Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices , Soochow University , Suzhou , Jiangsu 215123 , China.
ACS Appl Mater Interfaces. 2018 Dec 19;10(50):43493-43502. doi: 10.1021/acsami.8b17684. Epub 2018 Dec 5.
The abundant tumor extracellular matrix (ECM) could result in insufficient tumor retention and ineffective intratumor penetration of therapeutic agents as well as an acidic and hypoxic tumor microenvironment (TME), leading to unsatisfactory therapeutic outcomes for many types of therapies. Therefore, developing strategies to modulate the TME by selectively degrading the condensed ECM may be helpful to improve existing cancer therapies. Herein, collagenase (CLG)-encapsulated nanoscale coordination polymers (NCPs) are synthesized based on Mn and an acid-sensitive benzoic-imine organic linker and then modified by polyethylene glycol (PEG). Upon intravenous (iv) injection, these CLG@NCP-PEG nanoparticles show efficient accumulation within the tumor, in which CLG would be released because of the collapse of NCP structures within the acidic TME. The released CLG enzyme could then specifically degrade collagens, the major component of ECM, leading to a loosened ECM structure, enhanced tumor perfusion, and relieved hypoxia. As a result, the second wave of nanoparticles, chlorin e6 (Ce6)-loaded liposomes (liposome@Ce6), would exhibit enhanced retention and penetration within the tumor. Such phenomena together with relieved tumor hypoxia could then lead to greatly enhanced photodynamic therapeutic effect of liposome@Ce6 for mice pretreated with CLG@NCP-PEG. Our work thus presents a unique strategy for TME modulation using pH-responsive NCPs as smart enzyme carriers.
丰富的肿瘤细胞外基质 (ECM) 可能导致治疗剂在肿瘤内的滞留不足和渗透效果不佳，以及酸性和缺氧的肿瘤微环境 (TME)，从而导致许多类型的治疗效果不理想。因此，开发通过选择性降解致密 ECM 来调节 TME 的策略可能有助于改善现有的癌症治疗方法。本文基于锰和一种酸敏感的苯甲酸亚胺有机配体合成了胶原酶 (CLG) 包封的纳米级配位聚合物 (NCPs)，然后用聚乙二醇 (PEG) 进行修饰。静脉注射 (iv) 后，这些 CLG@NCP-PEG 纳米颗粒在肿瘤内高效积累，由于酸性 TME 中 NCP 结构的崩溃，CLG 会被释放。释放的 CLG 酶随后可以特异性地降解 ECM 的主要成分胶原，导致 ECM 结构松弛、肿瘤灌注增强和缺氧缓解。结果，第二波纳米颗粒，载有氯乙啶 (Ce6) 的脂质体 (liposome@Ce6)，在肿瘤内的保留和渗透能力增强。这种现象以及缓解肿瘤缺氧，可使经 CLG@NCP-PEG 预处理的小鼠的脂质体@Ce6 的光动力治疗效果大大增强。因此，我们的工作提出了一种使用 pH 响应 NCP 作为智能酶载体来调节 TME 的独特策略。
