Reduction of the uptake by a macrophagic cell line of nanoparticles bearing heparin or dextran covalently bound to poly(methyl methacrylate).
Amphiphilic and fluorescent covalently labelled core-shell nanoparticles based on poly(methyl methacrylate) (PMMA), were prepared by random copolymerisation of N-Vinyl carbazole (NVC) with MMA, initiated on polysaccharidic radicals, yielding diblock copolymers of either dextran-P(MMA-NVC) (Nanodex* particles), or heparin-P(MMA-NVC) (Nanohep* particles). Nanoparticles made from random copolymers of P(MMA-NVC) (PMMA*) were used as controls. The interactions between particles and a J774A1 murine macrophage-like cell line were quantified by direct measurement of the cell-associated fluorescence. The association with the cells occurred within 30 min. Nanodex* and Nanohep* showed considerably less association than the control PMMA* particles. Some of the particle uptake could be attributed to phagocytosis, but more than 50% of the cell-associated fluorescence persisted at low temperature or in the presence of cytochalasin B. The results suggest that both the adsorption and the internalisation processes can be inhibited by the presence of the polysaccharide chains. In conclusion, these results confirm that nanoparticles prepared with heparin or dextran chains on their surface, probably in a brush-like configuration, show "stealth" properties in vitro as had previously been observed in vivo. If this biomimetic approach can also be applied to biodegradable polymers, these systems would provide at least an alternative to PEG-modified particles as long-circulating drug carriers systems or imaging agents.
Laboratoire de Physico-Chimie, Pharmacotechnie et Biopharmacie, UMR CNRS 8612, Faculté de Pharmacie, Université Paris Sud-XI, 5 rue J. B. Clément, 92290 Châtenay-Malabry, France.
N
N
Jaulin
M
M
Appel
C
C
Passirani
G
G
Barratt
D
D
Labarre
D000818:Animals; D000925:Anticoagulants / Q000493:pharmacokinetics*; D003911:Dextrans / Q000493:pharmacokinetics; D006493:Heparin / Q000493:pharmacokinetics; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D011108:Polymers / Q000493:pharmacokinetics; D019904:Polymethyl Methacrylate / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured; D014665:Vasodilator Agents / Q000493:pharmacokinetics*
D000925:Anticoagulants; D003911:Dextrans; D011108:Polymers; D014665:Vasodilator Agents; D006493:Heparin; D019904:Polymethyl Methacrylate