pH-Responsive Persistent Luminescent Nanosystem with Sensitized NIR Imaging and Ratiometric Imaging Modes for Tumor Surgery Navigation.

Abstract

Owing to autofluorescence-free feature, persistent luminescent (PersL) nanoparticles (PLNPs) become potential materials for tumor surgical navigation. However, it is still challenging to enhance PersL intensity, contrast ratio, and imaging stability so as to meet clinical demand and avoid missed detection of microlesions. Herein, integrating a tumor microenvironment (TME)-responsive strategy, sensitization enhancement, and internal-standard ratiometric method, a dual-mode PersL imaging strategy is proposed: After loading pH-responsive fluorescent molecule Rh-ADM on PLNPs ZnGa₂O₄:Cr³⁺,Mn²⁺ (ZGCM-Rh8), the fluorescence resonance energy transfer (FRET) pathways between Cr³⁺ and Rh-ADM, as well as Mn²⁺ and Rh-ADM, could sensitize the NIR PersL emitted by Cr³⁺ and quench the green PersL from Mn²⁺ at acidic TME, respectively. As a result, ZGCM-Rh8 is endowed with WLED (white light LED)-excited NIR imaging mode and UV-excited ratiometric imaging mode. Under WLED, ZGCM-Rh8 realizes 4.5-fold PersL enhancement and 97.9 as the maximum tumor contrast after precise control of Rh-ADM contents, helping with the preoperative diagnosis of deep lesions. Under UV, ZGCM-Rh8 conducts ratiometric PersL imaging steadily, and the "NIR/Vis" ratios at the tumor keep larger than 110, succeeding in detecting out a 1.5 mm small lesion and serving thorough surgical elimination of H22 ectopic intramuscular tumor in balb/c mice. To our knowledge, ZGCM-Rh8 is the first to realize pH-responsive PersL sensitization and apply ratiometric PersL imaging technology to surgical navigation.