Modulatory Role of Surface Coating of Superparamagnetic Iron Oxide Nanoworms in Complement Opsonization and Leukocyte Uptake.
Notwithstanding rapid advances of nanotechnology in diagnostic imaging and drug delivery, the engineered nanocarriers still exhibit substantial lack of hemocompatibility. Thus, when injected systemically, nanoparticles are avidly recognized by blood leukocytes and platelets, but the mechanisms of immune recognition are not well understood and strategies to mitigate these phenomena remain underexplored. Using superparamagnetic dextran iron oxide (SPIO) nanoworms (NWs) we demonstrate an efficient and predominantly complement-dependent uptake by mouse lymphocytes, neutrophils and monocytes from normal and tumor bearing mice in vitro. Following intravenous injection into wild type mice, blood leukocytes as well as platelets became magnetically labeled, while the labeling was decreased by 95% in complement C3-deficient mice. Using blood cells from healthy and cancer patient donors, we demonstrated that neutrophils, monocytes, lymphocytes and eosinophils took up SPIO NWs, and the uptake was prevented by EDTA (a general complement inhibitor) and by antiproperdin antibody (an inhibitor of the alternative pathway of the complement system). Cross-linking and hydrogelation of SPIO NWs surface by epichlorohydrin decreased C3 opsonization in mouse serum, and consequently reduced the uptake by mouse leukocytes by more than 70% in vivo. Remarkably, the cross-linked particles did not show a decrease in C3 opsonization in human serum, but showed a significant decrease (over 60%) of the uptake by human leukocytes. The residual uptake of cross-linked nanoparticles was completely blocked by EDTA. These findings demonstrate species differences in complement-mediated nanoparticle recognition and uptake by leukocytes, and further show that human hemocompatibility could be improved by inhibitors of complement alternative pathway and by nanoparticle surface coating. These results provide important insights into the mechanisms of hemocompatibility of nanomedicines.
The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus , 12850 East Montview Blvd., Aurora, Colorado 80045, United States.
Swetha
S
Inturi
The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus , 12850 East Montview Blvd., Aurora, Colorado 80045, United States.
Guankui
G
Wang
Department of Gastrointestinal Surgery, China-Japan Union Hospital, Jilin University , 126 Xiantai Street, Changchun, Jilin 130033, China.
Fangfang
F
Chen
The Division of Rheumatology, School of Medicine, University of Colorado Anschutz Medical Campus , 1775 Aurora Court, Aurora, Colorado 80045, United States.
Nirmal K
NK
Banda
The Division of Rheumatology, School of Medicine, University of Colorado Anschutz Medical Campus , 1775 Aurora Court, Aurora, Colorado 80045, United States.
V Michael
VM
Holers
Nanomedicine Laboratory, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, Faculty of Health and Medical Sciences, Universitetsparken 2, University of Copenhagen , DK-2100 Copenhagen Ø, Denmark.
LinPing
L
Wu
Nanomedicine Laboratory, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, Faculty of Health and Medical Sciences, Universitetsparken 2, University of Copenhagen , DK-2100 Copenhagen Ø, Denmark.|NanoScience Centre, University of Copenhagen , DK-2100 Copenhagen Ø, Denmark.
Seyed Moein
SM
Moghimi
The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus , 12850 East Montview Blvd., Aurora, Colorado 80045, United States.
Dmitri
D
Simberg
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D003167:Complement Activation; D003176:Complement C3 / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000737:chemistry; D003911:Dextrans / Q000737:chemistry / Q000378:metabolism*; D004705:Endocytosis; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry; D007962:Leukocytes / Q000378:metabolism*; D058185:Magnetite Nanoparticles; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D009895:Opsonin Proteins / Q000378:metabolism*; D013499:Surface Properties; D014018:Tissue Distribution
D003176:Complement C3; D003432:Cross-Linking Reagents; D003911:Dextrans; D058185:Magnetite Nanoparticles; D009895:Opsonin Proteins; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; C065507:ferumoxides
alternative pathway; complement; immunity; iron oxide; leukocyte; leukocytes; nanoworms