'Adhesion and release' nanoparticle-mediated efficient inhibition of platelet activation disrupts endothelial barriers for enhanced drug delivery in tumors
'Adhesion and release' nanoparticle-mediated efficient inhibition of platelet activation disrupts endothelial barriers for enhanced drug delivery in tumors
复制标题
“粘附和释放”纳米颗粒介导的血小板激活的有效抑制破坏内皮屏障，增强肿瘤中的药物输送。
DOI：
10.1016/j.biomaterials.2020.120620
复制
发表时间：
2021-01-06
期刊：
影响因子：
14
通讯作者：
Zhang, Qizhi
中科院分区：
文献类型：
--
作者：
Cao, Jinxu;Yang, Peng;Zhang, Qizhi
活化的血小板可以维持肿瘤血管的完整性，从而导致肿瘤灌注有限和纳米颗粒药物的抗肿瘤功效不佳。在此，为了通过抑制静息血小板向活化血小板的转化来破坏肿瘤血管内皮屏障，构建了负载丹参酮IIA（TNA）的TM33肽修饰明胶/油酸纳米颗粒（TM33-GON/TNA）。 TM33-GON/TNA 可以通过特异性结合表面 P-选择素来粘附活化的血小板，并在基质金属蛋白酶 2 (MMP-2) 刺激下将 TNA 释放到细胞外空间，导致局部高 TNA 暴露。因此，在活化血小板周围的局部环境中发生的血小板活化、粘附和聚集被有效抑制，导致肿瘤内皮连接渗漏。因此，TM33-GON/TNA 治疗导致伊文思蓝（大分子标记物）、小尺寸 Nab-PTX（类似于 10 nm）和大尺寸 DOX-Lip（类似于 100 nm）的肿瘤渗透性分别增加 3.2、4.0 和 11.2 倍，而不会提高正常组织的药物递送。最终，TM33-GON/TNA 加上 Nab-PTX 在小鼠胰腺癌模型中表现出优异的抗肿瘤功效，且副作用极小。此外，TM33-GON/TNA诱导的内皮连接破坏在治疗后可逆性恢复，因为血小板数量没有减少，这意味着不良全身出血的风险较低。因此，TM33-GON/TNA 代表了一种临床转化辅助疗法，可放大现有纳米药物在胰腺癌和其他内皮细胞紧密的肿瘤中的抗肿瘤功效。
Activated platelets can maintain tumor vessel integrity, thereby leading to limited tumor perfusion and suboptimal antitumor efficacy of nanoparticle-based drugs. Herein, to disrupt the tumor vascular endothelial barriers by inhibiting the transformation of resting platelets to activated platelets, a TM33 peptide-modified gelatin/oleic acid nanoparticle loaded with tanshinone IIA (TNA) was constructed (TM33-GON/TNA). TM33-GON/TNA could adhere to activated platelets by specifically binding their superficial P-selectin and release TNA into the extra cellular space under matrix metalloproteinase-2 (MMP-2) stimulation, leading to local high TNA exposure. Thus, platelet activation, adhesion, and aggregation, which occur in the local environment around the activated platelets, were efficiently inhibited, leading to leaky tumor endothelial junctions. Accordingly, TM33-GON/TNA treatment resulted in a 3.2-, 4.0-, and 11.2-fold increase in tumor permeation of Evans blue (macromolecule marker), small-sized Nab-PTX (similar to 10 nm), and large-sized DOX-Lip (similar to 100 nm), respectively, without elevating drug delivery to normal tissues. Ultimately, TM33-GON/TNA plus Nab-PTX exhibited superior antitumor efficacy with minimal side effects in a murine pancreatic cancer model. In addition, the TM33-GON/TNA-induced disrupted endothelial junctions were reversibly restored after the treatment because the number of platelets was not reduced, which implies a low risk of the undesirable systemic bleeding. Hence, TM33-GON/TNA represents a clinically translational adjuvant therapy to magnify the antitumor efficacy of existing nanomedicines in pancreatic cancer and other tumors with tight endothelial lining.