Protease-Sensitive, Polymer-Caged Liposomes: A Method for Making Highly Targeted Liposomes Using Triggered Release
Protease-Sensitive, Polymer-Caged Liposomes: A Method for Making Highly Targeted Liposomes Using Triggered Release
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DOI：
10.1021/nn103362n
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发表时间：
2011-03-01
期刊：
影响因子：
17.1
通讯作者：
Bossmann, Stefan H.
中科院分区：
文献类型：
--
作者：
Basel, Matthew T.;Shrestha, Tej B.;Bossmann, Stefan H.
脂质体已经成为有用的和众所周知的药物递送载体，因为它们能够捕获药物而不对它们进行化学修饰，并且通过增强的渗透和保留（EPR）效应将它们稍微选择性地递送到肿瘤组织。虽然有用，但脂质体制剂仍然不太理想，因为特异性不完美，在肿瘤中的缓慢释放动力学，以及在到达肿瘤部位之前的泄漏。在肿瘤中差异表达的癌症相关蛋白酶（CAPs）最近也作为肿瘤靶向和药物递送的方法获得了关注。通过将EPR效应与CAP敏感性相结合，可以产生特异性更高的脂质体。本文所述的方法通过有意地产生非常不稳定的脂质体（装载有高渗媒介物），随后通过含有癌症相关蛋白酶的共有序列的交联聚合物壳（蛋白酶触发的笼状脂质体）稳定，产生了可以更特异性地靶向的改进的脂质体系统，具有更快的释放动力学和更低的一般泄漏。合成了一种胆固醇锚定的接枝共聚物，由尿激酶纤溶酶原激活剂（uPA）和聚（丙烯酸）的短肽序列组成，并将其掺入高渗透压下制备的脂质体中。在交联的聚合物，蛋白酶触发，笼状脂质体显示出显着的抵抗渗透溶胀和泄漏的内容物。蛋白酶触发的笼状脂质体在uPA的存在下也显示出内容物的显著和实质性差异释放，而裸脂质体在uPA的存在下没有显示出差异效应。因此，开发了具有快速释放动力学的蛋白酶敏感的脂质体系统，其可用于更特异性地靶向肿瘤。
Liposomes have become useful and well-known drug delivery vehicles because of their ability to entrap drugs without chemically modifying them and to deliver them somewhat selectively to tumorous tissue via the enhanced permeation and retention (EPR) effect. Although useful, liposome preparations are still less than ideal because of imperfect specificity, slow release kinetics in the tumor, and leakiness prior to reaching the tumor site. Cancer-associated proteases (CAPs), which are differentially expressed in tumors, have also gained traction recently as a method for tumor targeting and drug delivery. By combining the EPR effect with CAPs sensitivity, a much more specific liposome can be produced. The method described here creates an improved liposome system that can target more specifically, with faster release kinetics and lower general leaking, by deliberately producing a very unstable liposome (loaded with hyperosmotic vehicle) that is subsequently stabilized by a cross-linked polymer shell containing consensus sequences for cancer-associated proteases (protease-triggered, caged liposomes). A cholesterol-anchored, graft copolymer, composed of a short peptide sequence for urokinase plasminogen activator (uPA) and poly(acrylic acid) , was synthesized and incorporated into liposomes prepared at high osmolarities. Upon cross-linking of the polymers, the protease-triggered, caged liposomes showed significant resistance to osmotic swelling and leaking of contents. Protease-triggered, caged liposomes also showed significant and substantial differential release of contents in the presence of uPA, while bare liposomes showed no differential effect in the presence of uPA. Thus a protease-sensitive liposome system with fast release kinetics was developed that could be used for more specific targeting to tumors.