二聚体 Her2 特异性亲和体介导的顺铂载纳米颗粒用于肿瘤增强化疗-放疗。

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 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) mediated cisplatin-loaded mesoporous polydopamine/MnO/polydopamine nanoparticles (Pt@mPDA/MnO/PDA-Z 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. Z, 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 contrast enhancement at the tumor site. Moreover, these NPs achieved efficient tumor homing and penetration via the efficient internalization and penetrability of Z. 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.

背景：实体瘤缺氧环境会阻止由电离辐射产生的活性氧 (ROS) 和 DNA 双链断裂 (DSB) 的形成，这最终导致放射治疗 (RT) 抵抗。最近，纳米医学在减少缺氧方面取得了重大技术进展，通过促进原位 O 生成来实现这一目标，进而充当“放射增敏剂”，提高肿瘤细胞对电离辐射的敏感性。然而，高能射线对肿瘤周围健康组织的非靶向损伤往往是不可避免的，而且远离电离辐射焦点的肿瘤细胞可能会避免损伤。因此，迫切需要开发一种智能靶向纳米平台，以实现精确增强 RT 诱导的 DNA 损伤和联合治疗。

结果：报告了人表皮生长因子受体 2 (Her2) 特异性二聚体亲和体 (Z) 介导的载顺铂介孔聚多巴胺/MnO/聚多巴胺纳米粒子 (Pt@mPDA/MnO/PDA-Z NPs) 用于 MRI 和增强 Her2 阳性卵巢肿瘤的化疗放疗。这些 NPs 在模拟肿瘤微环境下可生物降解，导致顺铂加速释放，并局部产生 O。使用大肠杆菌表达系统产生的 Z 赋予 NPs 在 Her2 阳性 SKOV-3 细胞中具有 Her2 依赖性结合能力。体内 MRI 显示肿瘤部位明显的 T 对比增强。此外，这些 NPs 通过 Z 的高效内化和穿透能力实现了高效的肿瘤归巢和渗透。这些 NPs 在 X 射线照射下表现出优异的肿瘤生长抑制作用。免疫荧光分析表明，这些 NPs 显著降低了 HIF-1α 的表达并提高了 ROS 水平，从而实现了放射增敏。

结论：本研究中描述的纳米载体将 Her2 靶向、诊断和 RT 增敏集成到一个单一平台中，为转化肿瘤治疗提供了一种新方法。