Triapine/Ce6-loaded and lactose-decorated nanomicelles provide an effective chemo-photodynamic therapy for hepatocellular carcinoma through a reactive oxygen species-boosting and ferroptosis-inducing mechanism

A nanomicelles-based and lactose-decorated drug delivery system (DDS) is fabricated and loaded with a small molecule Triapine and a photosensitizer Ce6 to afford TCLMs. TCLMs is highly hepatocyte-targeted due to the specific recognition of lactose by human asialoglycoprotein receptor (ASGPR) and collapses in the acidic microenvironment of cancer cells to release cargos. The employment of Triapine and Ce6 allows a combined chemo-photodynamic therapy (CT-PDT), in which both Triapine and Ce6 act synergistically as boosters of cytotoxic reactive oxygen species (ROS) via Fenton reaction and near-infrared (NIR) light irradiation, respectively. Moreover, Triapine can evoke ferroptosis, a relatively new type of regulated cell death, and PDT is known to enhance ferroptosis mediated by singlet oxygen (1O2). In vitro, TCLMs show enhanced anticancer activity toward hepatocellular carcinoma (HCC) cells than Triapine. In vivo, the tumor-retarding ability of TCLMs outperforms Triapine not only in subcutaneous HCC-bearing mice but also in orthotopic HCC-bearing mice when assisted by an interventional therapy. Importantly, ferroptosis is demonstrated to be an essential mechanism underlying the anti-HCC activity of TCLMs. Collectively, the present work showcases nanomaterials-based DDS as a promising tool for combined CT-PDT against cancer.