Drug-Delivery Nanoplatform with Synergistic Regulation of Angiogenesis-Osteogenesis Coupling for Promoting Vascularized Bone Regeneration.
Drug-Delivery Nanoplatform with Synergistic Regulation of Angiogenesis-Osteogenesis Coupling for Promoting Vascularized Bone Regeneration.
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DOI：
10.1021/acsami.2c23107
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发表时间：
2023-04
影响因子：
9.5
通讯作者：
Yahong Li;Junjin Zhu;Xin Zhang;Yuanyuan Li;Shu Zhang;Linxin Yang;Ruyi Li;Q. Wan;X. Pei;Junyu Chen;Jian Wang
中科院分区：
文献类型：
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作者：
Yahong Li;Junjin Zhu;Xin Zhang;Yuanyuan Li;Shu Zhang;Linxin Yang;Ruyi Li;Q. Wan;X. Pei;Junyu Chen;Jian Wang
大量的血管化是骨组织工程修复大面积骨缺损的有效策略。局部应用去铁胺（DFO）是促进血管形成的最常见和最有效的方法之一，尽管其在血浆中的半衰期短、清除快和生物相容性差限制了其治疗适用性。本文中，选择沸石咪唑酯骨架-8（ZIF-8）作为载体以延长DFO的半衰期。本研究建立了纳米DFO-ZIF-8（DFO@ZIF-8）药物传递系统，以促进血管生成-骨生成偶联。对纳米颗粒进行表征，并检查其载药效率以确认纳米DFO@ZIF-8的成功合成。此外，由于DFO和Zn 2+的持续释放，DFO@ZIF-8 NP能够促进体外培养的人脐静脉内皮细胞（HUVEC）中的血管生成和骨髓干细胞（BMSC）中的成骨。此外，DFO@ZIF-8 NP通过增强H型血管和血管网络的表达来促进血管形成。DFO@ZIF-8纳米颗粒通过增加OCN和BMP-2的表达促进体内骨再生。RNA测序分析显示，PI 3 K-AKT-MMP-2/9和HIF-1α通路在HUVEC中被DFO@ZIF-8 NPs上调，最终导致新血管的形成。此外，DFO@ZIF-8 NPs促进骨再生的机制可能与MAPK途径的血管生成-骨生成偶联和Zn 2+介导的协同作用有关。综上所述，DFO@ZIF-8纳米颗粒被证明具有低细胞毒性和良好的血管生成和成骨偶联，代表了重建临界尺寸骨缺损的有希望的策略。
It has been confirmed that substantial vascularization is an effective strategy to heal large-scale bone defects in the field of bone tissue engineering. The local application of deferoxamine (DFO) is among the most common and effective methods for promoting the formation of blood vessels, although its short half-life in plasma, rapid clearance, and poor biocompatibility limit its therapeutic suitability. Herein, zeolitic imidazolate framework-8 (ZIF-8) was selected as a vehicle to extend the half-life of DFO. In the present study, a nano DFO-loaded ZIF-8 (DFO@ZIF-8) drug delivery system was established to promote angiogenesis-osteogenesis coupling. The nanoparticles were characterized, and their drug loading efficiency was examined to confirm the successful synthesis of nano DFO@ZIF-8. Additionally, due to the sustained release of DFO and Zn2+, DFO@ZIF-8 NPs were able to promote angiogenesis in human umbilical vein endothelial cells (HUVECs) culture and osteogenesis in bone marrow stem cells (BMSCs) in vitro. Furthermore, the DFO@ZIF-8 NPs promoted vascularization by enhancing the expression of type H vessels and a vascular network. The DFO@ZIF-8 NPs promoted bone regeneration in vivo by increasing the expression of OCN and BMP-2. RNA sequencing analysis revealed that the PI3K-AKT-MMP-2/9 and HIF-1α pathways were upregulated by DFO@ZIF-8 NPs in HUVECs, ultimately leading to the formation of new blood vessels. In addition, the mechanism by which DFO@ZIF-8 NPs promoted bone regeneration was potentially related to the synergistic effect of angiogenesis-osteogenesis coupling and Zn2+-mediation of the MAPK pathway. Taken together, DFO@ZIF-8 NPs, which were demonstrated to have low cytotoxicity and excellent coupling of angiogenesis and osteogenesis, represent a promising strategy for the reconstruction of critical-sized bone defects.