A Dual‐Functional Photosensitizer for Ultraefficient Photodynamic Therapy and Synchronous Anticancer Efficacy Monitoring

Abstract

A dual-functional photosensitizer that demonstrates exceptional photodynamic therapy (PDT) efficacy while simultaneously self-monitoring the therapeutic response in real time is reported here. Possessing an ultrahigh 1 O 2 quantum yield of 98.6% in water, the photosensitizer TPCI can efficiently induce cell death in a series of carcinoma cells (IC 50 values less than 300 × 10 −9 m) upon irradiation with an extremely low fluence (460 nm, 4 mW cm −2 for 10 min). In addition, TPCI can self-monitor cell death in real time. It is weakly fluorescent in living cells before irradiation and lights up the nuclei concomitantly with cell death during PDT treatment by binding with chromatin to activate its aggregation-induced emission, attributed to its strong binding affinity with DNA. In vivo studies using mouse models bearing H22 and B16F10 tumor cells validate the ultraefficient PDT efficacy of TPCI as well as the precise real-time noninvasive readout of the tumor response from the beginning of cancer treatment. The dual-functional TPCI serves as an excellent candidate for single-agent photodynamic theranostics, and this work represents a new paradigm for the development of molecules with multiple intrinsic functions for future self-reporting medical applications.in which an AIE-based fluorophore and a photosensitizer are conjugated by tumor-responsive linkers, e.g., caspase-responsive peptides, have been designed for real-time monitoring of PDT therapeutic effects, and have attracted great interest. [9] However, the in vivo application of such conjugates is typically limited in the complicated physiological environment. [10] In addition, the intricate design and sophisticated structures of such conjugates further increase the difficulty in developing them as drugs. Therefore, the development of small molecules that intrinsically combine the dual functions of exceptional noninvasive tumor ablation capability and real-time anticancer efficacy-reporting characteristics would represent an important, but highly challenging, breakthrough.In this study, we designed and synthesized a dual-functional molecule, namely TPCI (Figure 1A), which has exceptional PDT efficacy both in vitro and in vivo. TPCI is water soluble with an ultrahigh singlet oxygen quantum yield of ≈98.6%. In addition to its exceptional PDT efficacy, TPCI can self-report the therapeutic response in real time. It is weakly fluorescent in living cells before irradiation and instantly fluoresces in the nucleus during cell death upon irradiation, which can report the cell death in real time precisely and efficiently. We also validated the in vivo dual-function, single-molecular photodynamic theranostics in mice. TPCI can not only ablate cancer cells efficiently, but also report the anticancer effects in real time from the beginning of therapy.

Mitochondria-anchoring and AIE-active photosensitizer for self-monitored cholangiocarcinoma therapy

“…Recently, two AIEactive PSs were developed with self-monitoring ability, which could translocate from mitochondria to the nucleus and bind with nucleic acids during PDT treatment. 33,34 However, their ultimate binding with nucleic acids may lead to genotoxic, carcinogenic, and teratogenic risks. 35 To endow the AIE-active PSs with a safe self-monitoring ability, we herein develop an AIE-active PS, TTVPHE, which could not only efficiently destroy the mitochondria in cancer cells, but also in situ monitor the therapeutic process by translocating from the damaged mitochondria to the nuclear membrane.…”

A NIR-I light-responsive superoxide radical generator with cancer cell membrane targeting ability for enhanced imaging-guided photodynamic therapy

“…As presented in Table S1, † the large extinction coefficient (3 Â 10 4 ) and small DE ST values were favorable for ROS generation, and a large stoke-shi (140 nm) as exhibited in Fig. S33a-e and S34 † indicated their great potential for imagingguided PDT [50][51][52][53] In vitro ROS generation c would subsequently trigger a series of synergetic cascade reactions ( Fig. 1e), yielding more toxic ROS.…”

Promising Applications of AIEgens in Animal Models

“…Recently, Zhang et al presented a self‐reporting strategy that could be achieved by monitoring apoptosis during PDT in situ, which utilized the translocation of PS (TPE‐4EP+) from mitochondria to the nucleus. Gao et al reported another photosensitizer (TPCI), which was weakly fluorescent in living cells in the absence of irradiating light but showed enhanced emission from nuclei during PDT treatment ( Figure A). This was used for self‐reporting cell death during PDT in real time, as indicated by the excellent colocalization of TPCI and propidium iodide (PI) (Figure B).…”

“…C) Changes in tumor size (dashed black circles) at different times in a B16F10 melanoma‐bearing mouse model. Reproduced with permission . Copyright 2019, Wiley‐VCH.…”