RGD-Targeted Liposome Binding and Uptake on Breast Cancer Cells Is Dependent on Elastin Linker Secondary Structure.
RGD-Targeted Liposome Binding and Uptake on Breast Cancer Cells Is Dependent on Elastin Linker Secondary Structure.
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DOI：
10.1021/acs.bioconjchem.6b00205
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发表时间：
2016-08
影响因子：
4.7
通讯作者：
Eleftheria Veneti;R. Tu;D. Auguste
中科院分区：
文献类型：
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作者：
Eleftheria Veneti;R. Tu;D. Auguste
当设计靶向药物递送载体时，靶向部分和纳米颗粒之间的连接体经常被忽视。我们假设，pH触发的弹性蛋白样肽（ELP）接头的构象变化，重复VPGVG序列，可以改变良好建立的靶向部分精氨酸-甘氨酸-天冬氨酸（RGD）的结合亲和力，这是已知的增强纳米颗粒的递送到肿瘤细胞通过整合素过表达。从血液（pH 7.4）到肿瘤环境（pH 6）的pH变化用于引起ELP接头的构象变化，如圆二色性所述。原子力显微镜证实，相对于pH 7.4，RGD-ELP在pH 6下导致对MDA-MB-231和HCC 1806乳腺癌细胞的更强粘附。对于非肿瘤性MCF-10A细胞系和非靶向GDR-ELP肽，没有测量粘附力随pH的变化。这转化为相对于pH 7.4，在pH 6.0下RGD-ELP修饰的脂质体的显著结合和摄取。这些结果表明ELP接头的pH触发的构象结构将RGD介导的癌细胞靶向从非活性（pH 7.4）转变为活性（pH 6）。ELP二级结构的可逆移位可用于设计具有可调摄取的靶向药物递送载体。
The linker between the targeting moiety and the nanoparticle is often overlooked when engineering targeted drug delivery vehicles. We hypothesized that pH-triggered conformational changes of an elastin-like peptide (ELP) linker, with repeating VPGVG sequences, could alter the binding affinity of the well-established targeting moiety arginine-glycine-aspartic acid (RGD), which is known to enhance the delivery of nanoparticles to tumor cells via integrin overexpression. The pH change from blood (pH 7.4) to the tumor environment (pH 6) was used to elicit a conformational change in the ELP linker, as described by circular dichroism. Atomic force microscopy confirmed that RGD-ELP resulted in stronger adhesion to both MDA-MB-231 and HCC1806 breast cancer cells at pH 6 relative to pH 7.4. No change in adhesion force was measured as a function of pH for the non-neoplastic MCF-10A cell line and the nontargeting GDR-ELP peptide. This translated to significant binding and uptake of RGD-ELP modified liposomes at pH 6.0 relative to pH 7.4. These results indicate that the pH-triggered conformational structure of the ELP linker shifts RGD-mediated cancer cell targeting from non-active (pH 7.4) to active (pH 6). The reversible shift in ELP secondary structure may be used to engineer targeted drug delivery vehicles with tunable uptake.