Design and Engineering of Hypoxia and Acidic pH Dual‐Stimuli‐Responsive Intelligent Fluorescent Nanoprobe for Precise Tumor Imaging

Abstract

Many techniques and strategies, such as positron emission tomography, magnetic resonance imaging, and immunohistochemistry, have been explored to diagnose tumors efficiently. [3][4][5] Among them, due to the advantages of high sensitivity, simplicity, and noninvasiveness, fluorescence molecular imaging has become a promising approach that enables detecting and visualizing the tumorrelated biomarkers in vivo. [6][7][8][9] However, tumor microenvironment (TME), as a complex system that consist of tumor cells, nearby interstitial tissues, capillaries, and various cytokines, always exhibits aberrant physiologic conditions such as low concentration of oxygen (hypoxia), acidic pH and increased interstitial fluid pressure, was still an obstacle for accurate fluorescence molecular imaging of tumor cells. [10][11][12][13][14] Accurate imaging of the dynamic changes in TME allows for the early detection of tumor and noninvasive assessment during tumor development and proliferation, and thus facilitates employing personalized therapies to improve patient survival. [15,16] To this goal, great achievements have been made to characterize dynamic changes of molecular signatures in TME. [17][18][19][20] Stimulus-responsive fluorescence imaging modality shows great promise for detection of tumor due to the advantages of high sensitivity, simplicity and noninvasiveness. However, some non-cancer regions including nodules and inflammation may also exhibit a stimulus-related characteristic, which cause the problem of nonspecific responsiveness and then cause "false positive" results for tumor recognition. Herein, hypoxia and acidic pH, two typical features strongly associated with tumor invasion, progression and metastasis in tumor microenvironment (TME), are chosen as dual stimuli to fabricate "dual lock-and-key" fluorescent nanoprobe for highly specific and precise imaging of tumor cells. Mesoporous silica coated gold nanorods (AuNR@ mSiO 2 ) are employed as nanocarrier and nanoquencher to load the pH-sensitive fluorescent reporter (Rho-TP). Azobenzene (azo) which can be reduced to amines by the highly expressed azoreductase under hypoxic conditions, is elected as the effective gatekeeper for AuNR@mSiO 2 by forming complex with β-cyclodextrin polymer via host-guest interaction (azo/β-CDP). By elaborately combining the hypoxia-responsive gatekeeper and pH-responsive fluorescent signal reporter into one nanoprobe, sensitive and specific imaging of tumor cells can be realized. The fabricated dual lock-and-key fluorescent nanoprobe successfully further apply in tumor-bearing mice model, which indicate potential of early diagnosis and assessment of cancer treatment.

Self-Assembly of Small Organic Molecules into Luminophores for Cancer Theranostic Applications

“…So it is very important to monitor the microenvironment abnormality in the early stage of the tumor for timely intervention, avoiding the further progression and metastasis of cancer. Recently, dual lock-and-key fluorescent probes have been developed for the precise imaging of tumors in mice models, indicating the potential of small molecule-based fluorescent probes for precision diagnosis of cancer [ 32 , 33 ].…”

Recent Advances in Dual‐target‐activated Fluorescent Probes for Biosensing and Bioimaging

“…Recently, Chen et al fabricated a hypoxia/acidic pH nanoprobe (HADFN) for highly specific and precise tracking of tumor cells. [47] As shown in Figure 25, they firstly constructed core/shell nanocarrier AuNR@mSiO 2 with the sol-gel method and then reacted with 3-aminopropyltriethoxysilane (APTES) to attain AuNR@mSiO 2 -NH 2 , which could further react with 4-(phenylazo) benzoic acid to yield AuNR@mSiO 2 -azo. By dispering AuNR@m-SiO 2 -azo into Rho-TP solution and gently shaking, Rho-TP was loaded on AuNR@mSiO 2 -azo.…”

A “Dual‐Source, Dual‐Activation” Strategy for an NIR‐II Window Theranostic Nanosystem Enabling Optimal Photothermal‐Ion Combination Therapy

“…[27,28] The dualactivation strategy is ini tially in the "off" state; only specific recognition of dualtarget species can realize the "turnon" process, effectively improving stimulusresponse sensitivity. [29] Nevertheless, tumor masses are very heterogeneous, and the activation process tends to arise from the tumor cell properties, which results in various degrees of activation in the tumor region and thus seriously hinders the accurate spatiotemporal guidance for NIRII PTT. Besides the tumor cells, the TME comprises a mass of hetero geneous cell types (including fibroblasts, immune/inflamma tory cells, vascular endothelial cells, and alongside pericytes), especially cancerassociated fibroblasts (CAFs) that play a sig nificant role in all stages of cancer.…”