Cell-specific targeting of nanoparticles by multivalent attachment of small molecules.
Reference: R. Weissleder, K. Kelly, E.Y.Sun, T. Shtatland, L. Josephson. Nature Biotechnology 23(11), 1418-1423 (November, 2005).
Scientists from Harvard Medical School conjugated 146 different small molecules with such functional groups as primary amines, alcohols, carboxylic acids, sulfhydryl groups, and anhydrides to magnetofluorescent nanoparticles. They then screened this library to determine whether the surface modifications altered the affinity of various cell cultures to the nanoparticles. Uptake typically varied by three orders of magnitude within a single cell line, depending upon the chemical conjugate.
The physiological state of the cells also affected uptake. Macrophages at a resting state preferentially internalized one chemically modified nanoparticle, while macrophages activated by GM-CSF, oxidized low density lipoprotein (as occurs with atherosclerosis), or lipopolysaccharide (simulating an infection) preferred another.
The utility of modified nanoparticles for in vivo imaging was examined in a mouse pancreatic cancer model, using two conjugates that were found to show high cancer cell uptake, but little uptake by macrophages or endothelial cells. Fluorescent imaging accurately identified the pancreatic tumors in nude mice, as confirmed with fluorescence microscopy and quantitative biodistribution experiments.
This proof-of-concept investigation demonstrated that through simple chemical modification of nanoparticles, it is possible to create efficiently targeted, disease-specific agents for diagnostic and/or therapeutic use.
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