Nanoparticle ultrastructure allows reversible pH sensitivity using 19F NMR and in vivo19F MRI

Abstract

Fluorine-19 magnetic resonance imaging (¹⁹F MRI) is a powerful imaging modality that provides background-free imaging. Its sensitivity can be modulated through environmentally responsive probe designs exploiting paramagnetic relaxation enhancement (PRE) and related mechanisms. Here, we present a novel pH-sensitive ¹⁹F MRI nanosystem in which signal activation is governed by nanoparticle (NP) ultrastructure. Poly(lactic-co-glycolic acid) (PLGA) NPs were synthesized co-encapsulating perfluoro-15-crown-5-ether (PFCE) and lipophilic gadolinium (Gd) chelates, yielding either single-core or multi-core structures. While single-core NPs, the conventional structure for polymer-encapsulated perfluorocarbons, remained pH-insensitive, multi-core NPs exhibited a pronounced and reversible pH-dependent ¹⁹F signal modulation. The ¹⁹F T₁ decreased slightly (from ∼700 to ∼600 ms) in both NP types due to the presence of Gd, whereas T₂ shortened markedly at neutral pH (∼20 ms, “OFF” state) and increased substantially under acidic conditions (“ON” state); this variation was absent in single-core NPs. The pH-dependent ¹⁹F T₂ behaviour was consistent across both high-field (14 T) and low-field (3 T) MRI. Such behaviour of multi-core NPs was validated in vitro and in vivo, as the ¹⁹F signal reappeared only after lysosomal internalization in RAW 264.7 cells and was selectively activated within acidic tumour regions, but not at the neutral subcutaneous injection site. By exploiting nanoparticle ultrastructure to achieve reversible signal switching, this work introduces a general strategy for activatable ¹⁹F MRI probes for imaging applications in tumours and other pH-sensitive disease environments. It demonstrates, for the first time, PRE-driven signal enhancement and suppression governed by structural rearrangement rather than chemical modification in response to pH variation.