Type I Photosensitizers Based on Aggregation-Induced Emission: A Rising Star in Photodynamic Therapy

Abstract

Photodynamic therapy (PDT), emerging as a minimally invasive therapeutic modality with precise controllability and high spatiotemporal accuracy, has earned significant advancements in the field of cancer and other non-cancerous diseases treatment. Thereinto, type I PDT represents an irreplaceable and meritorious part in contributing to these delightful achievements since its distinctive hypoxia tolerance can perfectly compensate for the high oxygen-dependent type II PDT, particularly in hypoxic tissues. Regarding the diverse type I photosensitizers (PSs) that light up type I PDT, aggregation-induced emission (AIE)-active type I PSs are currently arousing great research interest owing to their distinguished AIE and aggregation-induced generation of reactive oxygen species (AIE-ROS) features. In this review, we offer a comprehensive overview of the cutting-edge advances of novel AIE-active type I PSs by delineating the photophysical and photochemical mechanisms of the type I pathway, summarizing the current molecular design strategies for promoting the type I process, and showcasing current bioapplications, in succession. Notably, the strategies to construct highly efficient type I AIE PSs were elucidated in detail from the two aspects of introducing high electron affinity groups, and enhancing intramolecular charge transfer (ICT) intensity. Lastly, we present a brief conclusion, and a discussion on the current limitations and proposed opportunities.

Keywords: aggregation-induced emission; phototheranostics; type I photosensitizers.

Figure 1

The illustration shows the working mechanisms of PSs described with the Jablonski diagram. The inserted box in the middle shows the ISC rate equation. The inserted box on the right shows the related cascaded reactions during the type I process.

Figure 2

(a) The chemical structures of α-TPA-PIO and β-TPA-PIO. (b) Resonance structures of the PIO radical ions. (c) Relative fluorescence intensity of hydroxyphenyl fluorescein (HPF) for OH^• detection. (d) Electron spin resonance (ESR) signals of 5-tert-butoxycarbonyl-5-methyl-1-pyrroline-N-oxide (BMPO) for free radical ROS detection of α-TPA-PIO and β-TPA-PIO with or without bovine serum albumin (BSA). (e) Relative fluorescence intensity of singlet oxygen sensor green (SOSG) and decomposition rates of 9,10-anthracenediyl-bis(methylene) dimalonic acid (ABDA) for ¹O₂ detection of α-TPA-PIO, β-TPA-PIO and MB. (f) Cyclic voltammograms of α-TPA-PIO and β-TPA-PIO. SOC value and ISC process of (g) α-TPA-PIO, and (h) β-TPA-PIO. (i) Images of mouse and tumors at 24 h post-injection of β-TPA-PIO. Reprinted with permission from [48], copyright 2020, Royal Society of Chemistry.

Figure 3

(a) Chemical structures and the order of ICT effect of TBZPy, MTBZPy, TNZPy, and MTNZPy. (b) 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA), (c) ABDA, (d) Dihydrorhodamine 123 (DHR 123) and (e) HPF for total ROS, ¹O₂, O₂^•−, OH^• detection, respectively. The survival rate of HeLa Cells for a range of concentrations of TNZPy and MTNZPy in (f) normoxic environments and (g) hypoxic environments under light irradiation. Reprinted with permission from [50], copyright 2020, Wiley-VCH.

Figure 4

(a) Chemical structures and design principles of DPP-TPA, 2TPAVDPP, TPATPEVDPP and 2TPEVDPP. (b) Optimized conformation of DPP-TPA, 2TPAVDPP, TPATPEVDPP and 2TPEVDPP. The text with blue or red color shows the torsion angles of the molecular backbones. (c) Relative fluorescence intensity of DCFH for total ROS detection of DPP-TPA, 2TPAVDPP, TPATPEVDPP and 2TPEVDPP. (d) ESR signals of BMPO for free radical ROS detection of DPP-TPA, 2TPAVDPP, TPATPEVDPP and 2TPEVDPP. Relative fluorescence of (e) DHR123 for O₂^•− detection, and (f) SOSG for ¹O₂ detection, of DPP-TPA, 2TPAVDPP, TPATPEVDPP and 2TPEVDPP. Reprinted with permission from [52], copyright 2022, American Chemical Society.

Figure 5

(a) Illustration of molecular design principle, nanotheranostics fabrication, and its application in nucleus-targeted type I photodynamic cancer treatment. (b) ESR analysis for OH^• generation of TTFMN and TFMN after white light irradiation (200 mW/cm²). (c) CLSM images of nuclear targeting delivery of TTFMN-NPs (2 µg/mL TTFMN) after incubation with 4T1 cells for 12 h. The blue color represents the fluorescence of Hoechst 33342 for locating cell nucleus and the red color represents the fluorescence of TTFMN-NPs. (d) Time-dependent in vivo FLI of tumor-bearing mice after injection with TTFMN-NPs. (e) The growth curves of tumors in different treatment groups (n = 5, * p < 0.001). (f) The tumor weights of mice after treatments for 15 days (n = 5, * p < 0.001). Reprinted with permission from [61], copyright 2021, Wiley-VCH.

Figure 6

(a) Chemical structure of MeOTTI and schematic illustration of triple-jump photodynamic theranostic protocol. (b) ROS generation type of MeOTTI determined by ESR test. (c) ROS production efficiency of MeOTTI NPs and MUM NPs at the same MeOTTI concentration under the irradiation of different light sources. (d) Cell viability of 4T1 cells treated with different conditions. (e) Tumor inhibition ratios of mice after different treatments, namely: (i) PBS, (ii) MUM NPs, (iii) 980 nm laser and white light, (iv) MeOTTI NPs and white light, (v) MUM NPs and white light, (vi) MUM NPs, 980 nm laser and white light (n = 5, * p < 0.001). Reprinted with permission from [63], copyright 2021, Wiley-VCH.

Figure 7

(a) Chemical structure of TPE-PTB and illustration of two-photon-excited FLI-guided PDT applications. (b) δ_2PA of the TPE-PTB NPs under different excitation wavelengths. (c) OH^• production ability of TPE-PTB NPs indicated by HPF. (d) Mechanism and calculation of OH^• generation analysis. (e) Flow cytometry of A375 cells stained by PI after treatment with different conditions. (f) Tumor growth curves of mice in different treatments. (* p < 0.05). Reprinted with permission from [66], copyright 2020, American Chemical Society.

Figure 8

(a) Schematic illustration of molecular design and properties, as well as the preparation of target NPs and their application in NIR-II FLI-guided type I PDT-PTT pancreatic cancer therapy. Variation in PL intensity (I/I₀) of (b) DCFH for total ROS detection, (c) DHR123 for O₂^•− detection, and (d) HPF for OH^• detection. (e) Photothermal performance of DCTBT NPs of different concentrations upon laser irradiation (808 nm, 0.8 W/cm², 6 min). (f) The average tumor weights of the subcutaneous PANC-1 tumor-bearing mice after different treatments recorded on day 17 (** p < 0.01). (g) The average tumor weights of the orthotopic PANC-1 tumor-bearing mice after different treatments recorded on day 16 (** p < 0.01). (h) In vivo NIR-II fluorescence images of subcutaneous PANC-1 tumor-bearing mice at different monitoring times after administration of lip-DCTBT NPs, a: non target NPs, b: target NPs. Reprinted with permission from [67], copyright 2022, Elsevier.

Figure 9

(a) Diagram of the preparation of TTVB@NM for antimicrobial applications. (b) CLSM imaging of bacteria and fungi co-incubated with TTVB. Relative fluorescence intensity of (c) DCFH for total ROS detection, (d) DHR123 for O₂^•− detection, and (e) HPF for OH^• detection of TTVB and RB under light irradiation (34 mW/cm²). (f) Microbial survival rate treated with NM or TTVB@NM in dark or under sunlight irradiation. (g) Antimicrobial experiment against pathogenic aerosols in dark or under sunlight irradiation. Survival rate of microbes under sunlight irradiation for (h) 5 min and (i) 10 min. Reprinted with permission from [77], copyright 2021, Elsevier.

Figure 10

(a) Schematic illustration of selectively removing HAB by TVP-A upon natural light irradiation. (b) Relative cell density of three algae after incubating with TVP-A at different concentrations after 96 h under the simulated daily cycles. M.A.: M. aeruginosa; C.R.: C. reinhardtii; C.V.: C. vulgaris. (c) Photos of C. reinhardtii (1.6 × 10⁷ cells/mL) in the presence of Alg (10 ppm and 100 ppm) or TVP-A (5 ppm and 10 ppm) under the simulated daily cycles on day 0 and day 5. (d) The change of the relative fluorescence intensity (I/I₀) in C. reinhardtii (1.6 × 10⁷ cells/mL) in the presence or absence of TVP-A (5 ppm) under different times of simulated natural light illumination. (e) Variation in relative absorbance of TVP-A at 462 nm with or without different natural light for evaluating the degradability of TVP-A. (f) The change of average heart rates of fish with or without TVP-A during the 14 days of cultivation time under the simulated daily cycles. Reprinted with permission from [82], copyright 2021, Elsevier.