The understanding of adhesive interaction at the nanoscale between functionalized nanoparticles and biological cells is of great importance to develop effective theranostic nanocarriers for targeted cancer therapy. Here, we report a combination of experimental and computational approaches to evaluate the adhesion between Triptorelin (a Luteinizing Hormone-Releasing Hormone (LHRH) agonist)-conjugated poly-(ethylene glycol) (PEG)-coated magnetite nanoparticles (Triptorelin-MNPs) and breast cells. The adhesion forces between Triptorelin-MNPs and normal/cancerous breast cells are obtained using atomic force microscopy. The corresponding work of adhesion is then estimated using Johnson-Kendall-Roberts model. Our results demonstrate that Triptorelin-MNPs have a fourteen-fold greater work of adhesion to breast cancer cells than to normal breast cells. In addition, the work of adhesion between Triptorelin-MNPs and breast cancer cells is found to be three times more than that between unmodified MNPs and breast cancer cells. Hence, the experimental observation indicates that Triptorelin ligands facilitate the specific targeting of breast cancer cells. Furthermore, molecular dynamics simulations are performed to investigate the molecular origins of the adhesive interactions. The simulations reveal that the interactions between molecules (e.g. Triptorelin and PEG) and LHRH receptors are dominated by van der Waals energies, while the interactions of these molecules with cell membrane are dominated by electrostatic interactions. Moreover, both experimental and computational results reveal that PEG serves as an effective coating that enhances adhesive interactions to breast cancer cells that over-express LHRH receptors, while reduces the adhesion to normal breast cells. Our results highlight the potential to develop Triptorelin-MNPs into tumor-specific MRI contrast agents and drug carriers.

Statement of Significance

Systematic investigation of adhesive interactions between functionalized nanoparticles and cancer cells is of great importance in developing effective theranostic nanocarriers for targeted cancer therapy. Herein, we use a combination of atomic force microscopy technique and molecular dynamics simulations approach to explore the adhesive interactions at the nanoscale between Triptorelin-conjugated polyethylene glycol (PEG)-coated magnetite nanoparticles and normal/cancerous breast cells. This study characterizes and quantifies the work of adhesion, as well as adhesion forces, at the nanocarrier/cell interfaces, unravels the molecular origins of adhesive interactions and highlights the effectiveness of PEG coatings and Triptorelin ligands in the specific targeting of breast cancer cells. Our findings expand the fundamental understanding of nanoparticle/cell adhesion and provide guidelines for the design of more rational nanocarriers.

对于功能化的纳米颗粒和生物细胞之间的纳米尺度的粘合剂相互作用的理解，对于开发有效的治疗性纳米载体用于靶向癌症治疗具有重要意义。在这里，我们报告实验和计算方法的组合，以评估曲普瑞林（一种促黄体激素释放激素（LHRH）激动剂）-共聚（乙二醇）（PEG）涂层的磁铁矿纳米颗粒（Triptorelin-MNPs）与乳腺细胞。使用原子力显微镜获得曲普瑞林-MNP与正常/癌性乳腺细胞之间的粘附力。然后使用Johnson-Kendall-Roberts模型估计相应的粘附力。我们的结果表明，曲普瑞林-MNP对乳腺癌细胞的粘附作用比对正常乳腺癌细胞的粘附作用大14倍。另外，发现曲普瑞林-MNP与乳腺癌细胞之间的粘附作用是未修饰的MNP与乳腺癌细胞之间的粘附作用的三倍。因此，实验观察表明曲普瑞林配体促进了乳腺癌细胞的特异性靶向。此外，进行分子动力学模拟以研究粘合剂相互作用的分子起源。模拟表明，分子（例如曲普瑞林和PEG）与LHRH受体之间的相互作用以范德华能量为主导，而这些分子与细胞膜的相互作用则以静电相互作用为主导。而且，实验和计算结果均表明，PEG可作为有效的涂层，增强与过度表达LHRH受体的乳腺癌细胞的粘附相互作用，同时降低与正常乳腺癌细胞的粘附力。我们的结果凸显了将曲普瑞林-MNPs开发为肿瘤特异性MRI造影剂和药物载体的潜力。

重要声明

系统化研究功能化的纳米颗粒和癌细胞之间的粘附相互作用对开发有效的治疗性纳米载体用于靶向癌症治疗具有重要意义。在本文中，我们结合使用原子力显微镜技术和分子动力学模拟方法来研究在曲普瑞林偶联的聚乙二醇（PEG）包覆的磁铁矿纳米颗粒与正常/癌性乳腺细胞之间的纳米级粘附相互作用。这项研究表征并量化了纳米载体/细胞界面上的粘附作用以及粘附力，揭示了粘附相互作用的分子起源，并强调了PEG涂层和曲普瑞林配体在乳腺癌细胞特异性靶向中的有效性。