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 T 1 decreased slightly (from ∼700 to ∼600 ms) in both NP types due to the presence of Gd, whereas T 2 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 T 2 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.
Mali et al. (Thu,) studied this question.