Xue Song, Zhou Xiaojun, Sang Weilin, Wang Cong, Lu Haiming, Xu Yiming, Zhong Yiming, Zhu Libo, He Chuanglong, Ma Jinzhong
Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, 201620, China.
Bioact Mater. 2021 Jan 26;6(8):2372-2389. doi: 10.1016/j.bioactmat.2021.01.017. eCollection 2021 Aug.
Cartilage-targeting delivery of therapeutic agents is still an effective strategy for osteoarthritis (OA) therapy. Recently, scavenging for reactive oxygen species (ROS) and activating autophagy have been increasingly reported to treat OA effectively. In this study, we designed, for the first time, a dual-drug delivery system based on metal organic framework (MOF)-decorated mesoporous polydopamine (MPDA) which composed of rapamycin (Rap) loaded into the mesopores and bilirubin (Br) loaded onto the shell of MOF. The collagen II-targeting peptide (WYRGRL) was then conjugated on the surface of above nanocarrier to develop a cartilage-targeting dual-drug delivery nanoplatform (RB@MPMW). Our results indicated the sequential release of two agents from RB@MPMW could be achieved via near-infrared (NIR) laser irritation. Briefly, the rapid release of Br from the MOF shell exhibited excellent ROS scavenging ability and anti-apoptosis effects, however responsively reduced autophagy activity, to a certain extent. Meanwhile, following the NIR irradiation, Rap was rapidly released from MPDA core and further enhanced autophagy activation and chondrocyte protection. RB@MPMW continuously phosphorylated AMPK and further rescued mitochondrial energy metabolism of chondrocytes following IL-1β stimulation via activating SIRT1-PGC-1α signaling pathway. Additionally, the cartilage-targeting property of peptide-modified nanocarrier could be monitored via Magnetic Resonance (MR) and IVIS imaging. More significantly, RB@MPMW effectively delayed cartilage degeneration in ACLT rat model. Overall, our findings indicated that the as-prepared dual-drug delivery nanoplatform exerted potent anti-inflammation and anti-apoptotic effects, rescued energy metabolism of chondrocytes and prevented cartilage degeneration , which thereby showed positive performance for OA therapy.
治疗剂的软骨靶向递送仍然是骨关节炎（OA）治疗的有效策略。最近，越来越多的报道表明清除活性氧（ROS）和激活自噬可有效治疗OA。在本研究中，我们首次设计了一种基于金属有机框架（MOF）修饰的介孔聚多巴胺（MPDA）的双药递送系统，该系统由负载在介孔中的雷帕霉素（Rap）和负载在MOF壳上的胆红素（Br）组成。然后将II型胶原靶向肽（WYRGRL）偶联在上述纳米载体表面，构建软骨靶向双药递送纳米平台（RB@MPMW）。我们的结果表明，通过近红外（NIR）激光刺激可实现RB@MPMW中两种药物的顺序释放。简而言之，Br从MOF壳中的快速释放表现出优异的ROS清除能力和抗凋亡作用，但在一定程度上会相应降低自噬活性。同时，在近红外照射后，Rap从MPDA核中快速释放，进一步增强自噬激活和软骨细胞保护。RB@MPMW持续磷酸化AMPK，并通过激活SIRT1-PGC-1α信号通路在IL-1β刺激后进一步挽救软骨细胞的线粒体能量代谢。此外，肽修饰的纳米载体的软骨靶向特性可通过磁共振（MR）和IVIS成像进行监测。更重要的是，RB@MPMW有效延缓了前交叉韧带切断（ACLT）大鼠模型中的软骨退变。总体而言，我们的研究结果表明，所制备的双药递送纳米平台具有强大的抗炎和抗凋亡作用，挽救了软骨细胞的能量代谢并防止了软骨退变，从而在OA治疗中表现出积极的效果。
