Department of Oncology and Clinical Research Center, Maoming People's Hospital, Maoming 525000, China; Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China; School of Medicine, Jinan University, Guangzhou 510632, China.
Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.
Carbohydr Polym. 2023 Nov 1;319:121192. doi: 10.1016/j.carbpol.2023.121192. Epub 2023 Jul 10.
Natural polysaccharides, represented by dextran, chitosan, and hyaluronic acid, are widely approved for use as pharmaceutical excipients and are important carrier materials for the design of advanced drug delivery systems, particularly in the field of anticancer drug delivery. The combination of stimuli-activable prodrug based chemotherapy and photodynamic therapy (PDT) has attracted increasing attention. Recent studies have verified the effectiveness of this strategy in the treatment of multiple aggressive cancers. However, in such combination, the stimuli-responsive chemotherapy and PDT have their own problems that need to be overcome. The uneven distribution of endogenous stimuli within tumor tissues makes it difficult for prodrug to be completely activated. And the inadequate tissue penetration depth of external light results in low efficiency of PDT. Aiming at these two bottlenecks, we designed a biocompatible dextran based - multi-component nanomedicine (PCL-NPs) that integrate a chemiluminescence agent luminol, a photosensitizer chlorine e6 (Ce6), and a reactive oxygen species (ROS)-activable thioketal-based paclitaxel (PTX) prodrug. The presence of overexpressed hydrogen peroxide (HO) inside tumor oxidizes the luminol moiety to generate in-situ light for PDT through chemiluminescence resonance energy transfer (CRET). The singlet oxygen (O) produced in this process not only directly kills tumor cells but also amplifies oxidative stress to accelerate the activation of PTX prodrug. We propose that the PCL-NPs have great therapeutic potential by simultaneously enhancing chemotherapy and PDT in a combination therapy.
天然多糖，以葡聚糖、壳聚糖和透明质酸为代表，被广泛认可为药物赋形剂，是设计先进药物传递系统的重要载体材料，特别是在抗癌药物传递领域。基于刺激激活前药的化学疗法和光动力疗法（PDT）的联合治疗引起了越来越多的关注。最近的研究已经验证了这种策略在治疗多种侵袭性癌症方面的有效性。然而，在这种联合治疗中，刺激响应性化学疗法和 PDT 都存在需要克服的自身问题。肿瘤组织内内源性刺激的不均匀分布使得前药难以完全激活。而外部光的组织穿透深度不足导致 PDT 效率低下。针对这两个瓶颈，我们设计了一种基于生物相容性葡聚糖的多组分纳米药物（PCL-NPs），该纳米药物整合了化学发光剂鲁米诺、光敏剂氯 e6（Ce6）和活性氧（ROS）激活的硫代缩酮型紫杉醇（PTX）前药。肿瘤内过表达的过氧化氢（HO）将鲁米诺部分氧化，通过化学发光共振能量转移（CRET）产生原位光用于 PDT。该过程中产生的单线态氧（O）不仅直接杀死肿瘤细胞，还放大氧化应激以加速 PTX 前药的激活。我们提出，PCL-NPs 通过在联合治疗中同时增强化学疗法和 PDT，具有很大的治疗潜力。
