Tumor Microenvironment-Responsive Fe(III)–Porphyrin Nanotheranostics for Tumor Imaging and Targeted Chemodynamic–Photodynamic Therapy

The development of effective and safe tumor nanotheranostics remains a research imperative. Herein, tumor microenvironment (TME)-responsive Fe(III)-porphyrin (TCPP) coordination nanoparticles (FT@HA NPs) were prepared using a simple one-pot method followed by modification with hyaluronic acid (HA). FT@HA NPs specifically accumulated in CD44 receptor-overexpressed tumor tissues through the targeting property of HA and upon endocytosis by tumor cells. After cell internalization, intracellular acidic microenvironments and high levels of glutathione (GSH) triggered the rapid decomposition of FT@HA NPs to release free TCPP molecules and Fe(III) ions. The released Fe(III) ions could trigger GSH depletion and Fenton reaction, activating chemodynamic therapy (CDT). Meanwhile, the fluorescence and photodynamic effects of the TCPP could be also activated, achieving controlled reactive oxygen species (ROS) generation and avoiding side effects on normal tissues. Moreover, the rapid consumption of GSH further enhanced the efficacy of CDT and photodynamic therapy (PDT). The in vivo experiments further demonstrated that the antitumor effect of these nanotheranostics was significantly enhanced and that their toxicity and side effects against normal tissues were effectively suppressed. The FT@HA NPs can be applied for activated tumor combination therapy under the guidance of dual-mode imaging including fluorescence imaging and magnetic resonance imaging, providing an effective strategy for the design and preparation of TME-responsive multifunctional nanotheranostics for precise tumor imaging and combination therapy.