Enhanced Ferroptosis by Oxygen-Boosted Phototherapy Based on a 2‑in‑1 Nanoplatform of Ferrous Hemoglobin for Tumor Synergistic Therapy

• Published in: ACS nano Vol. 14; no. 3; pp. 3414 - 3425
• Main Authors: Xu, Tian, Ma, Yuying, Yuan, Qinling, Hu, Huixin, Hu, Xinkai, Qian, Zhiyu, Rolle, Janiqua Kyiesha, Gu, Yueqing, Li, Siwen
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 24-03-2020
• Subjects: Animals; Antineoplastic Agents - analysis; Antineoplastic Agents - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell Survival - drug effects; Cells, Cultured; Dose-Response Relationship, Drug; Female; Ferroptosis - drug effects; Hemoglobins - chemistry; Humans; Mice; Mice, Inbred BALB C; Nanoparticles - chemistry; Oxygen - analysis; Oxygen - pharmacology; Photochemotherapy; Photosensitizing Agents - analysis; Photosensitizing Agents - pharmacology; ferroptosis; nanoplatform; synergistic therapy; photodynamic therapy; hemoglobin
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/acsnano.9b09426

Photodynamic therapy (PDT) combined with oxygenating strategies is widely employed in cancer treatment; however, oxygen-boosted PDT has failed to achieve an ideal effect due to the complexity, heterogeneity, and irreversible hypoxic environment generated by tumor tissues. With the emergence of Fe-dependent ferroptosis boasting reactive oxygen species (ROS) cytotoxicity as well, such a chemodynamic approach to cancer therapy has drawn extensive attention. In this study, hemoglobin (Hb) is connected with the photosensitizer chlorin e6 (Ce6) to construct a 2-in-1 nanoplatform (SRF@Hb-Ce6) with Sorafenib (SRF, ferroptosis promotor) loaded, combining oxygen-boosted PDT and potent ferroptosis. Benefiting from the intrinsic presence of Fe capable of binding oxygen, hemoglobin concurrently furnishes oxygen for oxygen-dependent PDT and Fe for Fe-dependent ferroptosis. Furthermore, amphiphilic MMP2-responsive peptide is incorporated into the skeleton of the nanoplatform to ensure drug-release specificity for safety improvement. Correlative measurements demonstrate the potentiation of PDT and ferroptosis with SRF@Hb-Ce6. More importantly, PDT strengthens ferroptosis by recruiting immune cells to secrete IFN-γ, which can sensitize the tumor to ferroptosis in our findings. The therapeutic effect of synergistic treatment with SRF@Hb-Ce6 in vitro and in vivo was proven significant, revealing the promising prospects of combined PDT and ferroptosis therapy with the 2-in-1 nanoplatform.