克服藥物投遞負(fù)載一直是癌癥研究中經(jīng)常被忽略的一個(gè)方面。盡管有針對(duì)固體腫瘤的所謂“智能藥物”的問(wèn)世，但現(xiàn)實(shí)問(wèn)題是這類藥物中有許多都需要高劑量服用，其中還有可能產(chǎn)生毒性，更有甚者，盡管劑量高，也只有很少量的藥物能夠滲入腫瘤中，因?yàn)檠苤械乃幬锿哆f是被動(dòng)、需要依賴其他條件的。
利用腫瘤成像和蛋白表達(dá)記錄技術(shù)，Jan Schnitzer等人發(fā)現(xiàn)膜聯(lián)蛋白annexin A1的一種裂開形式能夠獨(dú)一無(wú)二地集中到人類和嚙齒動(dòng)物的腫瘤血管的細(xì)胞膜穴樣內(nèi)陷中。
他們開發(fā)出一種特殊的抗體能夠以這種膜聯(lián)蛋白為目標(biāo)，可讓細(xì)胞膜穴樣內(nèi)陷快速將抗體從血液中抽出并穿過(guò)血管壁，逆濃度梯度地滲透到腫瘤中。
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. |
