Intra and extra-cellular pH are key factors in many biological and physiological processes. For example, the slightly lower extracellular pH in tumor micro-environments has a strong impact on tumor growth and drug delivery. Noninvasive in vivo pH imaging would therefore improve our understanding of the intra-tumoral pH regulation and its effects. Colloidal quantum dots (QDs) are interesting fluorescent probe candidates for in vivo pH imaging, thanks to their high quantum yield, adjustable emission and high photostability. We have designed a novel copolymeric QD surface ligand composed of dithiolane and sulfamethazine moieties. Reduced dithiolanes act as anchoring groups to the QD surface, while sulfamethazine provide pH-sensitivity through reversible protonation/deprotonation. Binding of peripheral gold nanoparticles (GNP) around the central QD is achieved using remaining dithiolanes. Neutralization of the sulfamethazine moieties at acidic pH causes shrinking of the polymer ligand shell and a concomitant decrease in QD-GNPs separation distance. Since GNPs are able to quench the QD fluorescence by non-radiative energy transfer with a highly distance-dependent efficiency, this pH-sensitive conformation change leads to a strong modulation of the QD fluorescence signal. We show that under physiological conditions, sulfamethazine polymer ligands enable a transition around pH 6, which is well adapted to the study of biological systems and this modulation is fully reversible within the physiological pH range (pH 5,5-8). In order to provide robust pH imaging, we propose two different ratiometric measurements, based either on QD fluorescence lifetimes or on ratiometric measurements of two QD populations functionalized with pH-sensitive or pH-insensitive surface chemistries, respectively. Finally, we integrate these probes in the cytoplasm of red blood cells to enhance their circulation lifetime in the blood stream. These probes remain functional and sensitive to extracellular pH. This polymeric surface chemistry is versatile and adaptable to any type of QDs, opening interesting possibilities for in vivo pH imaging in tumors or other tissues.

Polymeric surface chemistry for quantum dot-based pH imaging

256th National Meeting (2018)

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