Acidification of the extracellular matrix, an intrinsic characteristic of many solid tumors, is widely exploited for physiologically triggered delivery of contrast agents, drugs, and nanoparticles to tumor. However, pH of tumor microenvironment shows intra- and inter-tumor variation. Herein, we investigate the impact of this variation on pH-triggered delivery of magnetic nanoparticles (MNPs) modified with pH-(low)-insertion peptide (pHLIP). Fluorescent flow cytometry, laser confocal scanning microscopy and transmission electron microscopy data proved that pHLIP-conjugated MNPs interacted with 4T1 cells in two-dimensional culture and in spheroids more effectively at pH 6.4 than at pH 7.2, and entered the cell via clathrin-independent endocytosis. The accumulation efficiency of pHLIP-conjugated MNPs in 4T1 tumors after their intravenous injection, monitored in vivo by magnetic resonance imaging, showed variation. Analysis of the tumor pH profiles recorded with implementation of original nanoprobe pH sensor, revealed obvious correlation between pH measured in the tumor with the amount of accumulated MNPs.

细胞外基质的酸化是许多实体瘤的固有特征，被广泛用于生理触发的造影剂、药物和纳米颗粒向肿瘤的递送。然而，肿瘤微环境的pH值显示肿瘤内和肿瘤间的变化。在此，我们研究了这种变化对 pH 触发的 pH-（低）插入肽（pHLIP）修饰的磁性纳米粒子（MNP）递送的影响。荧光流式细胞术、激光共焦扫描显微镜和透射电子显微镜数据证明，pHLIP 缀合的 MNP 在 pH 6.4 下比在 pH 7.2 下更有效地与二维培养物和球体中的 4T1 细胞相互作用，并通过不依赖网格蛋白的内吞作用进入细胞。通过磁共振成像在体内监测，静脉注射后，pHLIP 缀合的 MNP 在 4T1 肿瘤中的积累效率显示出变化。对使用原始纳米探针 pH 传感器记录的肿瘤 pH 曲线进行分析，发现肿瘤中测量的 pH 值与累积的 MNP 量之间存在明显的相关性。