To investigate the potential of tumor-targeting photoactivated chemotherapy, a chiral ruthenium-based anticancer warhead, Λ/Δ-[Ru(Ph₂phen)₂(OH₂)₂]²⁺, was conjugated to the RGD-containing Ac-MRGDH-NH₂ peptide by direct coordination of the M and H residues to the metal. This design afforded two diastereoisomers of a cyclic metallopeptide, Λ-[1]Cl₂ and Δ-[1]Cl₂. In the dark, the ruthenium-chelating peptide had a triple action. First, it prevented other biomolecules from coordinating with the metal center. Second, its hydrophilicity made [1]Cl₂ amphiphilic so that it self-assembled in culture medium into nanoparticles. Third, it acted as a tumor-targeting motif by strongly binding to the integrin (K_d = 0.061 μM for the binding of Λ-[1]Cl₂ to α_IIbβ₃), which resulted in the receptor-mediated uptake of the conjugate in vitro. Phototoxicity studies in two-dimensional (2D) monolayers of A549, U87MG, and PC-3 human cancer cell lines and U87MG three-dimensional (3D) tumor spheroids showed that the two isomers of [1]Cl₂ were strongly phototoxic, with photoindexes up to 17. Mechanistic studies indicated that such phototoxicity was due to a combination of photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) effects, resulting from both reactive oxygen species generation and peptide photosubstitution. Finally, in vivo studies in a subcutaneous U87MG glioblastoma mice model showed that [1]Cl₂ efficiently accumulated in the tumor 12 h after injection, where green light irradiation generated a stronger tumoricidal effect than a nontargeted analogue ruthenium complex [2]Cl₂. Considering the absence of systemic toxicity for the treated mice, these results demonstrate the high potential of light-sensitive integrin-targeted ruthenium-based anticancer compounds for the treatment of brain cancer in vivo.

Breast-conserving surgery (BCS) is the standard of care for early breast cancer patients, while the high ratio of reoperation is still a challenge due to inaccurate margin assessments. In patients with locally advanced or advanced breast cancer, radiotherapy is an important treatment for local control or improvement of quality of life. However, enhancing sensitization to radiotherapy is an unmet medical need. To solve the above clinical predicaments, a glutathione (GSH) exhausting virus-like silicon dioxide nanoprobe with Gd coating and folic acid (FA) modification is designed. After loading ICG in the mesopores, the VGd@ICG-FA probe efficiently targets tumor cells with high resolution, due to its virus-like morphology and folate acid anchoring. Especially, the fabricated nanoprobe enables the identification of tiny cancers and navigates precise surgery under NIR-II fluorescence imaging. Moreover, after the nanoprobes enter into the cytoplasm of cancer cells, tetrasulfide linkages in the silica framework are broken under the triggering of high GSH concentrations. In turn, the broken framework exhausts GSH to disrupt intracellular reactive oxygen species (ROS) homeostasis, and Gd produces more ROS under radiotherapy, further activating ferroptosis, and resulting in the enhancement of radiotherapy in breast cancer. Therefore, our nanoprobe exhibits tremendous potential as a NIR-II fluorescence imaging agent with no systematic side effects for precise cancer surgery and nanotherapeutics for boosting radiation sensitivity in future clinical translation of breast cancer.