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Directed self-assembly of small molecules in living systems could enable a myriad of applications in biology and medicine, and already this has been used widely to synthesize supramolecules and nano/microstructures in solution and in living cells. However, controlling the self-assembly of synthetic small molecules in living animals is challenging because of the complex and dynamic in vivo physiological environment. Here we employ an optimized first-order bioorthogonal cyclization reaction to control the self-assembly of a fluorescent small molecule, and demonstrate its in vivo applicability by imaging caspase-3/7 activity in human tumour xenograft mouse models of chemotherapy. The fluorescent nanoparticles assembled in situ were imaged successfully in both apoptotic cells and tumour tissues using three-dimensional structured illumination microscopy. This strategy combines the advantages offered by small molecules with those of nanomaterials and should find widespread use for non-invasive imaging of enzyme activity in vivo.

γ-Glutamyltranspeptidase (GGT) is an important aminopeptidase overexpressed in many malignant tumors, and accurate detection of its activity is useful for the diagnosis and treatment of tumors. Herein, we report a GGT-activatable ratiometric fluorescent probe (1) constructed by covalently linking an 'always-on' BODIPY fluorophore with a GGT-activatable near-infrared (NIR) fluorescent substrate. Upon interaction with GGT, the NIR fluorescence at 735 nm in probe 1 is significantly enhanced, while the fluorescence of BODIPY at 517 nm remains unchanged. Using BODIPY fluorescence as an internal standard, significantly enhanced ratiometric fluorescence between 735 nm and 517 nm could be achieved, allowing accurate detection of the activity of GGT in living subjects independent of probe concentration. We demonstrate that probe 1 is feasible for the evaluation of GGT levels in different tumor cells and differentiation of GGT-positive tumor cells from GGT-negative normal tissue cells. Moreover, probe 1 is further applied for the visualization of tumor via noninvasive ratiometric fluorescence imaging of GGT activity, which could facilitate the detection of GGT-positive tumor tissues and study of GGT-related pathological processes. [ABSTRACT FROM AUTHOR]

Stimuli‐responsive smart photosensitizer (PS) nanoassemblies that allow enhanced delivery and controlled release of PSs are promising for imaging‐guided photodynamic therapy (PDT) of tumors. However, the lack of high‐sensitivity and spatial‐resolution signals and fast washout of released PSs from tumor tissues have impeded PDT efficacy in vivo. Herein, we report tumor targeting, redox‐responsive magnetic and fluorogenic PS nanoassemblies (NP‐RGD) synthesized via self‐assembly of a cRGD‐ and disulfide‐containing fluorogenic and paramagnetic small molecule (1‐RGD) for fluorescence/magnetic resonance bimodal imaging‐guided tumor PDT. NP‐RGD show high r1 relaxivity but quenched fluorescence and PDT activity; disulfide reduction by glutathione (GSH) promotes efficient disassembly into a small‐molecule probe (2‐RGD) and an organic PS (PPa‐SH), which could further bind with intracellular albumin, allowing prolonged retention and cascade activation of fluorescence and PDT to ablate tumors. [ABSTRACT FROM AUTHOR]

Mitochondria-targeting theranostic probes that enable the simultaneously reporting of and triggering of mitochondrial dysfunctions in cancer cells are highly attractive for cancer diagnosis and therapy. Three fluorescent mitochondria-targeting theranostic probes have been developed by linking a mitochondrial dye, coumarin-3-carboximide, with a widely used traditional Chinese medicine, artemisinin, to kill cancer cells. Fluorescence images showed that the designed coumarin-artemisinin conjugates localized mainly in mitochondria, leading to enhanced anticancer activities over artemisinin. High cytotoxicity against cancer cells correlated with the strong ability to accumulate in mitochondria, which could efficiently increase the intracellular reactive oxygen species level and induce cell apoptosis. This study highlights the potential of using mitochondria-targeting fluorophores to selectively trigger and directly visualize subcellular drug delivery in living cells. [ABSTRACT FROM AUTHOR]

Targeted delivery of intracellular stimuli-activatable photosensitizers (PSs) into tumor cells to achieve selective imaging and on-demand photodynamic therapy (PDT) of tumors has provided a vital opportunity for precise cancer diagnosis and therapy. In this paper, we report a tumor targeting and adenosine triphosphate (ATP)-activatable nanophotosensitizer Apt-HyNP/ BHQ2 by modifying hybrid micellar nanoparticles with both nucleolin-targeting aptamer AS1411 and quencher BHQj-labeled ATP-binding aptamer BHQ2-ATP-apt. We demonstrated that both of the fluorescence emissions at 555 and 627 nm were quenched by BHQ2 in Apt-HyNP/BHQ2, resulting in low PDT capacity. After selective entry into tumor cells through nucleolin-mediated endocytosis, the high concentration of intracellular ATP could bind to BHQj-ATP-apt and trigger Apt-HyNP/BHQ dissociation, leading to turning "on" both fluorescence and PDT. The "off-on" fluorescence emissions at both 555 and 627 nm were successfully applied for dual color fluorescence imaging of endogenous ATP levels and real-time monitoring of intracellular activation of Apt-HyNP/BHQ2 in tumor cells. Moreover, imaging-guided precise PDT of tumors in living mice was also demonstrated, allowing for selective ablation of tumors without obvious side effects. This study highlights the potential of using a combination of tumor-targeting and ATP-binding aptamers to design ATP-activatable PSs for both fluorescence imaging and imaging-guided PDT of tumors in vivo. [ABSTRACT FROM AUTHOR]