Cancer Institute of Xuzhou Medical University, Xuzhou, Jiangsu, China.
Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, Kunpeng North Road No. 9, Xuzhou, 221000, Jiangsu, China.
Radiat Oncol. 2024 Sep 12;19(1):119. doi: 10.1186/s13014-024-02511-9.
Glioblastoma (GBM), the most common primary brain malignancy in adults, is notoriously difficult to treat due to several factors: tendency to be radiation resistant, the presence of the blood brain barrier (BBB) which limits drug delivery and immune-privileged status which hampers effective immune responses. Traditionally, high-dose irradiation (8 Gy) is known to effectively enhance anti-tumor immune responses, but its application is limited by the risk of severe brain damage. Currently, conventional dose segmentation (2 Gy) is the standard radiotherapy method, which does not fully exploit the potential of high-dose irradiation for immune activation. The hypothesis of our study posits that instead of directly applying high doses of radiation, which is risky, a strategy could be developed to harness the immune-stimulating benefits of high-dose irradiation indirectly. This involves using nanoparticles to enhance antigen presentation and immune responses in a safer manner. Angiopep-2 (A2) was proved a satisfactory BBB and brain targeting and Dbait is a small molecule that hijack DNA double strand break damage (DSB) repair proteins to make cancer cells more sensitive to radiation. In view of that, the following two nanoparticles were designed to combine immunity of GBM, radiation resistance and BBB innovatively. One is cationic liposome nanoparticle interacting with Dbait (A2-CL/Dbait NPs) for radiosensitization effect; the other is PLGA-PEG-Mal nanoparticle conjugated with OX40 antibody (A2-PLGA-PEG-Mal/anti-OX40 NPs) for tumor-derived protein antigens capture and optimistic immunoregulatory effect of anti-OX40 (which is known to enhance the activation and proliferation T cells). Both types of nanoparticles showed favorable targeting and low toxicity in experimental models. Specifically, the combination of A2-CL/Dbait NPs and A2-PLGA-PEG-Mal/anti-OX40 NPs led to a significant extension in the survival time and a significant tumor shrinkage of mice with GBM. The study demonstrates that combining these innovative nanoparticles with conventional radiotherapy can effectively address key challenges in GBM treatment. It represents a significant step toward more effective and safer therapeutic options for GBM patients.
胶质母细胞瘤（GBM）是成人中最常见的原发性脑恶性肿瘤，由于多种因素，如对辐射的倾向、血脑屏障（BBB）的存在限制了药物输送以及免疫特权状态阻碍了有效的免疫反应，因此治疗难度很大。传统上，高剂量照射（8Gy）被认为可以有效地增强抗肿瘤免疫反应，但由于存在严重脑损伤的风险，其应用受到限制。目前，常规剂量分割（2Gy）是标准的放疗方法，但不能充分发挥高剂量照射对免疫激活的潜力。我们的研究假设，不是直接应用高剂量辐射，这是有风险的，而是可以开发一种策略，以更安全的方式利用高剂量辐射的免疫刺激益处。这涉及使用纳米颗粒以更安全的方式增强抗原呈递和免疫反应。Angiopep-2（A2）已被证明是 BBB 和脑靶向的满意配体，Dbait 是一种小分子，它劫持 DNA 双链断裂损伤（DSB）修复蛋白，使癌细胞对辐射更敏感。有鉴于此，我们创新性地设计了以下两种纳米颗粒来结合胶质母细胞瘤的免疫、辐射抗性和 BBB。一种是与 Dbait 相互作用的阳离子脂质体纳米颗粒（A2-CL/Dbait NPs），用于放射增敏作用；另一种是与 OX40 抗体偶联的 PLGA-PEG-Mal 纳米颗粒（A2-PLGA-PEG-Mal/anti-OX40 NPs），用于捕获肿瘤源性蛋白抗原和发挥抗 OX40 的免疫调节作用（已知抗 OX40 可增强 T 细胞的激活和增殖）。这两种类型的纳米颗粒在实验模型中均表现出良好的靶向性和低毒性。具体来说，A2-CL/Dbait NPs 和 A2-PLGA-PEG-Mal/anti-OX40 NPs 的联合应用导致携带 GBM 的小鼠的存活时间显著延长，肿瘤明显缩小。该研究表明，将这些创新性纳米颗粒与传统放疗相结合，可有效解决 GBM 治疗中的关键挑战。这代表着为 GBM 患者提供更有效和更安全的治疗选择迈出了重要一步。
