Department of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518000, China.
Nanomedicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
Nano Lett. 2024 Sep 4;24(35):10724-10733. doi: 10.1021/acs.nanolett.4c01610. Epub 2024 Aug 26.
Tumor acidity-driven nanomotors may offer robust propulsion for tumor-specific penetrating drug delivery. Herein, an acidity-actuated poly(amino acid) calcium phosphate (CaP) hybrid nanomotor (PCaPmotor) was designed, using a mPEG-PAsp-PPhe@THZ531 micelle (Poly@THZ) for CaP mineralization accompanied by αPD-L1 antibody encapsulation. Dissolution of the CaP layer in an acidic tumor environment gave off heat energy to propel the nanomotor to augment the cellular uptake and penetration into deeply seated cancer cells while facilitating αPD-L1 release. THZ531 delivered by the PCaPmotor inhibited CDK12 and its down-streamed phosphorylation of RNAP-II to increase the cancer immunogenicity events such as the DNA damage, cell apoptosis, immunogenic cell death, lysosomal function disturbance, and MHC-I upregulation. THZ531 and αPD-L1 cosupplied by PCaPmotor significantly increased the frequency of DCs maturation and intratumoral infiltration of CTLs, but the two free drugs did not. Consequently, the PCaP@THZ/αPD-L1 nanomotor resulted in synergistic anticancer immunotherapy in mice. This acid-actuated PCaPmotor represented a new paradigm for penetrating drug delivery.
肿瘤酸性驱动的纳米马达可为肿瘤特异性穿透药物递送提供强大的推进力。在此，设计了一种酸激活的聚（氨基酸）磷酸钙（CaP）杂化纳米马达（PCaPmotor），使用 mPEG-PAsp-PPhe@THZ531 胶束（Poly@THZ）进行 CaP 矿化，同时包封αPD-L1 抗体。在酸性肿瘤环境中 CaP 层的溶解会释放出热能，从而推动纳米马达，增强细胞摄取和穿透深层癌细胞的能力，同时促进αPD-L1 的释放。PCaPmotor 递送的 THZ531 通过抑制 CDK12 及其下游 RNAP-II 的磷酸化来增加癌症免疫原性事件，如 DNA 损伤、细胞凋亡、免疫原性细胞死亡、溶酶体功能障碍和 MHC-I 上调。PCaP@THZ/αPD-L1 纳米马达联合提供的 THZ531 和αPD-L1 显著增加了 DCs 的成熟频率和 CTLs 在肿瘤内的浸润，但两种游离药物则没有。因此，PCaP@THZ/αPD-L1 纳米马达在小鼠中产生了协同的抗癌免疫治疗效果。这种酸激活的 PCaPmotor 为穿透性药物递送提供了一种新的范例。
