Structure and functions of Aggregation-Induced Emission-Photosensitizers in anticancer and antimicrobial theranostics

Abstract

Photosensitizers with Aggregation-Induced Emission (AIE) can allow the efficient light-mediated generation of Reactive Oxygen Species (ROS) based on their complex molecular structure, while interacting with living cells. They achieve better tissue targeting and allow penetration of different wavelengths of Ultraviolet-Visible-Infrared irradiation. Not surprisingly, they are useful for fluorescence image-guided Photodynamic Therapy (PDT) against cancers of diverse origin. AIE-photosensitizers can also function as broad spectrum antimicrobials, capable of destroying the outer wall of microbes such as bacteria or fungi without the issues of drug resistance, and can also bind to viruses and deactivate them. Often, they exhibit poor solubility and cellular toxicity, which compromise their theranostic efficacy. This could be circumvented by using suitable nanomaterials for improved biological compatibility and cellular targeting. Such dual-function AIE-photosensitizers nanoparticles show unparalleled precision for image-guided detection of tumors as well as generation of ROS for targeted PDT in living systems, even while using low power visible light. In short, the development of AIE-photosensitizer nanoparticles could be a better solution for light-mediated destruction of unwanted eukaryotic cells and selective elimination of prokaryotic pathogens, although, there is a dearth of pre-clinical and clinical data in the literature.

Keywords: aggregation-induced emission; laser; light; nanoparticles; photosensitizers; theranostics.

FIGURE 1

Mechanism of AIE-photosensitization: AIE-photosensitizers at the ground state (S0) absorbs energy to become excited Singlet states (S1, S2), which then undergoes Intersystem Crossing (ISC) to the Triplet states for the transfer of electrons (T1) or energy (T2). Production of free radicals and singlet oxygen can be increased in T1 or T2 reactions by accelerating ISC from S1 to S2. Thus, it is ideal to have lower energy gap between S1 and S2 and a large spin-orbit coupling. Further, design of the AIE-photosensitizer molecules with a D-structure should allow aggregation-induced ISC. Unlike any other fluorescent dyes, AIE-photosensitizers can overcome Aggregation-Induced Quenching (AIQ) in their condensed state and are most suitable for theranostics. Abbreviations: O ₂ , Oxygen; ¹ O _2, Singlet oxygen; ROS, Reactive Oxygen Species.

FIGURE 2

Cellular effects of AIE-photosensitizers: The AIE-photosensitizers are classified as type I and II according to their process of synthesis of ROS. Transfer of electrons at low oxygen concentration creates oxide free radicals (type I photosensitization), while transfer of energy to the molecular oxygen generates singlet oxygen (type II photosensitization). Often, electron transfer may happen from AIE-photosensitizer to oxygen in type II reactions forming superoxide anions. The type II photosensitization is subdivided into 1) Donor-AIE (neutral)-Acceptor 2) AIE (donor)-Acceptor, and 3) combined electron and energy transfer mechanisms. While the type I photosensitization has anti-neoplastic effects due to the robust oxidation of biomolecules, the latter is mostly anti-microbial. Paradoxically, type II reaction with electron transfer mechanisms has been widely used in anticancer theranostics.

FIGURE 3

Illustrations for Donor-AIE(neutral)-Acceptor photosensitizers: In general, these are constructed on a tetraphenylethene (TPE) cytoskeleton. Alternatively, tetraphenylamine (TPA) can act as an electron donor and/or core of the AIE-photosensitizer. Source: DPBA-TPE (Feng et al., 2015a), MTi (Chen et al., 2019), TPETS (Gao et al., 2019a), TPETCAQ (Wu et al., 2017a). Please refer Tables 2–5 for details.

FIGURE 4

Illustrations for AIE(donor)-Acceptor photosensitizers: These are constructed on tetraphenylethene (TPE) cytoskeleton with a D-A or D-π-A structure. Addition of spacer (π) between donor (D) and acceptor (A) may decrease the singlet energy gap (ΔE _ST). Source: PTPEAQ (Wu et al., 2016), MP-TPEDCH (Huang et al., 2021), TPE-Py (Zhuang et al., 2019), BODIPY-TPA (Deng et al., 2021). Please refer Tables 2–5 for details.

FIGURE 5

Mode of action of AIE-photosensitizer nanoparticles: A selected number of biocompatible nanoparticles can be incorporated into AIE-photosensitizers for an efficient drug delivery with desirable biological effects. AIE-photosensitizer nanoparticles with emission maxima in the far-red to near-infrared have high penetration depth into tumors, which is useful for bio-imaging as well as targeted therapy in PDT. Further, they are able to detect specifically and eliminate pathogens from various environment and food sources. Abbreviations: AIE-PS, Aggregation-Induced Emission-Photosensitizer; NP, Nanoparticles.