Zuo Wenbao, Chen Dengyue, Fan Zhongxiong, Chen Luping, Zhu Zhaoyuan, Zhu Qixin, Zhu Xuan
Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, China.
Department of Biomaterials, College of Materials, Research Center of Biomedical Engineering of Xiamen & Key Laboratory of Biomedical Engineering of Fujian Province & Fujian Provincial Key Laboratory for Soft Functional Materials Research, Xiamen University, Xiamen 361005, China.
Acta Biomater. 2020 Jul 15;111:327-340. doi: 10.1016/j.actbio.2020.04.052. Epub 2020 May 17.
Carrier-free nanotheranostics with high drug loading and no carrier-related toxicity are highly promising cancer therapy agents. However, the limited tumor accumulation and poorly controlled drug release of these nanotheranostics continue to be major challenges that restrict clinical applications. In this study, we develop a tumor-recognizing carrier-free nanotheranostic with light/reactive oxygen species (ROS) cascade-responsiveness for spatiotemporally selective photo-chemotherapy. The nanotheranostic is constructed by co-assembly of the indocyanine green (ICG) photosensitizer and the mannose-thioketal-doxorubicin conjugate (MAN-TK-DOX) (abbreviated as IMTD), efficiently preventing premature DOX leakage during blood circulation while reducing nonspecific damage to normal tissues/cells. Once accumulated in tumor tissues, IMTD rapidly diffuses into cancer cells via lectin receptors-mediated endocytosis. Photoacoustic/fluorescence-imaging-guided laser irradiation induces local hyperthermia and ROS generation in tumor cells, thereby promoting apoptosis. Together, the ICG-generated ROS and the endogenous ROS in cancer cells synergistically enhance DOX release, resulting in more efficient chemotherapeutic effects. The in vitro and in vivo results consistently demonstrate that IMTD achieves superior tumor accumulation, highly controllable drug release, and synergetic photo-chemotherapy. Therefore, the co-assembly of an ROS-sensitive targeting ligand-chemodrug conjugate and a photosensitizer could be used to develop spatiotemporally light-activatable nanotheranostics for precision cancer therapy. STATEMENT OF SIGNIFICANCE: Synergistic phototherapy and chemotherapy have been considered as a promising cancer treatment modality to maximize the therapeutic efficacy. Unfortunately, most nanodrugs consisting of chemotherapeutic drug and photosensitizer suffer from suboptimal tumor accumulation and poorly controlled drug release, which results in reduced therapeutic outcome. In this study, Mannose (MAN) was conjugated to the anticancer drug doxorubicin (DOX) by a ROS-sensitive thioketal linker (TK), the obtained amphiphilic MAN-TK-DOX could serve as an ideal self-carrier material to deliver photosensitizer, thus to achieve high-efficient tumor-targeting, spatiotemporal controlled drug release, and superior antitumor effect. We believe that the ROS-sensitive amphiphilic targeting ligand-chemodrug conjugate could be developed as a universal approach for designing tumor-targeted nanodrugs with precisely controlled drug release.
具有高药物负载量且无载体相关毒性的无载体纳米诊疗剂是极具前景的癌症治疗药物。然而，这些纳米诊疗剂有限的肿瘤蓄积和药物释放控制不佳仍然是限制其临床应用的主要挑战。在本研究中，我们开发了一种具有光/活性氧（ROS）级联响应的肿瘤识别无载体纳米诊疗剂，用于时空选择性光化疗。该纳米诊疗剂通过吲哚菁绿（ICG）光敏剂与甘露糖-硫酮缩醛-阿霉素共轭物（MAN-TK-DOX）（简称为IMTD）共组装构建而成，可有效防止阿霉素在血液循环过程中过早泄漏，同时减少对正常组织/细胞的非特异性损伤。一旦在肿瘤组织中蓄积，IMTD通过凝集素受体介导的内吞作用迅速扩散到癌细胞中。光声/荧光成像引导的激光照射在肿瘤细胞中诱导局部热疗和ROS生成，从而促进细胞凋亡。同时，ICG产生的ROS与癌细胞中的内源性ROS协同增强阿霉素释放，从而产生更有效的化疗效果。体外和体内结果一致表明，IMTD实现了优异的肿瘤蓄积、高度可控的药物释放和协同光化疗。因此，ROS敏感的靶向配体-化学药物共轭物与光敏剂的共组装可用于开发用于精准癌症治疗的时空光激活纳米诊疗剂。重要性声明：协同光疗和化疗被认为是一种有前景的癌症治疗方式，可使治疗效果最大化。不幸的是，大多数由化疗药物和光敏剂组成的纳米药物存在肿瘤蓄积欠佳和药物释放控制不佳的问题，这导致治疗效果降低。在本研究中，甘露糖（MAN）通过ROS敏感的硫酮缩醛连接子（TK）与抗癌药物阿霉素（DOX）共轭，所得两亲性MAN-TK-DOX可作为理想的自载体材料来递送光敏剂，从而实现高效肿瘤靶向、时空可控药物释放和优异的抗肿瘤效果。我们相信，ROS敏感的两亲性靶向配体-化学药物共轭物可作为一种通用方法来设计具有精确药物释放控制的肿瘤靶向纳米药物。
