Enzyme-Activatable Near-Infrared Photosensitizer with High Enrichment in Tumor Cells Based on a Multi-Effect Design

Enzyme-activatable near-infrared (NIR) fluorescent probes and photosensitizers (PSs) have emerged as promising tools for molecular imaging and photodynamic therapy (PDT). However, in living organisms selective retention or even enrichment of these reagents after enzymatic activation at or near sites of interest remains a challenging task. Herein, we integrate non-covalent and covalent retention approaches to introduce a novel “1-to-3” multi-effect strategy—one enzymatic stimulus leads to three types of effects—for the design of an enzyme-activatable NIR probe or PS. Using this strategy, we have constructed an alkaline phosphatase (ALP)-activatable NIR fluorogenic probe and a NIR PS, which proved to be selectively activated by ALP to switch on NIR fluorescence or photosensitizing ability, respectively. Additionally, these reagents showed significant enrichment (over 2000-fold) in ALP-overexpressed tumor cells compared to the culture medium, accompanied by massive depletion of intracellular thiols, the major antioxidants in cells. The investigation of this ALP-activatable NIR PS in an in vivo PDT model resulted in complete suppression of HeLa tumors and full recovery of all tested mice. Encouragingly, even a single administration of this NIR PS was sufficient to completely suppress tumors in mice, demonstrating the high potential of this strategy in biomedical applications.     

Polydopamine as a Visible-Light Photosensitiser for Photoinitiated Polymerisation

Polydopamine (PDA) is a synthetic model for melanin and has a wide range of opto-electronic properties that underpin its utility in applied and biological settings, from broadband light absorbance to possessing stable free radical species. Here, we show that PDA free radicals are photo-responsive under visible light irradiation, enabling PDA to serve as a photo-redox catalyst. Steady-state and transient electron spin resonance spectroscopy reveals a reversible amplification in semiquinone radical population within PDA under visible light. This photo-response modifies the redox potential of PDA and supports sensitisation of exogenous species via photoinduced electron transfer (PET). We demonstrate the utility of this discovery by employing PDA nanoparticles to photosensitise a common diaryliodonium photoinitiator and initiate free-radical polymerisation (FRP) of vinylic monomers. In situ ¹H nuclear magnetic resonance spectroscopy reveals an interplay between PDA-driven photosensitising and radical quenching during FRP under blue, green, and red light. This work provides crucial insights into the photoactive free radical properties of melanin-like materials and reveals a promising new application for polydopamine as a photosensitiser.