Multifunctional Two-Photon AIE Luminogens for Highly Mitochondria-Specific Bioimaging and Efficient Photodynamic Therapy

Abstract

In recent years, photodynamic therapy (PDT) has drawn much attention as a noninvasive and safe cancer therapy method due to its fine controllability, good selectivity, low systemic toxicity, and minimal drug resistance in contrast to the conventional methods (for example, chemotherapy, radiotherapy, and surgery). However, some drawbacks still remain for the current organic photosensitizers such as low singlet oxygen (1O2) quantum yield, poor photostability, inability of absorption in the near-infrared (NIR) region, short excitation wavelength, and limited action radius of singlet oxygen, which will strongly limit the PDT treatment efficiency. As a consequence, the development of efficient photosensitizers with high singlet oxygen quantum yield, strong fluorescent emission in the aggregated state, excellent photostability, NIR excitation wavelength ranging in the biological transparency window, and highly specific targeting to mitochondria is still in great demand for the enhancement of PDT treatment efficiency. In this study, two new two-photon AIEgens TPPM and TTPM based on a rigid D−π–A skeleton have been designed and synthesized. Both AIEgens TPPM and TTPM show strong aggregation-induced emission (AIE) with the emission enhancement up to 290-folds, large two-photon absorption with the two-photon absorption cross section up to 477 MG, and highly specific targeting to mitochondria in living cells with good biocompatibility. They can serve as two-photon bioprobes for the cell and deep tissue bioimaging with a penetration depth up to 150 μm. Furthermore, high 1O2 generation efficiency with high 1O2 quantum yield under white light irradiation has been found for both TPPM and TTPM and high PDT efficiency to HeLa cells under white light irradiation has also been proven. To the best of our knowledge, AIEgens in this work constitute one of the strongest emission enhancements and one of the highest 1O2 generation efficiencies in the reported organic AIEgens so far. The great AIE feature, large two-photon absorption, high specificity to mitochondria in living cells, and high PDT efficiency to living cells as well as excellent photostability and biocompatibility of these novel AIEgens TPPM and TTPM reveal great potential in clinical applications of two-photon cell and tissue bioimaging and image-guided and mitochondria-targeted photodynamic cancer therapy.

Recent Advances in Two‐Photon AIEgens and Their Application in Biological Systems

“…In 2019, two new types of two‐photon AIEgens TPPM ( 6 ) and TTPM ( 7 ) based on a rigid D–π–A skeleton have been designed by Tang group (Figure 7). [13] Those two‐photon AIEgens 6 and 7 showed strong AIE with the emission enhancement up to 290‐folds, large two‐photon absorption (477 MG), and highly specific targeting to mitochondria with high Pearson's coefficient of 0.98 ( R r =0.98) and Manders’ coefficients ( m 1 =1.0, m 2 =0.98).…”

“…b)The application of these probes in two-photon cell and tissue bioimaging and mitochondria-targeted PDT. Reprinted with permission from ref [13]…”

Mito‐Bomb: Targeting Mitochondria for Cancer Therapy

“…Similarly, Zhuang et al. [ 43 ] also synthesized two multifunctional two‐photon AIEgens (TPPM and TTPM) containing pyridinium structure based on the rigid D‐π‐A backbone (Figure 10b). These AIEgens had the superiority of high quantum yields of 1 O 2 , precise mitochondria‐targeting properties, excellent photostability and biocompatibility.…”

Aggregation‐Induced Emission Luminogens for Mitochondria‐Targeted Cancer Therapy

“…Push‐pull effect was employed to guide the design of AIEgens with NIR emission and two‐photon excitation [29a,30] . Wang, Li and coworkers designed two new mitochondria‐targeting AIEgens ( 13 and 14 ) (Figure 7a) which show two‐photon absorption [29b] . The singlet oxygen quantum yields of 13 and 14 were considered as one of the highest singlet oxygen generation efficiency among the reported organic AIEgens.…”