Lip HoYin, Zetrini Abdulmottaleb, Park Elliya, Cai Ping, Abbasi Azhar Z, Huyan Ting, Alradwan Ibrahim, Rauth Andrew M, Wu Xiao Yu
Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON, M5S 3M2, Canada.
Department of Pharmaceutics, University of Tripoli, Tripoli, Libya.
Drug Deliv Transl Res. 2025 May 19. doi: 10.1007/s13346-025-01873-1.
Breast cancer is the most diagnosed cancer and the second leading cause of cancer death in women. Although treatments with major anti-cancer modalities are largely successful, resistance to treatments including widely applied radiation therapy (RT) can occur due largely to the multifaceted mechanisms in the tumor microenvironment (TME). The present work investigated the ability of Polymer-Lipid-Manganese Dioxide Nanoparticles (PLMD) to overcome hypoxia-associated radioresistant mechanisms and enhance RT-induced immunogenic cell death (ICD) and anti-tumor immunity for inhibiting growth of primary and distant tumors (the abscopal effect). The results showed that PLMD plus RT significantly inhibited the clonogenic survival of murine EMT6 and 4T1 breast cancer cells under hypoxic condition compared to RT alone. Analysis of ICD biomarkers revealed that PLMD profoundly enhanced RT-induced ICD compared to RT alone in EMT6 and 4T1 cells under hypoxic conditions but not under normoxic conditions. In a syngeneic murine breast tumor model with 4T1 orthotopic tumor, the PLMD treatment reduced tumor hypoxia significantly; PLMD + RT combination therapy increased infiltration of cytotoxic CD8 T cells and CD86 macrophages and decreased infiltration of immunosuppressive Tregs and CD163 macrophages, as compared to RT alone. Importantly, the PLMD + RT treatment generated an abscopal effect in a tumor growth experiment using a double-tumor model, where the growth of an untreated tumor was inhibited by treatment of a tumor grown on the opposite side. Overall, the PLMD + RT induced an anti-tumor immune response that inhibited both primary and distant tumor growths and extended median survival in the tumor model.
乳腺癌是女性中诊断出最多的癌症，也是癌症死亡的第二大主要原因。尽管主要抗癌方式的治疗在很大程度上是成功的，但对包括广泛应用的放射治疗（RT）在内的治疗产生耐药性，很大程度上是由于肿瘤微环境（TME）中的多方面机制。本研究调查了聚合物-脂质-二氧化锰纳米颗粒（PLMD）克服缺氧相关放射抗性机制、增强RT诱导的免疫原性细胞死亡（ICD）和抗肿瘤免疫力以抑制原发性和远处肿瘤生长（远隔效应）的能力。结果表明，与单独的RT相比，PLMD加RT在缺氧条件下显著抑制了小鼠EMT6和4T1乳腺癌细胞的克隆形成存活。对ICD生物标志物的分析表明，在缺氧条件下但在常氧条件下并非如此，与单独的RT相比，PLMD在EMT6和4T1细胞中显著增强了RT诱导的ICD。在具有4T1原位肿瘤的同基因小鼠乳腺肿瘤模型中，PLMD治疗显著降低了肿瘤缺氧；与单独的RT相比，PLMD + RT联合治疗增加了细胞毒性CD8 T细胞和CD86巨噬细胞的浸润，并减少了免疫抑制性Tregs和CD163巨噬细胞的浸润。重要的是，PLMD + RT治疗在使用双肿瘤模型的肿瘤生长实验中产生了远隔效应，其中未治疗肿瘤的生长受到对侧生长肿瘤治疗的抑制。总体而言，PLMD + RT诱导了抗肿瘤免疫反应，抑制了原发性和远处肿瘤的生长，并延长了肿瘤模型中的中位生存期。
