480442 Polymer Nanoparticles Co-Coated with Antibodies and Anti-Phagocytic Moieties Improve Specific Interactions and Uptake By Target Versus Phagocytic Cells

Monday, November 14, 2016
Grand Ballroom B (Hilton San Francisco Union Square)
Sauradeep Sinha1, Joshua Kim2, Janet Hsu2 and Silvia Muro2, (1)Chemical and Biomolecular Engineering, University of Maryland-College Park, College Park, MD, (2)Fischell Department of Bioengineering, University of Maryland-College Park, College Park, MD

Nanocarriers (NCs) have great potential for drug delivery to improve therapeutic effects. However, rapid clearance of drug NCs by the mononuclear phagocyte system (MPS) remains a major challenge. Phagocytic cells in the liver and spleen engulf and eliminate NCs out of the bloodstream, reducing their circulation time and therapeutic potential. Poly(ethylene glycol) (PEG) functionalization on NCs lowers phagocytosis and lengthens circulation. However, PEG can reduce specific NC interactions with target cells and render generation of anti-PEG antibodies. In nature, circulating erythrocytes avoid phagocytosis by expressing on their surface protein CD47. Similarly, NC coated with CD47 have reduced phagocytosis in the liver and spleen. Yet, these studies had not targeted NCs and whether CD47 coating alters binding and endocytosis of antibody-targeted NCs is unknown. To evaluate this we used fluorescent polystyrene or PLGA NCs targeted to ICAM-1, a receptor overexpressed on many diseased cells. Anti-ICAM/CD47 NCs were compared to control preparations (anti-ICAM NCs, IgG NCs, IgG/CD47 NCs) to determine phagocytosis by macrophages versus specific endocytosis by endothelial cells using fluorescent microscopy. Results showed that, compared to anti-ICAM and IgG NCs, presence of CD47 significantly reduced phagocytosis by macrophages (~50% reduction vs. absence of CD47). However, anti-ICAM/CD47 NCs had similar targeting to endothelial cells than control anti-ICAM NCs (~87% of control by 30 min). Anti-ICAM/CD47 NCs were endocytosed by endothelial cells similar to control anti-ICAM NCs (~99% of control at 5h). Furthermore, anti-ICAM/CD47 NCs used the same CAM-mediated endocytosis pathway as anti-ICAM NCs (~40% inhibition by amiloride versus no significant inhibition of clathrin pathway by MDC or caveolar route by filipin). Therefore, our results show that coating NCs with CD47 and a targeting antibody helps reduce macrophage phagocytosis while providing effective binding and uptake to target cells. This strategy can have a significant impact on improving the efficacy of targeted drug delivery systems.

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