文章摘要：

Elevating intratumoral levels of highly toxic reactive oxygen species (ROS) by nanocatalytic medicine for tumor-specific therapy without using conventional toxic chemodrugs is recently of considerable interest, which, however, still suffers from less satisfactory therapeutic efficacy due to the relatively poor accumulation at the tumor site and largely blocked intratumoral infiltration of nanomedicines. Herein, an ultrasound (US)-triggered dual size/charge-switchable nanocatalytic medicine, designated as Cu-LDH/HMME@Lips, is constructed for deep solid tumor therapy via catalytic ROS generations. The negatively charged liposome outer-layer of the nanomedicine enables much-prolonged blood circulation for significantly enhanced tumoral accumulation, while the positively charged Fenton-like catalyst Cu-LDH released from the liposome under the US stimulation demonstrates much enhanced intratumoral penetration via transcytosis. In the meantime, the co-released sonosensitizer hematoporphyrin monomethyl ether (HMME) catalyze the singlet oxygen (1O2) generation upon the US irradiation, and deep-tumoral infiltrated Cu-LDH catalyzes the H2O2 decomposition to produce highly toxic hydroxyl radical (·OH) specifically within the mildly acidic tumor microenvironment (TME). The efficient intratumoral accumulation and penetration via the dual size/charge switching mechanism, and the ROS generations by both sonosensitization and Fenton-like reactions, ensures the high therapeutic efficacy for the deep tumor therapy by the nanocatalytic medicine.

在不使用常规毒性化学药物的情况下，通过纳米催化药物提高肿瘤内高毒性活性氧(ROS)水平，以进行肿瘤特异性治疗，近年来引起了人们的极大兴趣，然而，由于纳米药物在肿瘤部位的积累相对较差，并且在很大程度上阻断了肿瘤内的浸润，其治疗效果仍不尽如人意。本文构建了一种超声(US)触发双尺寸/电荷可切换的纳米催化药物，命名为Cu-LDH/HMME@Lips，通过催化ROS世代用于深部实体肿瘤治疗。纳米药物外层带负电荷的脂质体可以延长血液循环，从而显著增强肿瘤积聚，而在US刺激下，脂质体释放的带正电荷的fenton样催化剂Cu-LDH通过胞吞作用增强了肿瘤内的渗透。同时，协同释放的声敏剂血卟啉单甲基醚(HMME)在US照射下催化单线态氧(1O2)生成，肿瘤深部浸润的Cu-LDH催化H2O2分解，在轻度酸性肿瘤微环境(TME)内特异性产生高毒羟基自由基(·OH)。通过双大小/电荷开关机制在肿瘤内的高效蓄积和渗透，以及超声敏化和芬顿样反应的ROS生成，确保了纳米催化药物对深部肿瘤的高疗效。