2. Academic Validation
  3. A multifunctional targeted nano-delivery system with radiosensitization and immune activation in glioblastoma

A multifunctional targeted nano-delivery system with radiosensitization and immune activation in glioblastoma

  • Radiat Oncol. 2024 Sep 12;19(1):119. doi: 10.1186/s13014-024-02511-9.
Xin Wen # 1 2 3,  Zhiying Shao # 1,  Xueting Chen # 1,  Hongmei Liu 4,  Hui Qiu 2,  Xin Ding 2 3,  Debao Qu 1 2,  Hui Wang 1,  Andrew Z Wang 5,  Longzhen Zhang 6 7 8
Affiliations

Affiliations

  • 1 Cancer Institute of Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 2 Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, Kunpeng North Road No. 9, Xuzhou, 221000, Jiangsu, China.
  • 3 Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 4 Department of Biomedical Engineering, Southern University of Science and Technology, 1088 Xueyuan Avenue, Shenzhen, Guangdong, China.
  • 5 Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 6 Cancer Institute of Xuzhou Medical University, Xuzhou, Jiangsu, China. [email protected].
  • 7 Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, Kunpeng North Road No. 9, Xuzhou, 221000, Jiangsu, China. [email protected].
  • 8 Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Jiangsu, China. [email protected].
  • # Contributed equally.
PMID: 39267113 DOI: 10.1186/s13014-024-02511-9
Abstract

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.

Keywords

Blood brain barrier (BBB); Glioblastoma; Immune; Nanoparticle; OX40; Radiosensitization.

Figures
Products