Chemical and Biological Engineering, Polytechnic Institute of NYU, 6 MetroTech Center, Brooklyn, NY 11201, USA.
Biomaterials. 2010 May;31(15):4409-16. doi: 10.1016/j.biomaterials.2010.01.064. Epub 2010 Feb 26.
To enable selective cell-kill, we designed functionalized lipid vesicles with pH-triggered heterogeneous membranes and encapsulated doxorubicin that exhibit tunable surface topography. These vesicles "hide" (mask) the targeting ligands from their surface during circulation in the blood, and only progressively "expose" these ligands as they gradually penetrate deeper into the tumor interstitium, where after endocytosis they burst release their contents. The stimulus to activate the binding reactivity is the pH gradient between the blood stream (pH 7.4-7.0) and the increasingly acidic pH inside the tumor interstitium (pH 6.7-6.5). Doxorubicin release is activated at the endosomal pH 5.5-5.0. We show that tunable functionalized vesicles exhibit environmentally-dependent (pH-dependent) association with cancer cells resulting in high cell-kill selectivity. When lowering the extracellular pH from 7.4 to 6.5, tunable functionalized vesicles deliver doxorubicin to cancer cells that increases from 41% to 93% of maximum resulting in cancer cell killing that increases from 23 to 71% of maximum, respectively. This proof-of-concept shows the potential of tunable targeted liposomal chemotherapy to selectively kill cancer cells in an environmentally-dependent way.
为了实现选择性细胞杀伤，我们设计了具有 pH 触发的异质膜的功能化脂质体，并包封了多柔比星，其表现出可调表面形貌。这些囊泡在血液循环中“隐藏”（屏蔽）其表面的靶向配体，并且仅当它们逐渐穿透到肿瘤间质深处时，才逐渐“暴露”这些配体，之后它们通过内吞作用爆裂释放其内容物。激活结合反应的刺激是血流（pH7.4-7.0）和肿瘤间质内越来越酸性的 pH（pH6.7-6.5）之间的 pH 梯度。阿霉素的释放是在内涵体 pH5.5-5.0 时被激活的。我们表明，可调功能化囊泡表现出与癌细胞的环境依赖性（pH 依赖性）关联，从而导致高细胞杀伤选择性。当将细胞外 pH 从 7.4 降低至 6.5 时，可调功能化囊泡向癌细胞递增多柔比星的比例从 41%增加至 93%，达到最大值，从而导致癌细胞杀伤率从 23%增加至 71%，分别达到最大值。这一概念验证表明，可调靶向脂质体化疗具有以环境依赖的方式选择性杀伤癌细胞的潜力。
