Microenvironment‐Tailored Catalytic Nanoprobe for Ratiometric NIR‐II Fluorescence/Photoacoustic Imaging of H₂O₂ in Tumor and Lymphatic Metastasis

Abstract

In vivo H2 O 2 visualization is crucial for disease diagnosis. Catalytic reactionbased probes show potential in H 2 O 2 detection, yet their in vivo application remains challenging because catalysts always require a specific pH to function and cellular glutathione (GSH) may suppress signaling by depletion of hydroxyl radicals and oxidized substrates. Here, a microenvironment-tailored catalytic nanoprobe (MTCN) comprising Fe 2+ , citric acid (CA), 2,2′-azino-bis(3ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), and downconversion nanoparticles in the liposomal cavity as well as a reference dye in the lipid membrane is reported, which utilizes the selective permeability of the liposomal membrane to offer a favorable pH for Fe 2+ catalyst with the aid of CA and to avoid GSH-triggered signal loss by preventing entry of GSH into the cavity. The MTCN displays a large NIR-II fluorescence (FL) ratio between 1550 and 1080 nm (FL 1550Em,808Ex /FL 1080Em,980Ex ), but a small photoacoustic (PA) ratio between 808 and 1048 nm (PA 808 /PA 1048 ). Upon exposure of MTCN to H 2 O 2 , catalytic conversion of ABTS into its oxidized form ABTS• + with 808 nm absorption causes a noticeable increment in PA 808 /PA 1048 accompanied by an apparent decrement in FL 1550Em,808Ex /FL 1080Em,980Ex , enabling bimodal ratiometric imaging of H 2 O 2 in the tumor and lymphatic metastasis.

Vision for Ratiometric Nanoprobes: In Vivo Noninvasive Visualization and Readout of Physiological Hallmarks

“…The insensitivity of the signals of QDs and Ln-doped DCNPs to most of the biological entities has made these nanoparticles suitable candidates for serving as the reference signal in a great deal of NIR-II emissive RNPs. Thus, the nanoprobes are designed by employing either of the nanoparticles along with another fluorescent agent whose emission profile can undergo a fluctuation by certain mechanisms in the presence of an analyte. − ,− …”

“…Recently, dual-modality ratiometric probes have been successfully developed in order to concurrently take advantage of the prominent characteristics of each of the modalities and provide multiscale data at several spatial and temporal scales. ,− For example, through finely designing a core–satellite nanosystem, an activatable photoacoustic and surface-enhanced Raman spectroscopy (SERS) dual-ratiometric probe for in vivo detecting the hydrogen peroxide (H 2 O 2 ) level was constructed (Figure ). The structure incorporated a 2-naphthalenethiol (NAT) Raman marker in its core whose SERS intensity (I 1418 cm –1 ) was protected from environmental-induced alterations by employing successive protective layers.…”

“…The reference and altered signals gave rise to a dual-ratiometric H 2 O 2 -responsive probe with the feasibility of inactively targeting the tumor site of mice bearing 4T1 breast cancer in order to precisely visualize the level of intratumoral H 2 O 2 . Moreover, contrary to the mice with healthy sentinel lymph nodes (SLNs), the injection of the probe to the mice suffering from metastatic SLNs led to a 4.1-fold enhancement and a 2.7-fold decline in the PA 808 /PA 1048 and F em:1550 ex:808 /F em:1080 ex:980 signals within 2 h, respectively, which allowed the quantification of the H 2 O 2 level in early stages of lymphatic metastasis …”

“…As reviewed above, some steps toward achieving the goal have been taken. For instance, dual-modality NIR-II emissive imaging agents were isolated from the interfering substances of the biological microenvironment . It can be expected that the idea of minimizing the affectability of RNPs from their surroundings multifaceted media might be further employed to prepare innovative RNPs with dynamic and reliable responses.…”

“…For instance, dual-modality NIR-II emissive imaging agents were isolated from the interfering substances of the biological microenvironment. 95 It can be expected that the idea of minimizing the affectability of RNPs from their surroundings multifaceted media might be further employed to prepare innovative RNPs with dynamic and reliable responses. We envision that such integrated strategies might have the most potential to be translated to clinical applications, in case that they satisfy the primary requirements such as biosafety and cost-effectiveness.…”