Dimeric Her2-Specific Affibody Mediated Cisplatin-Loaded Nanoparticles for Tumor Enhanced Chemo-Radiotherapy

Abstract Background: Solid tumor hypoxic conditions fails to facilitate reactive oxygen species (ROS) generation and formation of DNA double-strand breaks (DSBs) induced by ionizing radiation, ultimately lead to a crucial role in radiotherapy resistance. Recently, there have been significant technical advances in nanomedicine aid to relieve hypoxia by in situ production of O2, serving as “radiosensitizer” to induce tumor cells more sensitive to ionizing radiation. However, the off-target damage of surrounding healthy tissues caused by such high-energy radiation is often unavoidable and the tumor cells at some distance from the focal spot of ionizing radiation may avoid damage. Therefore, there is an urgent need to exploit an intelligently targeted nanoplatform to integrate both precisely enhance RT-induced DNA damage and combined therapy.Results: Herein, we developed human epidermal growth factor receptor 2 (Her2)-specific dimeric affibody (ZHer2) mediated cisplatin-loaded mesoporous polydopamine/MnO2/polydopamine nanoparticles (Pt@mPDA/MnO2/PDA-ZHer2 NPs) for MRI and enhanced chemo-radiotherapy of Her2-positive ovarian tumor. These NPs are biodegradable under simulated tumor microenvironment, resulting in cisplatin accelerated release, as well as production of O2. ZHer2 produced by the E. coli expression system endowed NPs with Her2-dependent binding ability in the Her2-positive SKOV-3 cells. In vivo MRI studies revealed an obvious T1 contrast enhancement at the tumor site. Moreover, these NPs achieved efficient tumor homing and penetration, attributing to the efficient internalization and penetrability of ZHer2. Under X-Ray irradiation, these NPs exhibited the highest tumor growth inhibition effect. Immunofluorescence assay showed these NPs significantly reduced the expression of HIF-1α and improved ROS level, resulting in radiosensitization. Conclusions: The nanocarriers constructed in this study integrated Her2 targeting, diagnosis, RT sensitization, thus providing a new idea for clinical translation in tumor theranostics.