Design and synthesis of a tetraphenylethene-porphyrin hetero-faced molecular cage for photodynamic therapy

Abstract The development of efficient photosensitizers for photodynamic therapy (PDT) remains a significant challenge due to the limitations of aggregation-caused quenching (ACQ) in commonly used chromophores. Here, we present the design and synthesis of a tetraphenylethene-porphyrin hetero-faced molecular cage (1•8Clˉ), where tetraphenylethene (TPE) with aggregation-induced emission (AIE) properties is covalently linked to porphyrin, which exhibits good photosensitivity but suffers from ACQ effects. The hetero-faced molecular cage is designed with a face-to-face configuration, facilitated by four p-xylylene linkers, ensuring precise spatial alignment of the TPE and porphyrin units. This cage-type molecular architecture not only enables the conversion of ACQ to AIE, but also populates the triplet state of porphyrin via efficient intramolecular energy and electron transfer owing to the favorable geometry. As a result, 1•8Clˉ demonstrates excellent ability to generate reactive oxygen species (ROS) and binds nicotinamide adenine dinucleotide (NADH) in aqueous solution, catalyzing the rapid photocatalytic oxidation of NADH to its oxide form (NAD+). Utilizing ROS generation and the disruption of the intracellular redox balance of NADH, 1•8Clˉ exhibits significant potential for effective photocatalysis-assisted PDT in hypoxic tumor environments. This study opens a new pathway for molecular design by combining molecular cage structures with photosensitizer functionality, enabling applications in fields like photocatalysis and photodynamic therapy.