Background Solid tumor hypoxic conditions prevent the generation of reactive oxygen species (ROS) and the formation of DNA double-strand breaks (DSBs) induced by ionizing radiation, which ultimately contributes to radiotherapy (RT) resistance. Recently, there have been significant technical advances in nanomedicine to reduce hypoxia by facilitating in situ O 2 production, which in turn serves as a “radiosensitizer” to increase the sensitivity of tumor cells to ionizing radiation. However, off-target damage to the tumor-surrounding healthy tissue by high-energy radiation is often unavoidable, and tumor cells that are further away from the focal point of ionizing radiation may avoid damage. Therefore, there is an urgent need to develop an intelligent targeted nanoplatform to enable precise enhanced RT-induced DNA damage and combined therapy. Results Human epidermal growth factor receptor 2 (Her2)-specific dimeric affibody (Z Her2 ) mediated cisplatin-loaded mesoporous polydopamine/MnO 2 /polydopamine nanoparticles (Pt@mPDA/MnO 2 /PDA-Z Her2 NPs) for MRI and enhanced chemo-radiotherapy of Her2-positive ovarian tumors is reported. These NPs are biodegradable under a simulated tumor microenvironment, resulting in accelerated cisplatin release, as well as localized production of O 2 . Z Her2 , produced using the E. coli expression system, endowed NPs with Her2-dependent binding ability in Her2-positive SKOV-3 cells. An in vivo MRI revealed obvious T 1 contrast enhancement at the tumor site. Moreover, these NPs achieved efficient tumor homing and penetration via the efficient internalization and penetrability of Z Her2 . These NPs exhibited excellent inhibition of tumor growth with X-ray irradiation. An immunofluorescence assay showed that these NPs significantly reduced the expression of HIF-1α and improved ROS levels, resulting in radiosensitization. Conclusions The nanocarriers described in the present study integrated Her2 targeting, diagnosis and RT sensitization into a single platform, thus providing a novel approach for translational tumor theranostics. Graphic abstract
Chordoma presents a formidable therapeutic challenge due to its distinct anatomical location, thus complicating its complete surgical resection coupled with marked resistance to both radiotherapy and chemotherapy. Currently, effective systemic therapies remain unavailable, contributing to a poor prognosis for patients. To address this critical unmet need, we have developed a targeted drug delivery system tailored to the tumor biology of chordoma. This system encapsulates the CDK7 inhibitor THZ1 within nanoparticles featuring diselenide bonds as dual-responsive release triggers. Upon exposure to low-dose X-ray irradiation (e.g., 2 Gy) and to the elevated reactive oxygen species (ROS) level in the tumor microenvironment, these diselenide bonds are cleaved and transformed into selenic acid (RSeOOH), which subsequently initiates rapid carrier disassembly and drug release. The synergy between RSeOOH and THZ1 enhances radiotherapy efficacy by modulating p53 signaling, inducing apoptosis, and promoting G2/M phase cell cycle arrest in U-CH1 cells, thereby overcoming the radiotherapy resistance commonly seen in chordoma. To further improve tumor-specificity, we functionalize the carrier with the EGFR-targeting GE11 peptide, which drives selective drug accumulation at tumor sites. In murine models, this delivery system has demonstrated substantial efficacy in combination with radiochemotherapy and yet produces minimal toxicity. Molecular dynamics simulations have further elucidated carrier self-assembly mechanisms, guiding the rational design of this nanoplatform.
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