Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, M5S 3M2 Toronto, ON, Canada.
Departments of Medical Biophysics and Radiation Oncology, University of Toronto, M5G 1L7 Toronto, ON, Canada.
Radiother Oncol. 2022 May;170:213-223. doi: 10.1016/j.radonc.2022.02.026. Epub 2022 Feb 25.
Radiation therapy (RT) is a major modality for the treatment of prostate cancer (PCa), especially castration-resistant PCa (CRPC). However, hypoxia, often seen in PCa tumors, leads to radiation-resistance. This work investigates the effect of a novel oxygen-generating polymer-lipid manganese dioxide nanoparticle (PLMDs) on improving RT outcomes in CRPC xenograft models by modulating the tumor microenvironment (TME) both before and after RT.
Human PC3 and DU145 PCa cells were used to investigate clonogenic inhibition and DNA repair pathways in vitro. Tumor hypoxia and post-RT angiogenesis were evaluated in a PC3-bearing SCID mouse model. PC3 and DU145 xenografts were used to study the efficacy of PLMD in combination with single or fractionated RT.
PLMD plus RT significantly inhibited clonogenic potential, increased DNA double-strand breaks, and reduced DNA damage repair in hypoxic PC3 and DU145 cells as compared to RT alone. PLMD significantly reduced hypoxia-positive areas, hypoxia induced factor 1α (HIF-1α) expression, and protein carbonyl levels (a measure of oxidative stress). Application of PLMD with RT decreased RT-induced angiogenic biomarkers by up to 3-fold. Treatment of the human CRPC xenografts with PLMD plus RT (single or fractionated doses) significantly prolonged median survival of the host compared to RT alone resulting in up to a 40% curative rate.
PLMD treatment modulated TME and sensitized hypoxic human CRPC cells to RT thus enhancing the efficacy of RT. These results confirmed the potential of PLMD as an adjuvant to RT for the treatment of hypoxic CRPC.
放射治疗（RT）是治疗前列腺癌（PCa）的主要手段，尤其是去势抵抗性 PCa（CRPC）。然而，PCa 肿瘤中常出现的缺氧会导致放射抵抗。本研究通过在 RT 前后调节肿瘤微环境（TME），研究了一种新型产氧聚合物-脂质二氧化锰纳米颗粒（PLMDs）对改善 CRPC 异种移植模型中 RT 结果的影响。
使用人前列腺癌细胞 PC3 和 DU145 来研究体外集落抑制和 DNA 修复途径。在 PC3 荷瘤 SCID 小鼠模型中评估肿瘤缺氧和 RT 后血管生成。使用 PC3 和 DU145 异种移植来研究 PLMD 与单次或分次 RT 联合的疗效。
与单独 RT 相比，PLMD 联合 RT 显著抑制了低氧 PC3 和 DU145 细胞的集落形成能力，增加了 DNA 双链断裂，并减少了 DNA 损伤修复。PLMD 显著降低了缺氧阳性区域、缺氧诱导因子 1α（HIF-1α）表达和蛋白羰基水平（氧化应激的一种衡量指标）。与 RT 联合应用 PLMD 可使 RT 诱导的血管生成生物标志物降低多达 3 倍。与单独 RT 相比，PLMD 联合 RT（单次或分次剂量）治疗人类 CRPC 异种移植显著延长了宿主的中位生存时间，使治愈率高达 40%。
PLMD 治疗调节了 TME，并使缺氧的人类 CRPC 细胞对 RT 敏感，从而提高了 RT 的疗效。这些结果证实了 PLMD 作为治疗缺氧性 CRPC 的 RT 辅助剂的潜力。
