Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN 55455, USA.
Curr Pharm Biotechnol. 2011 Aug;12(8):1135-43. doi: 10.2174/138920111796117328.
pH-sensitive liposomes undergo rapid destabilization under mildly acidic conditions such as those found in endocytotic vesicles. Though this makes them promising drug carriers, their application is limited due to their rapid clearance from circulation by the reticulo-endothelial system. Researchers have therefore used pH-sensitive liposomes that are sterically stabilized by polyethylene glycol (PEG) molecules (stealth liposomes) on the liposome surface. The goal of this study is to bring bio-functionality to pH-sensitive PEGylated liposomes in order to facilitate their potential use as a targeted drug delivery agent. To improve the selectivity of these nanoparticles, we included a targeting moiety, PR_b which specifically recognizes and binds to integrin α(5)β(1) expressing cells. PR_b (KSSPHSRN(SG)(5)RGDSP) is a novel fibronectin-mimetic peptide sequence that mimics the cell adhesion domain of fibronectin. Integrin α(5)β(1) is expressed on several types of cancer cells, including colon cancer, and plays an important role in tumor growth and metastasis. We have thoroughly studied the release of calcein from pH-sensitive PEGylated liposomes by varying the lipid composition of the liposomes in the absence and presence of the targeting peptide, PR_b, and accounting for the first time for the effect of both pH and time (photo-bleaching effect) on the fluorescence signal of calcein. We have demonstrated that we can design PR_b-targeted pH-sensitive PEGylated liposomes, which can undergo destabilization under mildly acidic conditions and have shown that incorporating the PR_b peptide does not significantly affect the pH-sensitivity of the liposomes. PR_b-targeted pH-sensitive PEGylated liposomes bind to CT26.WT colon carcinoma cells that express integrin α(5)β(1), undergo cellular internalization, and release their load intracellularly in a short period of time as compared to other formulations. Our studies demonstrate that PR_b-functionalized pH-sensitive targeted delivery systems have the potential to deliver a payload directly to cancer cells in an efficient and specific manner.
pH 敏感脂质体在轻微酸性条件下迅速失稳，如内吞小泡中存在的条件。虽然这使得它们成为有前途的药物载体，但由于它们被网状内皮系统迅速从循环中清除，其应用受到限制。因此，研究人员在脂质体表面使用了由聚乙二醇（PEG）分子稳定的 pH 敏感脂质体（隐形脂质体）。本研究的目的是为 pH 敏感的 PEG 化脂质体赋予生物功能，以便将其潜在用作靶向药物递送剂。为了提高这些纳米粒子的选择性，我们加入了一个靶向部分 PR_b，它特异性地识别并结合表达整合素 α(5)β(1)的细胞。PR_b（KSSPHSRN（SG）（5）RGDSP）是一种新型的纤连蛋白模拟肽序列，模拟纤连蛋白的细胞黏附结构域。整合素 α(5)β(1)在几种类型的癌细胞上表达，包括结肠癌，并在肿瘤生长和转移中发挥重要作用。我们通过改变脂质体的脂质组成，在不存在和存在靶向肽 PR_b 的情况下，深入研究了 calcein 从 pH 敏感的 PEG 化脂质体中的释放，并且首次考虑了 pH 和时间（光漂白效应）对 calcein 荧光信号的影响。我们已经证明，我们可以设计 PR_b 靶向 pH 敏感的 PEG 化脂质体，这些脂质体可以在轻微酸性条件下失稳，并表明掺入 PR_b 肽不会显著影响脂质体的 pH 敏感性。PR_b 靶向 pH 敏感的 PEG 化脂质体与表达整合素 α(5)β(1)的 CT26.WT 结肠癌细胞结合，发生细胞内化，并在短时间内将其负载物释放到细胞内，与其他制剂相比。我们的研究表明，PR_b 功能化 pH 敏感靶向递药系统具有以有效和特异的方式将有效载荷直接递送到癌细胞的潜力。
