Coupling optically active components to magnetic nanoparticles（NPs） is an attractive way to develop multifunctional
probes for highly sensitive biological imaging ａnd recognition.[1] While iron oxide NPs have been explored as robust
magnetic contrast ａnd therapeutic agents,[2] semiconductingquantum dots, fluorescent organic dyes, ａnd metal complexes are now commonly sought after for sensitive optical imaging applications.[3] Among all molecular optical probes studied thus far, lanthanide-based complexes have attracted particular interest due to their unique long luminescence lifetimes （micro- to milliseconds）, sharp emission bands, ａnd insensitivity to photobleaching.[4] Despite numerous efforts researching magnetic NPs ａnd lanthanide-based complexes for biomedical applications, conjugates containing both magnetic NPs ａnd lanthanide complexes have not been synthesized ａnd studied. Such conjugates with both magnetic and optical imaging capabilities should serve as new bifunctional probes for highly sensitive biorecognition applications. We have now designed ａnd prepared a luminescent lanthanide nanoparticle label based on sensitization of an organic chromophore. The particle is made up of Fe3O4 NPs coated with a lanthanide complex （Scheme 1）. Ligand 1b is comprised of a quinolone-based dye acting as light-absorption
antenna ａnd a polyethylene glycol 3,4-dihydroxybenzylamine （DBI-PEG-NH2） moiety, which enables binding to the surface of Fe3O4 NPs to give water-soluble NPs. These Fe3O4 NPs are strongly luminescent in aqueous solution ａnd have a long fluorescence lifetime. Folic acid （FA） is a high-affinity ligand for folate receptor （FR）, ａnd has been widely used for targeted delivery of FAconjugated molecular probes or nanoparticles to FR-overexpressing cancer cell lines （e.g., HeLa ａnd KB cell lines）.[5] Since salicylic acid has excellent coordination ability with rare-earth metal ions ａnd can sensitize their luminescence,[6] we used folate-（salicylic acidyl）-amine as cell-targeting agent
for further application in bioimaging based on Tb:1b. Synthesis of the luminescent Fe3O4 NPs is presented in
Scheme S1 （Supporting Information）. The PEG amine 1a was prepared from 1,w-diaminopolyoxyethylene （M=4000） and 3,4-dihydroxybenzaldehyde. 7-Amino-4-methyl-2（1H）-quinolinone （cs124） was covalently coupled with diethylenetriaminepentaacetic acid （DTPA） by means of its dianhydride, and the product was then treated with 1a to obtain 1b. Complex Tb:1b was formed by stirring 1b with TbCl3 overnight in DMF, ａnd then treated with folate-（salicylic acidyl）-amine in DMF to give Tb:1b-FA. Monodisperse Fe3O4 NPs coated with oleylamine with a size of 12 nm were synthesized by a previously published procedure.[7] Exchange of oleic acid ａnd oleylamine on the surface of Fe3O4 NPs with Tb:1b or Tb:1b-FA was easily achieved by mixing Tb:1b or Tb:1b-FA ａnd Fe3O4 NPs monodispersed in water （Figure S1, Supporting Information）; the NPs showed little change in core size after surface modification. According to the Tb/Fe weight percentage （105%）, about 2312 Tb units are bound to each Fe3O4 NP, corresponding to about 2312 ligands per Fe3O4 NP.[8] Magnetization of as-synthesized Fe3O4 NPs ａnd Tb:1b- FA-NPs was measured as a function of applied magnetic field （Figure S2, Supporting Information）. Little change in magnetic
properties was observed between the as-synthesized Fe3O4 NPs ａnd Tb:1b-FA-NPs. None of the samples showed
hysteresis, that is, the nanoparticles retain superparamagetism. The saturated magnetization （Ms） of as-synthesized
Fe3O4 NPs ａnd Tb:1b-NPs are 54.8 ａnd 17.8 Am2kg1, respectively. The dispersibility of Tb:1b-FA-NPs was tested by measuring the change of their hydrodynamic size during incubation under different conditions. Figure S3 （Supporting Information） shows that Tb:1b-FA-NPs are stable to dispersion in phosphate buffered saline （PBS） ａnd show no change in the statistical hydrodynamic size over the incubation time, and little change in the size of Tb:1b-FA-NPs occurs with varying temperature. The measured size increase from about 129 to about 219 nm in the presence of fetal bovine serum （FBS） is attributed to adsorption of FBS onto the NP surface, as reported previously.[9] On the other hand, at lower pH 6 （Figure S4, Supporting Information）, the particles can be stabilized for only 2 h before serious aggregation occurs. After 8 h, the size of the clustered nanoparticles reaches 190 nm, due to chemical bond cleavage between iron oxide and the catechol unit of 3,4-dihydroxybenzaldehyde under low-pH incubation conditions, which destabilizes the nanoparticle dispersion.[10]..........................................................................................................................................................................................................................................
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