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Optimized Fluorescent pH-Sensitive Dextran Conjugates Enable Ratiometric Measurement of Cerebral Blood pH In Vivo and In Situ.

Sophie Walter,Marine Tournissac,E. Chaigneau,Serge Charpak,Mayeul Collot

Published 2025 in ACS Applied Materials and Interfaces

ABSTRACT

Monitoring transient pH variations in vivo remains challenging, particularly in blood, a highly absorbing and dynamic tissue where sustained probe circulation is required. To address this, we developed a dual-emission ratiometric pH probe approach based on dextran conjugates to ensure stability in the circulation comprising (1) AF488, a pH-insensitive fluorophore, and (2) H-Ruby (HR), a red-emitting, fluorogenic, pH-sensitive dye. While H-Rubies are efficient pH indicators, their conjugation to dextran induces strong aggregation-caused quenching (ACQ), which limits both their loading capacity and brightness. To overcome this, we designed a PEGylated version of H-Ruby (HR-PEG), which displays improved water solubility and two-photon absorption while retaining a pKa of 7.5, suitable for physiological measurements. Upon conjugation to dextran, HR-PEG exhibits significantly reduced ACQ, resulting in brighter conjugates with preserved pKa and a 12-fold fluorescence increase in response to acidification from pH 7.4 to pH 6.4. These enhancements improved signal detection in blood vessels with in vivo two-photon imaging in mice and significantly increased fluorescence responses to blood acidification, thereby allowing accurate and quantitative measurement of the vascular acidosis caused by a brief hypercapnia.

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