“砒霜前药”多功能递送系统的构建及其原位激活用于肝癌联合治疗的研究

原发性肝癌死亡率居所有恶性肿瘤第三位，严重危害人类健康。中医常用“以毒攻毒”手段治疗肝癌。中药砒霜属大毒之剂，其有效成分三氧化二砷（As2O3）抗肝癌机制明确，但因其毒副作用明显、体内分布广和单药疗效欠佳等问题在临床上仅起姑息治疗作用。本项目根据砷毒性和药效与价态之间的密切关系，将低毒的砷酸根作为“砒霜前药”，构建“砒霜前药”多功能递送系统，独辟蹊径地利用MnS多功能载体在肿瘤微环境触发下生成的H2S作为还原性激活剂，于肿瘤原位激活“砒霜前药”为砒霜，避免了砒霜在正常组织器官产生毒副作用；同时，MnS多功能载体经原位激活后产生的Mn2+和H2S分别具有化学动力学治疗和气体治疗功能，可协同中药砒霜实现“中药-气体-化学动力学”联合治疗肝癌，提高肝癌治疗效果。本项目为有毒中药砒霜更安全高效靶向联合治疗肝癌及中药的现代化治疗提供新思路、新策略与新方法。

Primary hepatic carcinoma poses a serious threat to human health with the mortality rate ranking the third among all malignant tumors. Traditional Chinese medicine often treats liver cancer by "fighting poison with poison." Arsenic trioxide (As2O3), the active ingredient of traditional Chinese medicine arsenic, is of significant toxicity and has a definite curative effect on liver cancer. However, it can only play a palliative role in clinical application due to its severe side effect, low targeting efficiency, and limited therapeutic efficacy of a single drug. On the basis of the relationship among toxicity, potency and valence of As, the arsenic is designed for "arsenic prodrug" in this project to construct the "arsenic prodrug" loaded MnS multifunctional delivery system, innovatively using the H2S generated from MnS multifunctional nano-carrier under the trigger of the tumor microenvironment as a reductive activator to in situ activate the "arsenic prodrug" into arsenic, which can avoid the toxicity to normal organs; Simultaneously, MnS multifunctional nano-carrier was activated to release manganese ions (Mn2+) with chemodynamic therapeutic effect and hydrogen sulfide (H2S) with gas therapeutic effect, respectively, realizing the synergistic effect of "traditional Chinese medicine, gas therapy, and chemodynamic therapy" with enhanced anti-liver cancer efficacy. This project may provide novel ideas, strategies, and methods for safer and more effective application of toxic traditional Chinese medicine in the synergistic therapy of liver cancer and modern treatment of traditional Chinese medicine.