Nanoscale Mixed-Ligand Metal–Organic Framework for X-ray Stimulated Cancer Therapy

Concurrent localized radiotherapy and systemic chemotherapy are standards of care for many cancers, but these treatment regimens cause severe adverse effects in many patients. Herein, we report the design of a mixed-ligand nanoscale metal-organic framework (nMOF) with the ability to simultaneously enhance radiotherapeutic effects and trigger the release of a potent chemotherapeutic under X-ray irradiation. We synthesized a new functional quaterphenyl dicarboxylate ligand conjugated with SN38 (H₂QP-SN) via a hydroxyl radical-responsive covalent linkage. Because of the similar length of QP-SN and bis(<i>p</i>-benzoato)porphyrin (DBP) ligands, QP-SN was incorporated into Hf-DBP nMOF to afford a novel multifunctional mixed-ligand Hf-DBP-QP-SN nMOF with good biocompatibility. Hf-DBP-QP-SN not only enhances radiation damage to tumors via a unique radiotherapy-radiodynamic therapy (RT-RDT) process but also increases ·OH generation from radiolysis with electron-dense Hf₁₂ secondary building units (SBUs) to release SN38 from Hf-DBP-QP-SN for chemotherapy. Elevated levels of hydrogen peroxide in the tumor microenvironment further stimulate the release of SN38 by enhancing ·OH generation under X-ray irradiation. With low doses of X-ray irradiation, Hf-DBP-QP-SN suppressed the growth of CT26 colon and 4T1 breast tumors by 93.5% and 95.2%, respectively, without any sign of general toxicity. Our study highlights the potential of using ionizing radiation-mediated chemistry for on-demand activation of nanotherapeutics for synergistic radiotherapy and chemotherapy without causing severe adverse effects.