克服药物投递负载一直是癌症研究中经常被忽略的一个方面。尽管有针对固体肿瘤的所谓“智能药物”的问世，但现实问题是这类药物中有许多都需要高剂量服用，其中还有可能产生毒性，更有甚者，尽管剂量高，也只有很少量的药物能够渗入肿瘤中，因为血管中的药物投递是被动、需要依赖其他条件的。
利用肿瘤成像和蛋白表达记录技术，Jan Schnitzer等人发现膜联蛋白annexin A1的一种裂开形式能够独一无二地集中到人类和啮齿动物的肿瘤血管的细胞膜穴样内陷中。
他们开发出一种特殊的抗体能够以这种膜联蛋白为目标，可让细胞膜穴样内陷快速将抗体从血液中抽出并穿过血管壁，逆浓度梯度地渗透到肿瘤中。
原文摘要：
In vivo proteomic imaging analysis of caveolae reveals pumping system to penetrate solid tumors
Phil Oh, Jacqueline E Testa, Per Borgstrom, Halina Witkiewicz, Yan Li & Jan E Schnitzer
Technologies are needed to map and image biological barriers in vivo that limit solid tumor delivery and, ultimately, the effectiveness of imaging and therapeutic agents. Here we integrate proteomic and imaging analyses of caveolae at the blood-tumor interface to discover an active transendothelial portal to infiltrate tumors. A post-translationally modified form of annexin A1 (AnnA1) is selectively concentrated in human and rodent tumor caveolae. To follow trafficking, we generated a specific AnnA1 antibody that targets caveolae in the tumor endothelium. Intravital microscopy of caveolae-immunotargeted fluorophores even at low intravenous doses showed rapid and robust pumping across the endothelium to enter mammary, prostate and lung tumors. Within 1 h, the fluorescence signal concentrated throughout tumors to exceed the peak levels in blood. This transvascular pumping required the expression of caveolin 1 and annexin A1. Tumor uptake with other antibodies were >100-fold less. This proteomic imaging strategy reveals a unique target, antibody and caveolae pumping system for solid tumor penetration. |
