Liu Jinjian, Zhang Yumin, Li Qinghua, Feng Zujian, Huang Pingsheng, Wang Weiwei, Liu Jianfeng
Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.
Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China; Department of Polymer Science and Engineering, Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.
Acta Biomater. 2020 Sep 15;114:133-145. doi: 10.1016/j.actbio.2020.07.032. Epub 2020 Jul 17.
Brachytherapy is considered to be an unparalleled form of conformal radiation therapy, which involves the delivery of radiation directly to tumor lesions or the postoperative cavity. With the development of specific applicators, the exploitation of in situ drug-delivery platform introduces opportunities for the synchronous administration of radiosensitizers. In this study, an iodine-131 (I)-labeled injectable thermosensitive methoxy poly(ethylene glycol)-b-poly(tyrosine) hydrogel (denoted as PETyr-I) was developed via a facile method. The radioactive source of I was immobilized at the subcutaneous injection site and monitored via single-photon emission computed tomography in real time, and hematological and histopathological analyses revealed no obvious side effects. Additionally, the SmacN7 peptide conjugated with cell membrane-permeable oligosarginine (denoted as SmacN7-R9) was used to enhance the radiosensitivity of cancer cells, as confirmed by the results of reactive oxygen species detection, DNA damage assay, cell apoptosis assay, and clonogenic evaluation. Importantly, a synergistic brachytherapy treatment effect on tumor-bearing nude mice was achieved. The proposed thermosensitive supramolecular hydrogel platform, which conformally immobilizes radionuclides and delivers radiosensitizers by virtue of its proximity to the site of the primary tumor or the postoperative cavity, has great potential for achieving synergistic treatment outcomes with reduced radiation-related side effects. STATEMENT OF SIGNIFICANCE: In this work, a kind of radioiodinated thermosensitive supramolecular hydrogel was developed, which was facilely used as the radioactive source for brachytherapy. Meanwhile, SmacN7-R9 peptide was combined as a model radiosensitizer to facilitate the activation of tumor cell apoptosis pathways and promotion of radiation-induced cytotoxicity. Synergistic brachytherapy outcomes were achieved from the in vitro and in vivo evaluations. Therefore, from the practical standpoint, this thermosensitive supramolecular hydrogel platform holds great potential for the 3D-conformally immobilizing radionuclide and delivering radiosensitizer by virtue of its proximity to the site of primary tumor lesions or postoperative cavity, resulting in synergetic treatment outcomes with reduced radiation associated side effects.
近距离放射治疗被认为是一种无与伦比的适形放射治疗形式，它涉及将辐射直接传递到肿瘤病变或术后腔隙。随着特定施源器的发展，原位给药平台的开发为同步施用放射增敏剂带来了机遇。在本研究中，通过一种简便的方法制备了碘-131（I）标记的可注射热敏甲氧基聚（乙二醇）-b-聚（酪氨酸）水凝胶（称为PETyr-I）。将I的放射源固定在皮下注射部位，并通过单光子发射计算机断层扫描进行实时监测，血液学和组织病理学分析显示无明显副作用。此外，与细胞膜穿透性寡聚精氨酸偶联的SmacN7肽（称为SmacN7-R9）用于增强癌细胞的放射敏感性，活性氧检测、DNA损伤测定、细胞凋亡测定和克隆形成评估结果证实了这一点。重要的是，对荷瘤裸鼠实现了协同近距离放射治疗效果。所提出的热敏超分子水凝胶平台，通过靠近原发性肿瘤部位或术后腔隙，以适形方式固定放射性核素并递送放射增敏剂，在实现协同治疗效果并减少与辐射相关的副作用方面具有巨大潜力。重要意义声明：在本工作中，开发了一种放射性碘化热敏超分子水凝胶，它很容易用作近距离放射治疗的放射源。同时，结合SmacN7-R9肽作为模型放射增敏剂，以促进肿瘤细胞凋亡途径的激活和辐射诱导的细胞毒性的增强。通过体外和体内评估实现了协同近距离放射治疗效果。因此，从实际角度来看，这种热敏超分子水凝胶平台凭借其靠近原发性肿瘤病变部位或术后腔隙的特性，在三维适形固定放射性核素和递送放射增敏剂方面具有巨大潜力，从而实现协同治疗效果并减少与辐射相关的副作用。
