Photodynamic therapy (PDT), which uses photosensitizers to generate reactive oxygen species (ROS) under light irradiation to induce apoptosis of cancer cells, is a noninvasive treatment modality for multifarious cancers. Owing to the aberrant expression of microRNA (miRNA) in early-stage cancers, miRNA-triggered activation of photosensitizers attracts considerable attention as cancer photodynamic therapeutic approaches. However, the presence of circulation RNA might induce unwanted activation during the in vivo delivery to tumor cells, resulting in toxicity on normal tissues and organs. Therefore, developing external switches for controllable triggering the miRNA-responsive probes has become a key avenue to achieve the precise PDT of early-stage cancers.
Taking advantages of upconversion nanoparticles (UCNPs), which can convert near-infrared (NIR) irradiation to multiple emissions of UV and visible lights, Ju’s group has designed upconversion nanocapsules (Biomaterials 2018, 163, 55) and upconversion nano-onions (Biomaterials 2019, 225, 119501) for siRNA delivery and gene therapy, DNA-azobenzene nanopump for chemotherapy (Angew. Chem. Int. Ed. 2019, 58, 18207), as well as the “energy-concentrating zone” strategy for PDT (Angew. Chem. Int. Ed. 2019，58, 12117). These works effectively boost luminance energy transfer efficiency and upconversion luminescent intensity of UCNPs, and improve the efficacy of gene therapy, chemotherapy and PDT.
To resist the interference of circulation RNA, Ju’s group recently designed a NIR photo-caged DNA nanocomb based on upconversion nanoparticle as miRNA amplifier to achieve the amplified precise PDT for early-stage cancers. The nanocomb was self-assembled with a “photozipper” protected hairpin (H0) and two kinds of hairpin probes (H1 and H2) on a long DNA skeleton, and then covalently immobilized on NaYF4:Tm,Yb,Gd@NaYF4:Nd,Yb core-shell UCNPs (Figure 1). These hairpins were labelled with the photosensitizer pyropheophorbide-a' (PPa'), a derivative of pyropheophorbide-a (PPa), and corresponding quencher black hole quencher (BHQ). Upon 808-nm light irradiation, the “photozipper” could be cleaved under the UV emission of UCNPs to expose a sequence complementary with miRNA-21 for triggering the cascade hybridization reaction in the presence of miRNA-21 overexpressed in cancer cells, and magnifying the activation of PPa' for ROS generation under blue emission of UCNPs to achieve the enhanced precise PDT of early-stage cancers. In vitro experiments proved that miRNA-21 could effectively triggered the cascade hybridization reaction in the presence of NIR light irradiation, which is successfully blocked by the “photozipper” on H0. This NIR-switched miRNA amplifier demonstrated prominent suppression for both cell proliferation in vitro and early-stage tumor growth in vivo, thus indicating promising application for precise therapy of early-stage cancers.
This work has been published online in Angew. Chem. Int. Ed. (DOI: 10.1002/anie.202009263) on Aug 14, entitled as “Near-Infrared Photo-Switched MicroRNA Amplifier for Precise Photodynamic Therapy of Early-Stage Cancers”. Yue Zhang and Weiwei Chen are the co-first authors. Professor Huangxian Ju and Professor Ying Liu are the co-corresponding authors.