Tushe Ada, Marinelli Elena, Musca Beatrice, Ventura Annavera, Zumerle Sara, Slukinova Olga, Zampardi Giulia, Volpin Francesco, Bonaudo Camilla, Della Puppa Alessandro, Repellin Mathieu, Guerriero Giulia, Lollo Giovanna, Mandruzzato Susanna
Veneto Institute of Oncology IOV, IRCCS, Padua, Italy.
Department of Surgery, Oncology and Gastroneterology, University of Padua, Padua, Italy.
Nanomedicine (Lond). 2025 Jun;20(11):1223-1234. doi: 10.1080/17435889.2025.2497747. Epub 2025 May 6.
Glioblastoma multiforme (GBM) is characterized by a highly immunosuppressive tumor microenvironment (TME), posing significant challenges for efficient therapy's outcomes. Nanomedicine combined with immunotherapy holds the potential to modulate the TME and reactivate immune responses. This study proposes a polymeric nanosystem (NPs) encapsulating diaminocyclohexane-platinum II (DACHPt), an oxaliplatin derivative, to induce immunogenic cell death (ICD) in GBM cells.
MATERIALS & METHODS: An ionic-gelation technique was employed to generate polymeric nanoparticles (NPs) with an approximate size of 200 nm. NPs internalization was analyzed in GBM cell lines, -derived macrophages, and in leukocytes and tumor cells from GBM patient via flow cytometry and confocal imaging. ICD was assessed by measuring two of its main markers: adenosine triphosphate (ATP) and high-mobility group box 1 (HMGB1).
NPs were efficiently incorporated by myeloid and tumor cells, but not by lymphocytes. DACHPt-loaded NPs demonstrated enhanced cytotoxicity compared to free drug, with increased ATP and HMGB1 release from GBM cells, confirming ICD induction.
Our findings suggest that DACHPt-loaded NPs represent a promising therapeutic strategy capable of targeting both tumor cells and tumor-promoting immune cells while inducing ICD.
多形性胶质母细胞瘤（GBM）的特征是具有高度免疫抑制性的肿瘤微环境（TME），这给有效治疗的结果带来了重大挑战。纳米医学与免疫疗法相结合有潜力调节TME并重新激活免疫反应。本研究提出一种包裹二氨基环己烷 - 铂II（DACHPt，一种奥沙利铂衍生物）的聚合物纳米系统（NPs），以诱导GBM细胞发生免疫原性细胞死亡（ICD）。
采用离子凝胶技术制备尺寸约为200 nm的聚合物纳米颗粒（NPs）。通过流式细胞术和共聚焦成像分析了GBM细胞系、源自GBM患者的巨噬细胞以及白细胞和肿瘤细胞对NPs的摄取情况。通过测量免疫原性细胞死亡的两个主要标志物：三磷酸腺苷（ATP）和高迁移率族蛋白B1（HMGB1）来评估免疫原性细胞死亡。
NPs能被髓样细胞和肿瘤细胞有效摄取，但不能被淋巴细胞摄取。与游离药物相比，负载DACHPt的NPs表现出增强的细胞毒性，GBM细胞中ATP和HMGB1的释放增加，证实了免疫原性细胞死亡的诱导。
我们的研究结果表明，负载DACHPt的NPs代表了一种有前景的治疗策略，能够在诱导免疫原性细胞死亡的同时靶向肿瘤细胞和促进肿瘤生长的免疫细胞。
