Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland BT52 1SA, UK.
Department of HPB Surgery, Mater Hospital, Belfast, Northern Ireland BT14 6AB, UK.
J Control Release. 2017 Oct 28;264:333-340. doi: 10.1016/j.jconrel.2017.09.004. Epub 2017 Sep 8.
Photodynamic therapy (PDT) is a clinically approved anti-cancer treatment that involves the activation of an otherwise inactive sensitiser drug with light, which in the presence of molecular oxygen, generates cytotoxic reactive oxygen species (ROS). As oxygen is a key requirement for the generation of ROS in PDT and given the fact that hypoxia is a characteristic of most solid cancerous tumours, treating hypoxic tumours using PDT can be a challenge. In this manuscript, we have prepared a CaO nanoparticle (NP) formulation coated with a pH-sensitive polymer to enable the controlled generation of molecular oxygen as a function of pH. The polymer coat was designed to protect the particles from decomposition while in circulation but enable their activation at lower pH values in hypoxic regions of solid tumours. The oxygen generating capability of the polymer coated NPs was demonstrated in aqueous solution with minimal oxygen produced at pH7.4, whereas it increased significantly when the pH was reduced to 6.2. The polymer coated CaO NPs were also observed to significantly increase tumour pO levels (p<0.05) in mice bearing ectopic human xenograft MIA PaCa-2 pancreatic tumours with an average increase in tumour pO of 6.5mmHg in the period 10-30min following administration. A statistically significant improvement in PDT mediated efficacy (p<0.001) was also observed when the particles were administered to mice bearing the same tumours 20min prior to PDT treatment. These results suggest that the polymer coated CaO NP formulation offers significant potential as an in situ method for oxygen generation to enhance the efficacy of treatments that depend on the presence of oxygen to elicit a cytotoxic effect.
光动力疗法（PDT）是一种临床认可的抗癌治疗方法，涉及用光激活原本不活跃的敏化剂药物，在分子氧存在的情况下，产生细胞毒性活性氧（ROS）。由于氧气是 PDT 中产生 ROS 的关键要求，并且缺氧是大多数实体癌肿瘤的特征，因此使用 PDT 治疗缺氧肿瘤可能是一个挑战。在本文中，我们制备了一种涂有 pH 敏感聚合物的 CaO 纳米颗粒（NP）制剂，以实现分子氧的受控生成，作为 pH 的函数。聚合物涂层的设计目的是在循环过程中保护颗粒免受分解，但能在低 pH 值下在实体瘤的缺氧区域中激活它们。在水溶液中，涂有聚合物的 NPs 的产氧能力得到了证明，在 pH7.4 时产生的氧气最少，而当 pH 降低至 6.2 时，氧气的产生量显著增加。还观察到涂有聚合物的 CaO NPs 显著增加了携带异位人异种移植 MIA PaCa-2 胰腺肿瘤的小鼠的肿瘤 pO 水平（p<0.05），在给药后 10-30 分钟内，肿瘤 pO 平均增加 6.5mmHg。当将这些颗粒施用于携带相同肿瘤的小鼠时，在 PDT 治疗前 20 分钟给药，还观察到 PDT 介导的疗效有统计学显著改善（p<0.001）。这些结果表明，涂有聚合物的 CaO NP 制剂具有作为原位产氧方法的显著潜力，可增强依赖氧气产生细胞毒性作用的治疗方法的疗效。
