文献：Homologous and Mitochondrial Targeting Synergistic Induction of Apoptosis and Ferroptosis Enhanced PDT Performance Against Osteosarcoma HOS

文献链接：

作者：Yang Wang，Liang Zhang，Guosheng Zhao，Yuan Zhang，Fangbiao Zhan，Zhiyu Chen，Tao He，Yang Cao，Lan Hao，Zhigang Wang，Zhengxue Quan，Yunsheng Ou

相关产品：PEG-PLGA（聚乙二醇-聚乳酸-羟基乙酸共聚物）

原文摘要：

Background: There have been no prominent advancements in osteosarcoma (OS) treatment in the past 20 years. Although photodynamic therapy (PDT) is an emerging technique for cancer therapy, its lack of targeting in OS treatment severely limits its applications.

Methods: In this study, we constructed a potential theranostic nanoplatform by using (poly (ethylene glycol) polylactic-co-Glycolic acid (PEG-PLGA) nanoparticles (NPs) wrapping IR780 into the core (PEGPLGA-IR780 NPs), which was further camoufl aged with human OS cell membranes from the HOS cell line(MH-PEG-PLGA-IR780 NPs) to show homologous and mitochondrial targeting capacities. In addition, the potential underlying anticancer mechanisms of MH-PEG-PLGA-IR780 NPs-mediated PDT was investigated.

Results: We demonstrated that the MH-PEG-PLGA-IR780 NPs had excellent tumor/mitochondrial targeting with the help of homologous targeting to HOS cell line. Moreover, the excellent photoacoustic (PA)/fl uorescence (FL) imaging ability of MH-PEG-PLGA-IR780 NPs laid a foundation for further applications. Under near-infrared (NIR) irradiation, we demonstrated that dual-targeting NPs-mediated PDT could signifi cantly induce HOS cell apoptosis and ferroptosis, and further explored apoptosis was triggered by cytochrome c-activated mitochondrial apoptosis (endogenous apoptosis), and the specifi c molecular mechanisms of ferroptosis is the activation of NCOA4-mediated ferritinophagy and the passivation of GPX4 in vitro, synergistically leading to the excessive accumulation of ROS. In addition,MH-PEG-PLGA-IR780 NPs-induced PDT also showed an obvious inhibitory effect on tumor growth in vivo.

Conclusion: These results suggest the dual-targeting-based theranostic nanoplatform provides an effective method to improve PDT performance in OS and paves a new and promising way for OS therapy.  

PEG-PLGA：PEG 即聚乙二醇（Polyethylene Glycol），是一种由环氧乙烷聚合而成的线性聚合物。它的化学结构简单，分子链上有大量的醚键（-O-），这种结构使得 PEG 具有良好的亲水性。PLGA 是聚乳酸-羟基乙酸共聚物（Poly (lactic - co - glycolic acid)），它是由乳酸（Lactic Acid）和羟基乙酸（Glycolic Acid）通过缩聚反应形成的。乳酸有 L - 乳酸和 D - 乳酸两种异构体，不同异构体的比例以及乳酸和羟基乙酸的比例都会影响 PLGA 的性能。比如，当羟基乙酸比例较高时，PLGA 的亲水性会增强，降解速度也会加快。基于PEG-PLGA的性质，MH-PEG-PLGA-IR780 NPs的合成如下：

图：PEG-PLGA结构式

MH-PEG-PLGA-IR780 NPs的合成：

i)将PEG-PLGA和IR780溶解在二氯甲烷中，然后使用超声波探针乳化阳离子。随后，将聚乙烯醇（PVA）加入乳化溶液中，经第二次超声处理均质，形成W/O/W双乳液。然后，将异丙醇溶液加入制备的乳液中，机械搅拌去除二氯甲烷，然后离心，得到PEG-PLGAIR780 NPs。

ii)为制备HOS细胞膜，HOS细胞在T-75培养液中培养，要求完全融合。用EDTA磷酸盐缓冲盐水（PBS）分离，在PBS中洗涤。随后，细胞溶解膜和细胞质蛋白提取包包含PMSF，反复冻融循环后离心收集细胞上清液，最后，离心一段时间后的沉淀为HOS细胞膜（MH）。

iii) MH-PEG-PLGA-IR780 NPs最终通过物理挤压相同浓度的PEG-PLGA-IR780 NPs和MH的混合物多次通过聚碳酸酯多孔膜合成IR780NPs。最终产品储存在4°C下，以供以后使用。

图：表征图像

结论：

该文献成功制备出基于PEG-PLGA合成的MH-PEG-PLGA-IR780 NPs。实验表明，MH-PEG-PLGA-IR780 NPs具有良好的tumour/线粒体靶向性，还具有良好的光声（PA）/荧光（FL）成像能力。此外，MH-PEG-PLGA-IR780 NPs 诱导的PDT在体内对tumour生长也有明显的抑制作用。