School of Life Science , Beijing Institute of Technology , No. 5 South Street , Zhong Guan Cun, Beijing 100081 , China.
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering , Chinese Academy of Sciences , 1 North Second Street , Zhong Guan Cun, Beijing 100190 , China.
ACS Nano. 2019 Feb 26;13(2):1469-1478. doi: 10.1021/acsnano.8b07141. Epub 2019 Feb 18.
Although adoptive T-cell therapy has been successful in hematological malignancy treatment, its application in solid tumors remains a great challenge. Here, using a pH-sensitive benzoic-imine bond and inverse electron-demand Diels-Alder cycloaddition, we prepared magnetic nanoclusters (NCs) armed with responsive PD-1 antibody (aP), which could then bind onto effector T cells due to their PD-1 expression. After adoptive transfer, the magnetization and superparamagnetism of NCs enabled us to magnetically recruit effector T cells and aP simultaneously to tumor sites with MRI guidance. Owing to the acidic intratumoral microenvironment, the benzoic-imine bond then hydrolyzed, leading to the release of aP. The therapeutic effects of adoptive T cells and free aP could thus be spatiotemporally coupled. As a result, we achieved inhibition of tumor growth with few side effects, demonstrating the great promise of such a chemical approach for safe and high-performance adoptive T-cell therapy against solid tumors.
虽然过继性 T 细胞疗法在血液恶性肿瘤的治疗中已取得成功，但它在实体瘤中的应用仍然是一个巨大的挑战。在这里，我们使用 pH 敏感的苯甲酸亚胺键和反向电子需求 Diels-Alder 环加成反应，制备了带有响应性 PD-1 抗体 (aP) 的磁性纳米团簇 (NCs)，由于其 PD-1 的表达，NCs 可以结合到效应 T 细胞上。在过继转移后，NCs 的磁化和超顺磁性使我们能够在 MRI 引导下将效应 T 细胞和 aP 同时磁募集到肿瘤部位。由于肿瘤内酸性微环境，苯甲酸亚胺键随后发生水解，导致 aP 的释放。因此，过继 T 细胞和游离 aP 的治疗效果可以时空偶联。结果，我们实现了肿瘤生长的抑制，副作用很少，这表明这种化学方法在安全高效的针对实体瘤的过继性 T 细胞治疗方面具有巨大的应用前景。
