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. 2025 Jul 31;4(1):100–104. doi: 10.1021/cbmi.5c00082

A Caspase-3-Activatable Near-Infrared AIEgen for Tumor Apoptosis Imaging In Vivo

Lingling Xu †,‡, Yuanyuan Jin ‡, Zhanjun Yang ‡, Wenjun Zhan †,§,∥, Gaolin Liang †,§,∥,*, Shurong Shen †,*
PMCID: PMC12848816  PMID: 41613761

Abstract

Near-infrared (NIR) fluorescence imaging of tumor caspase-3 activity can be applied for real-time monitoring of the therapeutic effect of an anticancer drug in vivo. Aggregation-induced emission luminogens (AIEgens) are highly sensitive, unique fluorophores, but there is no NIR AIEgen reported for the above purpose. Herein, we rationally developed an activatable NIR AIEgen, Ac-Asp-Glu-Val-Asp-Pra-QMT (Ac-DEVD-Pra-QMT), to sensitively image caspase-3 activity in apoptotic 4T1 cells and tumor. After being internalized by cisplatin-induced apoptotic tumor cells, Ac-DEVD-Pra-QMT is subjected to caspase-3 cleavage to yield hydrophobic Pra-QMT, which spontaneously aggregates into nanoparticles to turn “On” the NIR fluorescence. Experimental results show that Ac-DEVD-Pra-QMT renders 14.9-fold and 2.7-fold higher NIR fluorescent intensities compared to those of the control groups in vitro and in vivo, respectively. We expect that Ac-DEVD-Pra-QMT could serve as a valuable tool for the early tracking of chemotherapeutic effects in the near future.

Keywords: AIEgens, caspase-3, near-infrared, tumor apoptosis, in vivo imaging

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1. Introduction

Apoptosis, a tightly regulated process of programmed cell death, is critical for normal development and homeostasis maintenance. Deregulation of apoptosis contributes to a variety of diseases, such as tumors, neurodegenerative disorders, leukemia, immunodeficiency, and autoimmune diseases. , In the apoptosis signaling cascade, caspase-3 functions as a critical effector caspase and is widely regarded as a key biomarker of programmed cell death. − Caspase-3 exists as inactive zymogens in normal cells but is activated through a series of proteolytic events during early apoptosis. Once activated, caspase-3 executes its function by selectively cleaving the tetrapeptide Asp-Glu-Val-Asp (DEVD) substrates, leading to the dismantling of cellular structures and ultimately cell death. − Given the central role of caspase-3 and its substrate specificity in apoptosis, there has been considerable interest in developing tools that can selectively monitor caspase-3 activity in real time, particularly in living organisms. , Such tools would not only enhance our understanding of apoptotic mechanisms but also have significant implications for drug screening and therapeutic evaluation.

Fluorescence imaging techniques have gained considerable attention for caspase-3 detection due to its exceptional sensitivity and rapid response characteristics. − Various fluorescence probes have been developed based on different mechanisms, including photoinduced electron transfer, Förster resonance energy transfer, intramolecular charge transfer, and aggregation-induced emission (AIE). − Notably, AIE-based probes have emerged as particularly promising tools owing to their excellent photostability, large Stokes shift, strong resistance to photobleaching, and good biocompatibility. − Despite these advantages, the development of activatable AIE luminogens (AIEgens) for real-time monitoring of caspase-3 in vivo remains relatively unexplored. In this regard, near-infrared (NIR) AIEgens, which offer enhanced signal-to-noise ratios and deeper tissue penetration, − could significantly improve the sensitivity of caspase-3 imaging in living subjects. However, to the best of our knowledge, caspase-3-responsive NIR-emitting AIE probes have not yet been reported for in vivo visualization of tumor apoptosis.

Herein, we rationally designed a caspase-3-responsive NIR AIEgen Ac-Asp-Glu-Val-Asp-Pra-QMT (Ac-DEVD-Pra-QMT) for tumor apoptosis imaging in vivo. Specifically, Ac-DEVD-Pra-QMT was synthesized by integrating an AIE fluorophore QMT , with a caspase-3-cleavable peptide Ac-DEVD via an l-propargylglycine (Pra) linker (Figure ). The fluorescence signal of hydrophilic Ac-DEVD-Pra-QMT is initially “Off” due to its molecularly dispersed state in an aqueous medium. Upon uptake by cisplatin-induced apoptotic tumor cells, Ac-DEVD-Pra-QMT is subjected to caspase-3 cleavage to yield hydrophobic Pra-QMT. Pra-QMT spontaneously aggregates into nanoparticles, thereby turning “On” the NIR fluorescence for real-time monitoring of tumor apoptosis in vivo.

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Schematic illustration of caspase-3-activatable NIR AIEgen Ac-DEVD-Pra-QMT for tumor apoptosis imaging.

2. Results and Discussion

We first synthesized and characterized Ac-DEVD-Pra-QMT and Pra-QMT (Schemes S1 and S2, Figures S1–S6). Then, to investigate the responsiveness of Ac-DEVD-Pra-QMT toward caspase-3, we incubated 10 μM Ac-DEVD-Pra-QMT with 0.5 μg/mL caspase-3 in a working buffer (pH 7.4, 1 mM EDTA, 100 mM NaCl, 25 mM HEPES, 10 mM DTT, 0.1% CHAPS, and 1% DMSO) for 4 h. High-performance liquid chromatography (HPLC) results showed that after caspase-3 treatment, Ac-DEVD-Pra-QMT (retention time: 9.4 min) was almost undetectable, while a new product peak (retention time: 11.8 min) appeared (Figure a and Table S1). The identical retention times of the enzymatic product and synthetic Pra-QMT indicated that the enzymatic product of Ac-DEVD-Pra-QMT with caspase-3 was Pra-QMT. Further mass spectrometry analysis revealed that this new product was indeed Pra-QMT (Figure S7). In addition, transmission electron microscopy (TEM) images further confirmed the formation of nanoparticles with a mean diameter of 18.9 ± 8.9 nm (Figures b and S8). Conversely, 10 μM Ac-DEVD-Pra-QMT (below its critical aggregation concentration (CAC) of 13.0 μM) remained nonaggregated (Figures S9 and S10). Moreover, detailed photophysical properties of Ac-DEVD-Pra-QMT and Pra-QMT are displayed in Figures S11 and S12. The absorbance exhibited a concentration-dependent enhancement with an increasing concentration of both Ac-DEVD-Pra-QMT and Pra-QMT. Furthermore, compared with the same concentration of Ac-DEVD-Pra-QMT (10 μM), the absorbance of Pra-QMT at its maximum absorption wavelength decreased significantly due to the light scattering effects of nanoparticles (Figure S13). Next, the fluorescence spectra of Ac-DEVD-Pra-QMT before and after caspase-3 treatment were recorded. As shown in Figure c, after Ac-DEVD-Pra-QMT was incubated with 0.5 μg/mL caspase-3 for 4 h, its fluorescence emission at 665 nm increased by 14.9-fold. Moreover, Ac-DEVD-Pra-QMT showed only marginal fluorescence responses to other potential interfering enzymes (Figure d), including caspase-1 (Casp1), cathepsin C (Cath C), leucine aminopeptidase (LAP), granzyme B (GrazB), and carboxylesterase (CES), indicating its high selectivity toward caspase-3. We further evaluated the stability of Ac-DEVD-Pra-QMT in PBS buffer (10 mM, pH 6.5, and 1% DMSO) or 10% serum via HPLC monitoring. Figure S14 reveals that the retention time of Ac-DEVD-Pra-QMT was unaltered following a 24 h incubation in both media, demonstrating its outstanding in vitro stability. Above results indicated that Ac-DEVD-Pra-QMT exhibited excellent responsiveness toward caspase-3 to afford a significant “Turn-On” NIR AIE fluorescence.

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(a) HPLC traces of Ac-DEVD-Pra-QMT (10 μM) and Ac-DEVD-Pra-QMT (10 μM) treated with 0.5 μg/mL caspase-3 for 4 h and Pra-QMT (10 μM). (b) TEM image of Pra-QMT nanoparticles. (c) Fluorescence spectra of Ac-DEVD-Pra-QMT (10 μM) and Ac-DEVD-Pra-QMT (10 μM) treated with 0.5 μg/mL caspase-3 for 4 h, λex = 460 nm. (d) Fluorescence intensity of Ac-DEVD-Pra-QMT at 665 nm after incubation with caspase-3 and other different enzymes. ***p < 0.001.

Before investigating the ability of Ac-DEVD-Pra-QMT to detect caspase-3 activity in apoptotic tumor cells, we first evaluated cytotoxicity against 4T1 breast cancer cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. After incubation with Ac-DEVD-Pra-QMT for 24 h, 4T1 cells maintained high viability (>80%) at a probe concentration of up to 200 μM, demonstrating the good biocompatibility of Ac-DEVD-Pra-QMT (Figure S15). Subsequently, normal 4T1 cells or cisplatin-pretreated 4T1 cells were incubated with 10 μM Ac-DEVD-Pra-QMT, followed by fluorescence microscopy observations. As shown in Figures and S16, the NIR fluorescence signal of cisplatin-induced apoptotic 4T1 cells gradually turned “on” over time and plateaued at 2 h. In contrast, almost no fluorescence signal was observed in 4T1 cells without cisplatin treatment, confirming the specific activation of Ac-DEVD-Pra-QMT by intracellular caspase-3. Western blot results revealed a large amount of cleaved caspase-3 in cisplatin-treated 4T1 cells (Figure S17), implying that the fluorescence signals are associated with caspase-3. Taken together, these findings indicated that Ac-DEVD-Pra-QMT could achieve efficient and sensitive NIR fluorescence imaging of caspase-3 in apoptotic tumor cells.

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Fluorescence images of 4T1 cells and cisplatin-pretreated 4T1 cells incubated with 10 μM Ac-DEVD-Pra-QMT for 2 h.

Finally, we evaluated the capability of Ac-DEVD-Pra-QMT for real-time NIR fluorescence imaging of caspase-3 activity in 4T1 tumor-bearing nude mice. For the control group, each mouse was treated with 1.35 mg/kg Ac-DEVD-Pra-QMT via tail vein injection. While in the experimental group (i.e., “Cis Treatment” group), each mouse was intratumorally injected with 2.0 mg/kg cisplatin for 24 h to establish tumor apoptosis models, followed by a tail vein injection of 1.35 mg/kg Ac-DEVD-Pra-QMT for specific imaging of tumor apoptosis. As shown in Figure , the tumor regions of the control group mice exhibited weak NIR fluorescence signals. In contrast, the NIR fluorescence intensity of cisplatin-treated tumors gradually increased over time, reaching a maximum at 8 h (Figures S18 and S19). Quantitative analysis indicated that, at 8 h postadministration, the tumor fluorescence intensity of the “Cis Treatment” group was a 2.7-fold increase compared to the control group (Figure S20). Furthermore, the mice were dissected, and their major organs and tumors were collected for ex vivo fluorescence imaging. The results revealed that only cisplatin-treated tumors emitted strong NIR signals (Figure S21), whereas the tumor in the control group and major organs in both groups exhibited undetectable fluorescence, indicating that Ac-DEVD-Pra-QMT was selectively activated in apoptotic tumors. Overall, these results confirmed the efficacy of AC-DEVD-Pra-QMT in real-time and sensitive monitoring of caspase-3-mediated tumor apoptosis in vivo. The unique properties of Ac-DEVD-Pra-QMT endow it with a wide range of potential applications in the clinic. First, Ac-DEVD-Pra-QMT enables early detection of tumor apoptosis, improving malignancy diagnosis and prognosis. Second, it allows real-time monitoring of chemotherapy response by visualizing an apoptotic tumor. Additionally, it facilitates rapid screening of proapoptotic drug candidates, accelerating anticancer drug development.

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Time-course fluorescence imaging of 4T1 tumor-bearing mice and cisplatin-pretreated 4T1 tumor-bearing mice with a tail vein administration of 1.35 mg/kg Ac-DEVD-Pra-QMT.

3. Conclusion

In conclusion, we successfully developed an NIR AIEgen Ac-DEVD-Pra-QMT that could be effectively turned “On” by caspase-3 in apoptotic tumor cells. In vitro experiments validated that, upon caspase-3 cleavage, the hydrophilic Ac-DEVD-Pra-QMT evolved into hydrophobic Pra-QMT, which spontaneously aggregated into nanoparticles to activate the NIR-emitting AIE signal. Cell imaging results validated that the turn-on fluorescence of Ac-DEVD-Pra-QMT enabled real-time monitoring of caspase-3 activity in apoptotic tumor cells. Furthermore, we successfully used Ac-DEVD-Pra-QMT to directly visualize the tumor response to chemotherapy. To our knowledge, Ac-DEVD-Pra-QMT represents the first NIR AIEgen developed for caspase-3 detection in vivo. Compared with the existing caspase-3-responsive AIEgens that emit in the visible range, Ac-DEVD-Pra-QMT exhibits superior potential for biological applications due to its reduced autofluorescence interference and enhanced tissue penetration. We envision that our NIR AIEgen Ac-DEVD-Pra-QMT could be applied for fluorescence imaging of tumor apoptosis in the clinic in the future.

Supplementary Material

im5c00082_si_001.pdf (1.4MB, pdf)

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant 22234002), the China Postdoctoral Science Foundation (Grant 2025M771069), the Full-time Talents Program of Hebei Province (Grant 2023HBQZYCXY027), and the Yangzhou Lv-Yang-Jin-Feng Talent Project.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/cbmi.5c00082.

  • Experimental section, synthetic route, MS and NMR spectra, CAC analysis, UV–vis absorption spectra, cell cytotoxicity of Ac-DEVD-Pra-QMT, Western blot analysis, time-course fluorescence images, and ex vivo fluorescence imaging of main organs (PDF)

The authors declare no competing financial interest.

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Supplementary Materials

im5c00082_si_001.pdf (1.4MB, pdf)

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