The short-wave infrared region (SWIR; 1000-2000 nm) has excellent properties for in vivo imaging: low autofluorescence, reduced scattering, and little light absorption by blood and tissue. However, broad adoption of SWIR imaging in biomedical research is hampered by the availability of versatile and bright contrast materials. Quantum dots (QDs) are bright, compact SWIR emitters with narrow size distributions and emission spectra, qualities that make them ideal for labeling and multiplex SWIR imaging. Nevertheless, SWIR QDs have limited applications due to the shortcomings of established ligand systems. Established ligands result in QD probes with limited colloidal stability, large size and broad size distribution, or all three limitations. To address these limitations, we turned to polymeric ligands, beginning with the polymeric imidazole ligand (PIL) initially developed for visible-emitting CdSe/CdxZn₁₋xS QDs with L-type native ligands. We studied ligand exchange with PIL and InAs/CdSe/CdS SWIR QDs with native X-type ligands in a variety of conditions but only saw limited exchange. Our results combined with reports in the literature suggest that the mechanism of X-to-L ligand exchange is not amenable to polymeric ligands. These results led us to the concept of ligand-type matching: for straightforward exchange, QD native ligands should be the same type as the binding groups on the polymer. Thus, we synthesized InAs/CdSe/ZnS with L-type native ligands, which exchanged readily with PIL to produce probes with (<14 nm hydrodynamic diameter, Hd). We also synthesized a new ligand that is compatible with oleate-capped QDs: the polymeric acid ligand (PAL), which features carboxylic acids as the binding group and PEG₁₁ chains to solubilize the QD-ligand construct. We exchanged PAL with oleate-capped PbS and PbS/CdS QDs, resulting in compact probes ( <11 nm Hd) with narrow size distribution. The small size and narrow size distribution of these constructs are preserved for several months when stored in isotonic saline solution in air, addressing the size and stability limitations of existing ligand systems for SWIR QDs. Our constructs are bright in vivo and to demonstrate their suitability for imaging, we performed whole-body imaging as well as lymphatic imaging, including visualization of lymphatic flow.;
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