We report a series of investigations of the pH-sensitive magnetic resonance (MR) responses of various surface-functionalized SPIONs (superparamagnetic iron oxide nanoparticles). First, functionalization of ~12 nm highly monocrystalline SPION cores with three different generations of melamine-dendrons was optimized to give agents with high molar relaxivities (e.g. R₂^m ~300 mM^-1·s^-1 at 7 T and R₁^m ~20-30 mM^-1·s^-1 at 0.5 T) and excellent aqueous stabilities. Molar relaxivities were found to exhibit great sensitivity to pH at physiologically-relevant ionic strengths, with sharp inflections observed at pH values near the pK_a of the melamine monomer. The strength of the effect was observed to grow with increasing dendron generation (with concomitant shift in the position of the main pH inflection). Opposing behavior in R₂^m and R₂^m * trends may be exploited to provide a ratiometric MR response to pH. Combined with TEM and corresponding MR measurements from solutions of varying ionic strengths, these results are consistent with the pH-sensitive behavior originating from transient, reversible SPION clustering modulated by an interplay between SPION surface charge density and solution ionic strength. Studies of SPION cellular uptake and MR response in HeLa cell cultures are also presented. Finally, comparisons with the MR responses of SPIONs with alternative functionalities-derivatives of nitrilotriacetic acid or poly(1-vinylimidazole)-indicate that these types of pH-sensitive MR responses can be highly dependent upon the chemical composition of the surface species (and thus amenable to modulation through rational design).

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