Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, PR China.
Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, PR China; Key Laboratory of Biorheological Science and Technology, Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing, 400044, PR China.
Biomaterials. 2021 Aug;275:120990. doi: 10.1016/j.biomaterials.2021.120990. Epub 2021 Jun 24.
The exploration of an intelligent multifunctional imaging-guided therapeutic platform is of great significance because of its ideal delivery efficiency and controlled release. In this work, a tumor microenvironment (TME)-responsive nanocarrier (denoted as MB@MSP) is designed for on-demand, sequentially release of a short D-peptide antagonist of programmed cell death-ligand 1 (named as PPPA-1) and a photosensitizer methylene blue (MB). FeO-Au located in the core of MB@MSP is used as a magnetic resonance imaging and micro-computed tomography imaging contrast agent for noninvasive diagnosis of solid tumors and simultaneous monitoring of drug delivery. The PPPA-1 coated on MB@MSP can be shed due to the cleavage of the peptide substrate by matrix metalloproteinase-2 (MMP-2) that is highly expressed in the tumor stroma, and disulfide bonding is further broken when it encounters high levels of glutathione (GSH) in TME, which finally leads to significant size reduction and charge-reversal. These transitions facilitate penetration and uptake of nanocarriers against tumors. Noticeably, the released PPPA-1 can block the immune checkpoint to create an environment that favors the activation of cytotoxic T lymphocytes and augment the antitumor immune response elicited by photodynamic therapy, thus significantly improving therapeutic outcomes. Studies of the underlying mechanisms suggest that the designed MMP-2 and GSH-sensitive delivery system not only induce apoptosis of tumor cells but also modulate the immunosuppressive tumor microenvironment to eventually augment the suppression tumor metastasis effect of CD8 cytotoxic T cells. Overall, the visualization of the therapeutic processes with comprehensive information renders MB@MSP an intriguing platform to realize the combined treatment of metastatic tumors.
智能多功能成像引导治疗平台的探索具有重要意义，因为它具有理想的输送效率和可控的释放。在这项工作中，设计了一种肿瘤微环境（TME）响应性纳米载体（表示为 MB@MSP），用于按需顺序释放短肽拮抗剂程序性死亡配体 1（命名为 PPPA-1）和光敏剂亚甲蓝（MB）。位于 MB@MSP 核心的 FeO-Au 用作磁共振成像和微计算机断层扫描造影剂，用于无创诊断实体瘤和同时监测药物输送。涂覆在 MB@MSP 上的 PPPA-1 可以由于基质金属蛋白酶-2（MMP-2）切割肽底物而脱落，MMP-2 在肿瘤基质中高度表达，并且当在 TME 中遇到高水平谷胱甘肽（GSH）时，二硫键进一步断裂，最终导致显著的尺寸减小和电荷反转。这些转变促进了纳米载体对肿瘤的穿透和摄取。值得注意的是，释放的 PPPA-1 可以阻断免疫检查点，创造有利于细胞毒性 T 淋巴细胞激活的环境，并增强光动力疗法引起的抗肿瘤免疫反应，从而显著改善治疗效果。对潜在机制的研究表明，设计的 MMP-2 和 GSH 敏感递药系统不仅诱导肿瘤细胞凋亡，而且调节免疫抑制性肿瘤微环境，最终增强 CD8 细胞毒性 T 细胞抑制肿瘤转移的效果。总体而言，具有全面信息的治疗过程可视化使 MB@MSP 成为实现转移性肿瘤联合治疗的一个有趣平台。
