Tianjin Key Laboratory of Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 300072, China.
J Mater Chem B. 2019 Apr 21;7(15):2499-2511. doi: 10.1039/c9tb00089e. Epub 2019 Mar 18.
Photothermal therapy (PTT) has shown promising potential and bright prospects in damaging primary tumors; however, it is limited to metastatic and recrudescent tumors as PTT requires straightforward light irradiation. Moreover, metastatic and recrudescent tumor immunosuppression due to host T-cell antitumor activity is dramatically impeded because of programmed cell death 1 ligand (PD-L1) and programmed cell death receptor 1 (PD-1) pathways and immune checkpoint blockade (ICB) therapy. In this work, we demonstrate that PTT combined with ICB could not only eliminate primary tumors, but also prevent tumor metastasis to the lungs/liver. In particular, we have designed immunoadjuvant nanomedicine carriers on the basis of polydopamine (PDA) simultaneously loaded with resiquimod (R848)-a kind of toll-like receptor 7 (TLR7) agonist-and carbon dots (CDs)-a fluorescent agent. This nanomedicine is defined as PDA-PEG-R848-CD nanoparticle (NP). The multitasking PDA-PEG-R848-CD NPs can destroy 4T1 breast tumors by PTT under near-infrared laser irradiation in addition to generating tumor-associated antigens. Moreover, the PTT effect triggered the release of R848, thereby inducing a strong antitumor immune response. Meanwhile, this synergistic therapy also shows the abscopal effects by completely inhibiting the growth of untreated distant tumors by effectively triggering the tumors infiltrated by CD3/CD8. Such findings suggest that PDA-PEG-R848-CD NPs could significantly potentiate the systemic therapeutic efficiency of PD-L1 checkpoint blockade therapy by activating both innate and adaptive immune systems in the body.
光热疗法（PTT）在破坏原发性肿瘤方面显示出了巨大的潜力和广阔的前景；然而，它仅限于转移性和复发性肿瘤，因为 PTT 需要直接的光照射。此外，由于程序性细胞死亡 1 配体（PD-L1）和程序性细胞死亡受体 1（PD-1）途径以及免疫检查点阻断（ICB）治疗，宿主 T 细胞抗肿瘤活性导致转移性和复发性肿瘤的免疫抑制作用受到严重阻碍。在这项工作中，我们证明了 PTT 联合 ICB 不仅可以消除原发性肿瘤，还可以防止肿瘤转移到肺部/肝脏。特别是，我们基于聚多巴胺（PDA）设计了免疫佐剂纳米药物载体，同时负载了雷西莫德（R848）——一种 Toll 样受体 7（TLR7）激动剂和碳点（CDs）——一种荧光剂。这种纳米药物被定义为 PDA-PEG-R848-CD 纳米颗粒（NP）。多功能 PDA-PEG-R848-CD NPs 可以在近红外激光照射下通过 PTT 破坏 4T1 乳腺癌肿瘤，同时产生肿瘤相关抗原。此外，PTT 效应触发了 R848 的释放，从而引发了强烈的抗肿瘤免疫反应。同时，这种协同治疗也通过有效地触发浸润性 CD3/CD8 的肿瘤，显示出非靶区效应，从而完全抑制未治疗的远处肿瘤的生长。这些发现表明，PDA-PEG-R848-CD NPs 通过激活体内固有和适应性免疫系统，可显著增强 PD-L1 检查点阻断治疗的全身治疗效果。
