Recent Advances in the Enzyme-Activatable Organic Fluorescent Probes for Tumor Imaging and Therapy

Abstract

The exploration of advanced probes for cancer diagnosis and treatment is of high importance in fundamental research and clinical practice. In comparison with the traditional "always-on" probes, the emerging activatable probes enjoy advantages in promoted accuracy for tumor theranostics by specifically releasing or activating fluorophores at the targeting sites. The main designing principle for these probes is to incorporate responsive groups that can specifically react with the biomarkers (e. g., enzymes) involved in tumorigenesis and progression, realizing the controlled activation in tumors. In this review, we summarize the latest advances in the molecular design and biomedical application of enzyme-responsive organic fluorescent probes. Particularly, the fluorophores can be endowed with ability of generating reactive oxygen species (ROS) to afford the photosensitizers, highlighting the potential of these probes in simultaneous tumor imaging and therapy with rational design. We hope that this review could inspire more research interests in the development of tumor-targeting theranostic probes for advanced biological studies.

Keywords: enzyme-activatable probes; functional groups; peptide-responsive; photodynamic therapy; tumor fluorescent imaging.

Figure 1

Demonstration of the working mechanism for an enzyme‐activable probe. Reproduced with permission from Ref. [38]. Copyright 2018, Elsevier.

Figure 2

Schematic illustration for (a) the synthesis and (b) the antitumor mechanism of MCGPD‐RGD NPs. Reproduced with permission from Ref. [40]. Copyright 2021 The Royal Society of Chemistry.

Figure 3

(a) Chemical structures of CP1 and Gad‐AIE; (b) sensing mechanism of CP1; (c) time‐lapse fluorescence imaging of apoptotic HeLa cells incubated with CP1 (50 μm) prior to apoptosis induction with sodium tetradecyl sulfate (STS, 1 μm). Reproduced with permission from Ref. [42]. Copyright 2019 American Chemical Society.

Figure 4

(a) Molecular design and chemical structure of the tumor‐selective cascade activatable self‐detained system; (b) schematic illustration of the working mechanism of probe 1; (c) representative NIR fluorescence images of probes 1, 2 and 3 on H460 tumor‐bearing mice after intravenous injection. Images were acquired at 1, 4, 12, 24 h and 5 days post injection. Probes 2 and 3 are the control probes. The probe concentration used in the in vivo experiment was 14 mg kg⁻¹; (d) normalized fluorescence intensity in tumors in c; (e) NIR fluorescence images and normalized fluorescence intensity of tumor on tumor‐bearing mice after IV injection. Reproduced with permission from Ref. [43]. Copyright 2019 Springer Nature.

Figure 5

(a) Schematic illustration of the self‐assembly process and chemical structure of the probe with four motifs; (b) the time‐dependent NIR fluorescent images of mice bearing CAFs from 2–120 h after intravenous administration of Molecule  1 and Molecule  4; (c) NIR fluorescence distribution in heart, liver, spleen, lung, kidney, and tumor of Molecules  1 and 4 at 48 h post intravenous injection at a dose of 14 mg kg⁻¹. Molecule  1 is the probe, and Molecule  4 is the control probe. Reproduced with permission from Ref. [47]. Copyright 2019 Wiley‐VCH.

Figure 6

(a) Illustration for the responsive mechanism of probe CyA−P−CyB; (b) NIR images of tumor‐bearing mice were collected over 48 h after the intravenous injections of PEG‐PLA/CyA−P−CyB; (c) photos of mice bearing H640 tumors on day 14 after administration of the indicated treatments. Reproduced with permission from Ref. [50]. Copyright 2017, Elsevier.

Figure 7

Schematic illustration of the self‐assembly process and furin detection using the probe C‐3. Reproduced with permission from Ref. [52]. Copyright 2019, American Chemical Society.

Figure 8

(a) Schematic illustration of the assembly process of DQM‐ALP; (b) fluorescence imaging of tumors and normal tissues after immersion in DQM‐ALP solution. Reproduced with permission from Ref. [60]. Copyright 2020, Wiley‐VCH.

Figure 9

Schematic representation of the reaction process of BOD‐NQO1 and polymeric micelle assembly of nanoprobes with ratiometric response to NQO1. Reproduced with permission from Ref. [63]. Copyright 2017, Elsevier.

Figure 10

Schematic illustration of probe AP−N=N−CY in response to azoreductase. Reproduced with permission from Ref. [66]. Copyright 2020, American Chemical Society.

Figure 11

(a) Proposed reaction mechanism of the TYR‐catalyzed release of MB from MB1; (b) toxicity of MB1 to B16F10 cells and HeLa cells with and without laser irradiation. Reproduced with permission from Ref. [69]. Copyright 2018, American Chemical Society.

Figure 12

(a) Schematic illustration of the response process of ICy−N for NTR; (b) ICy−N induced apoptosis assays of 4T1 cells. Confocal microscopy imaging of annexin V‐FITC and PI stained 4T1 cells after different treatments. The green channel of annexin V‐FITC was excited at 488 nm and collected at 500–550 nm; the red channel of PI was excited at 561 nm and collected at 590–640 nm. Reproduced with permission from Ref. [73]. Copyright 2019, The Royal Society of Chemistry.

Figure 13

Schematic illustration of proposed drug release and action mechanism for the probe BDP−L−CPT. Reproduced with permission from Ref. [79]. Copyright 2022, American Chemical Society.