School of Pharmacy and Pharmaceutical Sciences, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK.
Department of Cellular Pathology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Grosvenor Road, Belfast, Northern Ireland BT12 6BA, UK.
Eur J Pharm Biopharm. 2021 Jun;163:49-59. doi: 10.1016/j.ejpb.2021.03.005. Epub 2021 Mar 31.
Sonodynamic therapy (SDT) is an emerging stimulus-responsive approach for the targeted treatment of solid tumours. However, its ability to generate stimulus-responsive cytotoxic reactive oxygen species (ROS), is compromised by tumour hypoxia. Here we describe a robust means of preparing a pH-sensitive polymethacrylate-coated CaO nanoparticle that is capable of transiently alleviating tumour hypoxia. Systemic administration of particles to animals bearing human xenograft BxPC3 pancreatic tumours increases oxygen partial pressures (PO) to 20-50 mmHg for over 40 min. RT-qPCR analysis of expression of selected tumour marker genes in treated animals suggests that the transient production of oxygen is sufficient to elicit effects at a molecular genetic level. Using particles labelled with the near infra-red (nIR) fluorescent dye, indocyanine green, selective uptake of particles by tumours was observed. Systemic administration of particles containing Rose Bengal (RB) at concentrations of 0.1 mg/mg of particles are capable of eliciting nanoparticle-induced, SDT-mediated antitumour effects using the BxPC3 human pancreatic tumour model in immuno-compromised mice. Additionally, a potent abscopal effect was observed in off-target tumours in a syngeneic murine bilateral tumour model for pancreatic cancer and an increase in tumour cytotoxic T cells (CD8) and a decrease in immunosuppressive tumour regulatory T cells [T (CD4, FoxP3)] was observed in both target and off-target tumours in SDT treated animals. We suggest that this approach offers significant potential in the treatment of both focal and disseminated (metastatic) pancreatic cancer.
声动力学疗法（SDT）是一种新兴的刺激响应方法，可用于靶向治疗实体瘤。然而，其产生刺激响应细胞毒性活性氧（ROS）的能力受到肿瘤缺氧的影响。在这里，我们描述了一种制备 pH 敏感的聚甲基丙烯酸酯包覆的 CaO 纳米粒子的有效方法，该纳米粒子能够暂时缓解肿瘤缺氧。将粒子系统地施用于患有人类异种移植物 BxPC3 胰腺肿瘤的动物中，可将氧分压（PO）提高到 20-50mmHg 以上 40 多分钟。对治疗动物中选定的肿瘤标志物基因表达的 RT-qPCR 分析表明，氧气的短暂产生足以在分子遗传水平上产生影响。使用近红外（nIR）荧光染料吲哚菁绿标记的粒子，观察到粒子被肿瘤选择性摄取。以 0.1mg/mg 粒子的浓度系统地给予含有 Rose Bengal（RB）的粒子，能够在免疫功能低下的小鼠中使用 BxPC3 人胰腺肿瘤模型引发纳米粒子诱导的 SDT 介导的抗肿瘤作用。此外，在胰腺癌的同源性双侧肿瘤模型中观察到了明显的远隔效应，在 SDT 治疗的动物中，在靶肿瘤和远隔肿瘤中均观察到肿瘤细胞毒性 T 细胞（CD8）增加和免疫抑制性肿瘤调节性 T 细胞[T（CD4，FoxP3）]减少。我们认为，这种方法在治疗局部和播散性（转移性）胰腺癌方面具有重要的潜力。
