State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, China.
ACS Appl Mater Interfaces. 2022 Jul 6;14(26):29537-29549. doi: 10.1021/acsami.2c05276. Epub 2022 Jun 26.
Activatable polymeric nanosystems have attracted great interest, and their interactions with endo-exogenous stimulations are highly vital for therapeutic efficacy, which urgently needs systematic study. Herein we focus on systematically investigating these interactions on an enzyme-nanosystem model, the tumor-overexpressed hyaluronidase (HAase) and the doxorubicin-loaded hyaluronic-acid-porphyrin nanoassemblies (DOX@HPNAs), to augment photo-sono-chemo therapies. The HAase degrades the HPNAs in acidic solution at a higher rate than that in neutral solution, which leads to structure disassembly at the nano level, chain cleavage at the molecular level, and strong radiative recovery at the energy level. Upon excitation with light and ultrasound, the enzymatically degraded sample produces ∼2.5 times more singlet oxygen than the HPNAs because of the absence of aggregation-induced quenching and O migration limitation. The nanosystem can be activated by trimodal stimulations (acidity, ultrasound, and HAase), exerting the controllable release behavior and high release content. Moreover, the nanosystem exhibits synergistic effects among efficient photodynamic therapy, high tissue-penetrating sonodynamic therapy, and lasting chemotherapy, which induces significant necrosis and apoptosis of cancer cells. With high compatibility, tumor-targeting ability, and fluorescent-imaging-guided capability, the nanosystem achieves the highest inhibition rate of malignant tumors than the single or dual-modal therapies. Thus, the enzyme-activatable nanosystem enables the therapeutic synergy and also provides insights to develop other polymeric nanosystems.
可激活的聚合物纳米系统引起了极大的关注，它们与内源性和外源性刺激的相互作用对于治疗效果至关重要，这迫切需要系统的研究。在此，我们专注于系统地研究酶-纳米系统模型中的这些相互作用，该模型为肿瘤过表达的透明质酸酶（HAase）和载多柔比星的透明质酸-卟啉纳米组装体（DOX@HPNAs），以增强光声化疗效果。HAase 在酸性溶液中比在中性溶液中以更高的速率降解 HPNAs，导致纳米级结构解体、分子级链断裂和能量级强辐射恢复。在光和超声的激发下，由于不存在聚集诱导猝灭和 O 迁移限制，酶降解的样品比 HPNAs 产生约 2.5 倍的单线态氧。该纳米系统可以通过三模态刺激（酸度、超声和 HAase）进行激活，表现出可控的释放行为和高释放含量。此外，该纳米系统在高效光动力治疗、高组织穿透声动力治疗和持久化疗之间表现出协同作用，诱导癌细胞发生显著的坏死和凋亡。该纳米系统具有高兼容性、肿瘤靶向能力和荧光成像引导能力，其对恶性肿瘤的抑制率高于单一或双重模式治疗。因此，酶激活的纳米系统能够实现治疗协同作用，并为开发其他聚合物纳米系统提供了思路。
