Muradova Zeinaf, Carmès Léna, Brown Needa, Rossetti Fabien, Guthier Romy, Yasmin-Karim Sayeda, Lavelle Michael, Morris Toby, Guidelli Eder Jose, Isikawa Mileni, Dufort Sandrine, Bort Guillaume, Tillement Olivier, Lux François, Berbeco Ross
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02215, USA.
NH TherAguix SA, Meylan, 38240, France.
J Nanobiotechnology. 2025 Jul 1;23(1):466. doi: 10.1186/s12951-025-03542-4.
High atomic number metal-based nanoparticles (NPs) enhance radiotherapy efficacy by improving tumor multimodal imaging and intensifying radiation dosage. AGuIX-Bi represents a theranostic NP comprising gadolinium and bismuth chelates grafted on a polysiloxane core. We hypothesize that modulating the surface of AGuIX-Bi with targeted peptides will enhance the therapeutic responses of radiation therapy. The cyclic Arg-Gly-Asp (cRGD) peptide has a high affinity to RGD-binding integrins overexpressed on various tumor cells, including lung cancer. In the present study, we introduced cRGD peptides onto the surface of AGuIX-Bi NPs using a PEG spacer to form an amide bond with the free amino functions present at the surface of the NPs. In vitro, AGuIX-Bi-cRGD showed enhanced internalization of NPs via integrin binding and increased radiosensitization. In murine Lewis lung carcinoma (LLC) tumors, AGuIX-Bi-cRGD exhibited increased accumulation and retention in tumors without causing systemic toxicity. Combined with fractionated irradiation, AGuIX-Bi-cRGD converted a “cold” LLC tumor microenvironment (TME) into a “hot” one by inducing the overexpression of the immunogenic cell death marker HMGB1 and increasing the density of tumor-infiltrating CD3 CD8 cytotoxic T cells and thereby delaying tumor growth and improving mice survival. Therefore, these results suggest a potential strategy for using targeted AGuIX-Bi-cRGD NPs to sensitize lung tumors to radiation and immunotherapies.
The online version contains supplementary material available at 10.1186/s12951-025-03542-4.
高原子序数金属基纳米颗粒（NPs）通过改善肿瘤多模态成像和增加辐射剂量来提高放疗疗效。AGuIX-Bi是一种治疗诊断纳米颗粒，由接枝在聚硅氧烷核上的钆和铋螯合物组成。我们假设用靶向肽调节AGuIX-Bi的表面将增强放射治疗的治疗反应。环状精氨酸-甘氨酸-天冬氨酸（cRGD）肽对在包括肺癌在内的各种肿瘤细胞上过度表达的RGD结合整合素具有高亲和力。在本研究中，我们使用聚乙二醇间隔物将cRGD肽引入AGuIX-Bi NPs的表面，以与纳米颗粒表面存在的游离氨基官能团形成酰胺键。在体外，AGuIX-Bi-cRGD通过整合素结合显示出纳米颗粒内化增强和放射增敏作用增加。在小鼠Lewis肺癌（LLC）肿瘤中，AGuIX-Bi-cRGD在肿瘤中的积累和滞留增加，而不会引起全身毒性。与分次照射相结合，AGuIX-Bi-cRGD通过诱导免疫原性细胞死亡标志物HMGB1的过度表达和增加肿瘤浸润性CD3 CD8细胞毒性T细胞的密度，将“冷”LLC肿瘤微环境（TME）转变为“热”微环境，从而延缓肿瘤生长并提高小鼠存活率。因此，这些结果提示了一种使用靶向AGuIX-Bi-cRGD NPs使肺肿瘤对放疗和免疫疗法敏感的潜在策略。
在线版本包含可在10.1186/s12951-025-03542-4获取的补充材料。
