基于过氧化氢爆发效应的乏氧实体肿瘤光动力治疗体系构建及活性研究

Cancer stem cells are directly related to cancer recurrence, metastasis, and resistance to radiotherapy and chemotherapy; the cancer will be cured only when all the cancer stem cells are killed. It has attracted great attention in this field of cancer treatment because of its important scientific and practical significance. However, the cancer stem cells are located at the hypoxic part of solid tumor tissue, which makes them hard to be treated by conventional and effective therapies. Finding effective ways to kill the cancer stem cells are very important for cancer treatment. In order to overcome this problem, we will prepare pH-response calcium phosphate drug delivery nanosystem to co-load catalase and zinc phthalocyanine of high hydrogen peroxide burst efficiency in this project. In previous works, the “hydrogen peroxide burst effect” was observed when certain cancer cell lines were induced to apoptosis during photodamage by some phthalocyanine derivatives. The nanosystem can accumulate in tumor tissue through the enhanced permeability and retention (EPR) effect and effectively kill all of the cancer cells, including cancer stem cells in hypoxic position, through the following process: producing hydrogen peroxide after photodynamic therapy, generating catalytic oxygen, resulting oxygen enrichment in hypoxic zone via oxygen diffusion, then photodynamic therapy again, and the repeating of this process is analogous to that of “domino” reaction. The relationship between structure of phthalocyanine derivatives and hydrogen peroxide burst efficiency, the hydrogen peroxide burst mechanism, antitumor activity and influence factors including the types of phosphate calcium, preparation methods of nanosystems, loading modes and drug loading ratios will be studied systematically. Finally, the best system that is suitable for the treatment of hypoxic solid tumors with high activity will be selected for further research.

肿瘤干细胞与肿瘤的复发、转移和放化疗抵抗直接相关，只有杀灭肿瘤干细胞才能彻底治愈癌症。因此，杀灭肿瘤干细胞的研究具有十分重要的意义。本课题针对肿瘤干细胞处于乏氧环境，常规治疗手段难以杀伤这一关键问题，基于申请人课题组前期研究发现的部分锌酞菁光敏损伤肿瘤细胞、诱发其凋亡过程中过氧化氢爆发这一效应，设计合成过氧化氢爆发效果好的酞菁，构建pH响应的磷酸钙共载酞菁及过氧化氢酶的纳米体系。该体系经高渗透长滞留效应在肿瘤组织富集后，通过“光动力治疗产生过氧化氢、催化产氧、氧气扩散使乏氧区富氧、再次光动力治疗……”的类似“多米诺”式治疗过程，实现包括乏氧区肿瘤干细胞在内的所有肿瘤细胞的有效杀灭。项目的开展将明确酞菁结构与过氧化氢爆发效果的关系，阐明过氧化氢爆发机制，获得结构、载药量、载药比及磷酸钙种类等因素对体系自产氧“多米诺”式治疗效果的影响规律，最终优化出适用于体内乏氧实体肿瘤治疗的新型药物体系。

癌症已成为威胁人类健康的重大疾病，寻求高效的治疗方法或治疗药物具有重要的理论及实际意义。因而肿瘤微环境呈现缺氧特征。严重降低PDT、化疗、放疗等疗法的治疗效果。通过催化肿瘤细胞内源的H2O2产生O2，实现肿瘤富氧，是目前广泛应用于解决实体肿瘤乏氧的策略之一。但是肿瘤细胞内源H2O2含量较低，且不同肿瘤细胞中H2O2的含量差异较大，限制了催化产氧缓解乏氧的广谱性。本项目提出四种创新性解决方案：一是诱导细胞内H2O2爆发，进一步增加实体肿瘤细胞内源H2O2的含量，通过引入催化剂催化H2O2产氧，有效缓解实体肿瘤乏氧，促进PDT治疗效果。二是直接携带O2到实体肿瘤部位，缓解肿瘤乏氧。三是设计合成高效催化剂，提升催化H2O2产氧效果，最大限度的利用细胞内的H2O2。四是设计合成具有干扰细胞内缺氧诱导因子表达功能的光敏剂，提升细胞对其PDT治疗的敏感性。项目相关研究成果不仅为乏氧肿瘤光动力治疗体系构建提供新思路和新方法，也为光动力疗法临床治疗实体肿瘤的研究与应用做出有价值的借鉴。