Anti-lung cancer synergy of low-dose doxorubicin and PD-L1 blocker co-delivered via mild photothermia-responsive black phosphorus

• Published in: Drug delivery and translational research 2025, Vol.15 (1), p.269-290
• Main Authors: Xu, Hua-Zhen, Chen, Fei-Xiang, Li, Ke, Zhang, Quan, Han, Ning, Li, Tong-fei, Xu, Yong-Hong, Chen, Yun, Chen, Xiao
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Original Article; Pharmaceutical Sciences/Technology
• ISSN: 2190-393X; 2190-3948
• DOI: 10.1007/s13346-024-01595-w

We have previously identified a latent interaction mechanism between non-small cell lung cancer cells (NSCLCC) and their associated macrophages (TAM) mediated by mutual paracrine activation of the HMGB1/RAGE/NF-κB signaling. Activation of this mechanism results in TAM stimulation and PD-L1 upregulation in the NSCLCC. In the present work, we found that free DOX at a low concentration that does not cause DNA damage could activate the HMGB1/RAGE/NF-κB/PD-L1 pathway byinducing oxidative stress. It was thus proposed that a combination of low-dose DOX and a PD-L1 blocker delivered in the NSCLC tumor would achieve synergistic TAM stimulation and thereby synergetic anti-tumor potency. To prove this idea, DOX and BMS-202 (a PD-L1 blocker) were loaded to black phosphorus (BP) nanoparticles after dosage titration to yield the BMS-202/DOX@BP composites that rapidly disintegrated and released drug cargo upon mild photothermal heating at 40 °C. In vitro experiments then demonstrated that low-dose DOX and BMS-202 delivered via BMS-202/DOX@BP under mild photothermia displayed enhanced tumor cell toxicity with a potent synergism only in the presence of TAM. This enhanced synergism was due to an anti-tumor M1-like TAM phenotype that was synergistically induced by low dose DOX plus BMS-202 only in the presence of the tumor cells, indicating the damaged tumor cells to be the cardinal contributor to the M1-like TAM stimulation. In vivo, BMS-202/DOX@BP under mild photothermia exhibited targeted delivery to NSCLC graft tumors in mice and synergistic anti-tumor efficacy of delivered DOX and BMS-202. In conclusion, low-dose DOX in combination with a PD-L1 blocker is an effective strategy to turn TAM against their host tumor cells exploiting the HMGB1/RAGE/NF-κB/PD-L1 pathway. The synergetic actions involved highlight the value of TAM and the significance of modulating tumor cell-TAM cross-talk in tumor therapy. Photothermia-responsive BP provides an efficient platform to translate this strategy into targeted, efficacious tumor therapy. Graphical Abstract