2021 11.189 BDDS 葡萄EVs装载 Dox Heparin-Based NPs for Glioma Therapy
DNs，EVs
unprecedented 4-fold drug loading capacity compared to traditional encapsulation for EVs 4倍药物负载能力
a high-abundance accumulation of EV-DNs can be detected at glioma tissues, enabling the maximal brain tumor uptake of EV-DNs and great antiglioma efficacy in vivo 在胶质瘤组织中检测到EV-DNS的高丰度积累，使得最大脑肿瘤摄取EV-DNS和体内巨大的抗抗瘤疗效
he introduction of DNs could improve the retention time of EV-DN2 in a metabolicorgan, thereby facilitating long circulation of EV-DN2 in blood 引入DNS可以改善代谢器官中EV-DN2的保留时间，从而促进EV-DN2在血液中的长循环
heparin was employed to increase the stability and improve the bioavailability of EVs in vivo 肝素提高稳定性和生物利用度
its good anticomplement activation capacity 肝素有良好的抗补体激活能力
promote DOX release in the tumor acidic microenvironment 提高DOX在肿瘤环境的释放
prepared DOX-loaded heparin-based nanoparticles with pH-sensitive property (pHsensitive DNs) into which a pH-sensitive adipic acid dihydrazide (ADH)-DOX (AD) was synthesized using a hydrazone bond to link ADH and DOX 将pH敏感的ADH与DOX相连
cRGD capable of binding with integrin αvβ3 receptor in glioma cells was also conjugated with the carboxyl group of heparin to increase the targeted capacity of DNs cRGD可以和胶质瘤细胞受体αvβ3结合，还能和肝素羧基整合，提高DNs靶向能力
abundant phosphatidylethanolamine (PE) and cell membrane proteins on the grapefruit-derived EVs,they can provide active amino groups to readily react with the additional carboxyl groups of heparin in DNs, thereby patching DNs onto the surface of EVs (to generate EV-DNs) EVs丰富的PE和膜蛋白提供活性氨基能同时和与DNs结合
excellent bypassing BBB/BBTB and penetration ability 优越的跨BBB和渗透能力
135 ± 5 nm, 43 ± 1nm
随DNS浓度增大，粒径变大
似乎证明着粒径的增大不代表无法通过BBB
EV-DN2, 192 ± 7 nm 4倍来源
usually 0.014−0.48 μg of DOX/1 μg o f EVs
EV-DN2 were enriched in EVs’ protein markers (Alix, TSG101, CD81, and CD9) and the lack of endoplasmic reticulum marker (Calnexin) was similar as the purified grapefruit EVs, suggesting that the introduction of DNs did not influence the biological properties of EV-DN2 富集EVS蛋白质标记物（Alix，TSG101，CD81和CD9）以及缺乏内质网标记物（Calnexin),符合植物外泌体
DNS的引入没有影响EV-DN2的生物学性质
EVs
优势
various cell membrane proteins on the surface of EVs 膜蛋白
have natural cellular uptake ability enabling it to more efficiently traverse physiological barrier such as BBB and penetrate dense structural tissue 天然细胞摄取能力
the unique intracellular uptake ability of EVs could promote the internalization of DNs EVS的独特的细胞内摄取能力可以促进DNS的内化
abundant phosphatidylethanolamine (PE) and cell membrane proteins on the grapefruit-derived EVs,they can provide active amino groups to readily react with the additional carboxyl groups of heparin in DNs, thereby patching DNs onto the surface of EVs (to generate EV-DNs) EVs丰富的PE和膜蛋白提供活性氨基能同时和与DNs结合
the ability of EV-DN2 to avoid P-gp efflux pump was attributed to EVs thereby facilitating them to bypass BBB EV-DN2避免P-GP流出泵的能力归因于EVS，从而促进它们绕过BBB
DNS的引入可能部分地影响EV-DN2的膜融合活性(降低
diversely synthetic nanoparticles 合成NPs
优势
easily achieve high drug loading 高负载
convenient surface functionalization 表面修饰容易
controlled release ability 控制药物释放
缺陷
poor blood circulation time 循环时间短
low bypassing BBB efficiency BBB通过率低
inherently compact anatomical structures of brain tissue hinders the delivery efficiency of nanoparticles by classical enhanced permeability and retention (EPR) effect 胶质瘤结构紧凑，阻碍了EPR效应
the EPR effect is relatively weak and limited for brain
glioma treatment
