School of Biomedical Engineering, State Key Laboratory of Oncology in South China , Sun Yat-sen University , Guangzhou , Guangdong 510006 , China.
Department of Biological and Environmental Engineering , Cornell University , Ithaca , New York 14853 , United States.
Nano Lett. 2019 May 8;19(5):3256-3266. doi: 10.1021/acs.nanolett.9b00824. Epub 2019 Apr 15.
Breast cancer develops from local tissue but is characterized by a distinct metastatic pattern involving regional lymph nodes and distant organs, which is the primary cause of high mortality in breast cancer patients. Herein, optimal docking nanoparticles (NPs) composed of a laurate-functionalized Pt(IV) prodrug (Pt(lau)), human serum albumin (HSA), and lecithin were predicted by computational modeling, prepared by nanoprecipitation, and validated by fluorescence spectroscopy. As macrophages have been reported to be preferentially recruited by breast cancer, Rex, the exosome spontaneously secreted by murine RAW 264.7 cells, was isolated to encapsulate the NPs. This high-performance delivery system, called NPs/Rex, possessed the desired physicochemical properties, enhanced colloidal stability, and redox-triggered release profile. Investigations of cytodynamics proved that NPs/Rex was internalized through multiple pathways, avoided entrapment by bilayers, and successfully platinized nucleic acids after bioreduction in the cytosol. Intracellular activation of Pt(lau) was confirmed by observing the characteristic effects of cisplatin on cell proliferation and the cell cycle following treatment with NPs/Rex. During in vivo application, the bioinspired Rex coating endowed docking NPs with prolonged blood circulation, smart organ tropism, and enhanced biocompatibility, as well as robust platinum (Pt) chemotherapy for breast cancer cells in orthotopic tumors of fat pads and metastatic nodules of lungs. Therefore, this favorable nanoplatform might provide valuable insight into the derivatization and development of Pt anticancer drugs used currently in the clinic.
乳腺癌起源于局部组织，但具有明显的转移模式，涉及区域淋巴结和远处器官，这是乳腺癌患者高死亡率的主要原因。在此，通过计算建模预测了由月桂酸功能化的 Pt(IV)前药（Pt(lau)）、人血清白蛋白（HSA）和卵磷脂组成的最佳对接纳米颗粒（NPs），通过纳米沉淀法制备，并通过荧光光谱法进行验证。由于已经报道巨噬细胞优先被乳腺癌募集，因此分离出 Rex，即鼠 RAW 264.7 细胞自发分泌的外泌体，以包裹 NPs。这种称为 NPs/Rex 的高性能递药系统具有所需的物理化学性质、增强的胶体稳定性和氧化还原触发的释放特性。细胞动力学研究证明，NPs/Rex 通过多种途径被内化，避免被双层膜捕获，并在细胞质中生物还原后成功地使核酸铂化。通过观察用 NPs/Rex 处理后细胞增殖和细胞周期中顺铂的特征作用，证实了 Pt(lau)的细胞内激活。在体内应用中，仿生 Rex 涂层使对接 NPs 具有延长的血液循环、智能器官趋向性和增强的生物相容性，以及针对脂肪垫原位肿瘤和肺部转移性结节中乳腺癌细胞的强大铂化疗作用。因此，这种有利的纳米平台可能为目前临床上使用的铂类抗癌药物的衍生化和开发提供有价值的见解。
