College of Chemistry and Chemical Engineering of Inner Mongolia University, Inner Mongolia University, Huhhot, 010021, China.
State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.
Small. 2021 Apr;17(13):e2007882. doi: 10.1002/smll.202007882. Epub 2021 Mar 10.
Colorectal cancer (CRC) ranks as the third common and the fourth lethal cancer type worldwide. Immune checkpoint blockade therapy demonstrates great efficacy in a subset of metastatic CRC patients, but precise activation of the antitumor immune response at the tumor site is still challenging. Here a versatile prodrug nanoparticle for second near-infrared (NIR-II) fluorescence imaging-guided combinatory immunotherapy of CRC is reported. The prodrug nanoparticles are constructed with a polymeric oxaliplatin prodrug (PBOXA) and a donor-spacer-acceptor-spacer-donor type small molecular fluorophore TQTCD. The later displays large Stokes shift (>300 nm), fluorescence emission over 1000 nm, and excellent photothermal conversion performance for NIR-II fluorescence imaging-guided photothermal therapy (PTT). The prodrug nanoparticles show seven times higher intratumoral OXA accumulation than free oxaliplatin. TQTCD-based PTT and PBOXA-induced chemotherapy trigger immunogenic cell death of the tumor cells and elicit antitumor immune response in a spatiotemporally controllable manner. Further combination of the prodrug nanoparticle-based PTT/chemotherapy with programmed death ligand 1 blockade significantly promotes intratumoral infiltration of the cytotoxic T lymphocytes and eradicates the CRC tumors. The NIR-II fluorescence imaging-guided immunotherapy may provide a promising approach for CRC treatment.
结直肠癌（CRC）是全球第三大常见癌症，也是第四大致死癌症类型。免疫检查点阻断疗法在一部分转移性 CRC 患者中显示出了很好的疗效，但在肿瘤部位精确激活抗肿瘤免疫反应仍然具有挑战性。本研究报道了一种多功能前药纳米颗粒，可用于 CRC 的第二近红外（NIR-II）荧光成像引导联合免疫治疗。该前药纳米颗粒由聚合奥沙利铂前药（PBOXA）和给体-间隔基-受体-间隔基-给体型小分子荧光团 TQTCD 构建而成。后者具有较大的斯托克斯位移（>300nm）、超过 1000nm 的荧光发射和出色的近红外二区（NIR-II）荧光成像引导光热治疗（PTT）的光热转换性能。与游离奥沙利铂相比，该前药纳米颗粒在肿瘤内的 OXA 积累量高出七倍。基于 TQTCD 的 PTT 和 PBOXA 诱导的化疗以时空可控的方式触发肿瘤细胞的免疫原性细胞死亡，并引发抗肿瘤免疫反应。进一步将基于前药纳米颗粒的 PTT/化疗与程序性死亡配体 1 阻断联合使用，显著促进了肿瘤内细胞毒性 T 淋巴细胞的浸润，并根除了 CRC 肿瘤。NIR-II 荧光成像引导的免疫治疗可能为 CRC 的治疗提供一种很有前景的方法。
