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

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Abstract

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.

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The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Funding

This research was supported by the National Natural Science Foundation of China [82272718].

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Author notes

  1. Hua-Zhen Xu and Fei-Xiang Chen contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Donghu Avenue No.185, Wuhan, 430072, China

    Hua-Zhen Xu & Xiao Chen

  2. Department of Biomedical Engineering, Hubei Province Key Laboratory of Allergy and Immune Related Disease, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Donghu Avenue No.185, Wuhan, 430072, China

    Fei-Xiang Chen & Yun Chen

  3. Center for Lab Teaching, School of Basic Medical Sciences, Wuhan University, Donghu Avenue No.185, Wuhan, 430072, China

    Ke Li

  4. Department of Anatomy and Embryology, School of Basic Medical Sciences, Wuhan University, Donghu Avenue No.185, Wuhan, 430072, China

    Quan Zhang

  5. School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Hubei, 442000, China

    Ning Han & Tong-fei Li

  6. Institute of Ophthalmological Research, Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Yong-Hong Xu

  7. Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430072, China

    Xiao Chen

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Contributions

All authors contributed to the conception and design. H-ZX and F-XC conducted experiments in vitro and in vivo. KL, QZ, NH made data analysis. T-FL and Y-HX conducted part of the experiments. YC and XC designed and supervised the work. The first draft of the manuscript was written by XC, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yun Chen or Xiao Chen.

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Xu, HZ., Chen, FX., Li, K. et al. Anti-lung cancer synergy of low-dose doxorubicin and PD-L1 blocker co-delivered via mild photothermia-responsive black phosphorus. Drug Deliv. and Transl. Res. (2024). https://doi.org/10.1007/s13346-024-01595-w

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