7][8] This may decrease the injected dose by as much as 50% within a few hours. 9 Thus, for medical applications, it is often desired to synthesize NPs that are rather repellent to plasma protein interaction.…”

Influence of polyethylene glycol coating on biodistribution and toxicity of nanoscale graphene oxide in mice after intravenous injection

“…NGO of smaller sizes may be quickly eliminated via the renal route, whereas NGO of larger sizes and NGO aggregates may be taken up by macrophages and cleared through the biliary pathway into the feces or by other mechanisms. 28 However, In the present study, the influence of the PEG coating on the toxicity of NGO was determined using an evaluation system that included assessment of body weight, a blood biochemical analysis, and a histopathological examination. A relatively low dose of NGO (5 mg/kg) was chosen because of the increased mortality in mice that received a higher dose of NGO in the preliminary experiment, which may have been due to dyspnea resulting from blocking of the pulmonary blood vessels by NGO aggregations.…”

Engineered PRINT® nanoparticles for controlled delivery of antigens and immunostimulants

“…Formulation of vaccines with alum adjuvants can be a major limitation for vaccines where balanced antibody and cell-mediated immune response is desirable, as alum biases the response toward B-cell antibody response. 29 In addition, extracellular proteins are taken up by dendritic cells (DC) and processed through MHC class II pathway, while uptake of PRINT nanoparticles by DC engages both MHC class I as well as MHC class II pathways 1,30 which, importantly, leads to activation of both antigen-specific CD4 + and CD8 + T-cells. As such, PRINT-based vaccines provide a way to elicit a multipronged immune response against challenging pathogens.…”