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

## TL;DR

Researchers developed a pH-sensitive 19F MRI nanosystem that can reversibly switch signals based on nanoparticle structure, useful for imaging tumors and other acidic disease environments.

## Contribution

A novel strategy for pH-sensitive 19F MRI using nanoparticle ultrastructure instead of chemical modification.

## Key findings

- Multi-core nanoparticles showed reversible pH-dependent 19F signal modulation, unlike single-core nanoparticles.
- 19F T2 relaxation times changed significantly with pH in multi-core NPs, validated in vitro and in vivo.
- The strategy works across high- and low-field MRI and is activated in acidic tumor regions.

## 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.

PLGA nanoparticle internal structure enables pH-responsive fluorine-19 magnetic resonance imaging (19F MRI) upon co-encapsulation of perfluorocarbon and gadolinium.