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SCIENCE CHINA Materials, Volume 61, Issue 11: 1484-1494(2018) https://doi.org/10.1007/s40843-018-9238-6

Macrophages loaded CpG and GNR-PEI for combination of tumor photothermal therapy and immunotherapy

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  • ReceivedFeb 7, 2018
  • AcceptedMar 3, 2018
  • PublishedMar 27, 2018

Abstract

Nano-therapeutic approach for clinical implementation of tumors remains a longstanding challenge in the medical field. The main challenges are rapid clearance, off-target effect and the limited role in the treatment of metastatic tumors. Toward this objective, a cell-mediated strategy by transporting photothermal reagents and CpG adjuvant within macrophage vehicles is performed. The photothermal reagents are constructed by conjugating of hyperbranched polyethyleimine (PEI) to golden nanorode (GNR) via S-Au bonds. GNR-PEI/CpG nanocomposites, formed via electrostatic interaction and displayed excellent near-infrared (NIR) photothermal performance, exhibit immense macrophage uptake and negligible cytotoxic effect, which is essential for the fabrication of GNR-PEI/CpG loaded macrophages. GNR-PEI/CpG loaded macrophages demonstrated admirable photothermal response in vitro. Benefited from the functionalization of the binding adhesion between macrophages and 4T1 cells, GNR-PEI/CpG loaded macrophages significantly promoted tumor accumulation in vivo and dramatically enhanced the efficiency of photothermal cancer therapy. Moreover, the immune system is activated after photothermal therapy, which is mainly attributed to the generation of tumor specific antigens and CpG adjuvant in situ. Our findings provide a potential cell-mediated nanoplatform for tumor therapy by combination of near infrared photothermal therapy and immunotherapy.


Funded by

the National Natural Science Foundation of China(51390484,21474104,51403205,51503200,51520105004)

National program for support of Top-notch young professionals

Jilin province science and technology development program(20160204032GX,20180414027GH)


Acknowledgment

This work was financially supported by the National Natural Science Foundation of China (51390484, 21474104, 51403205, 51503200 and 51520105004), National program for support of Top-notch young professionals, and Jilin province science and technology development program (20160204032GX, 20180414027GH).


Interest statement

The authors declare no conflict of interest.


Contributions statement

Chen J, Yan N and Guo Z designed and synthesized the samples; Chen J, Lin L, Hu Y, Fang H and Sun P performed the experiments; Chen J wrote the paper with support from Tian H and Chen X. All authors contributed to the general discussion.


Author information

Jie Chen, born in 1982, is currently an associate professor in Changchun Institute of Applied Chemistry, Chinese Academy of Sciences. His research interests are focused on gene delivery and immunotherapy. He has published more than 50 papers in SCI journals and 5 Chinese invention patents.


Lin Lin, born in 1982, is currently an assistant professor in Changchun Institute of Applied Chemistry, Chinese Academy of Sciences. Her research interests are focused on gene carriers design and evaluation. She has published more than 20 papers in SCI journals and 3 Chinese invention patents.


Huayu Tian was born in 1977. Currently, he is a professor in Changchun Institute of Applied Chemistry, Chinese Academy of Sciences. His research interests are focused on polymeric carriers for gene diagnosis and combinational therapy. He published more than 100 papers in SCI journals, such as Progress in Polymer Science, Nano Letters, Biomaterials and Small. He was authorized 15 Chinese invention patents. He was funded by the National Natural Science Funds for excellent Young Scholar and selected for National Program for support of Top-notch Young Professionals.


Xuesi Chen was born in 1959. Currently, he is a professor in Changchun Institute of Applied Chemistry, Chinese Academy of Sciences. His research interests are focused on polymers chemistry on biomedical polymers, drug/gene controlled released carriers designed by biodegradable polymers, bone repair parts and tissue engineering scaffolds from biodegradable polymers. He published more the 500 papers in SCI journals, such as Progress in Polymer Science, Advanced Materials, Advanced Functional Materials, Advanced Drug Delivery Review, and Nano Letters. He was authorized more than 110 Chinese invention patents.


Supplement

Supplementary information

Supporting data are available in the online version of the paper.


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  • Scheme 1

    Macrophages loaded GNR-PEI/CpG for tumor treatment by combination of photothermal therapy and immunotherapy.

  • Figure 1

    Synthesis route of GNR-PEI.

  • Figure 2

    The geometric morphology and absorption spectra of GNR-PEI and GNR-PEI/CpG. TEM images of (a) GNR-PEI and (b) GNR-PEI/CpG (scale bar = 200 nm), (c) UV-vis absorption spectra of GNR-PEI and GNR-PEI/CpG (the final concentration of GNR-PEI was 20 µg mL−1), (d) TGA curves of GNR and GNR-PEI.

  • Figure 3

    Cytocompatibility of GNR-PEI/CpG in RAW264.7 cells.

  • Figure 4

    Cellular uptake of GNR-PEI/CpG in RAW264.7 cells. (a) Flow cytometry analysis of cellular uptake of GNR-PEI/CpG at different incubation time. (b) Cellular uptake of GNR-PEI/CpG for 5 h, the commercial PEI25k was used as the control. (c) CLSM observation of the cellular uptake of GNR-PEI/CpG and PEI25k/CpG for 5 h. The final concentration of GNR-PEI was 20 µg mL−1. CpG was labeled with carboxyfluorescein (FAM, green) and the nucleus was labeled with DAPI (blue). Scale bar is 50 µm.

  • Figure 5

    Photothermal effect of GNR-PEI/CpG-laden-RAW264.7 cells. (a) RAW264.7 cells were incubated with GNR-PEI/CpG for 5 h and the thermographic monitoring was measured in the conditions of different cell numbers and laser intensity. (b) Calcein AM/PI staining (live cells were stained green with Calcein AM and dead cells were stained red with PI), the scale bar is 200 µm. (c) Cell apoptosis analysis (apoptotic cells were stained with Annexin V-FITC and dead cells were stained with PI).

  • Figure 6

    The effects of conditioned extracellular secretions (ES) on 4T1 tumor cells. Data represent mean ± SD with four replicates. **P<0.01.

  • Figure 7

    The in vitro migration effect of RAW264.7 cells. (a) Migration assays were performed using transwell chambers, (b) tumor cell tropism assay of macrophages. Macrophages were labeled with CFSE (green) and other cells were labeled with DIR (red). The overlapping cells were marked in circles (white circles). The scale bar is 50 µm.

  • Figure 8

    In vivo photothermal effect of GNR-PEI/CpG-laden-macrophages. The 4T1 tumor-bearing Balb/c mice were intravenous injected with PBS and GNR-PEI/CpG-laden-macrophages. Afterwards, the thermographic images and temperature change of tumor sites were measured after NIR irradiation (1.0 W cm−2, 10 min). The near-infrared thermographic images were captured after 240 s of tumor-bearing mice after NIR irradiation: (a) PBS, (b) GNR-PEI/CpG-laden-macrophages. (c) Thermographic monitoring in the tumor sites of PBS and GNR-PEI/CpG-laden-macrophages treated tumor-bearing mice.

  • Figure 9

    4T1 tumor-bearing mice were given intravenous injections of PBS and GNR-PEI/CpG-laden macrophages at 2.5×106 cells per mouse with or without laser treatment (1.0 W cm−2, 10 min). (a) Flow cytometric analysis of activated myeloid dendritic cells in tumors or draining lymph nodes, (b) the proportion of CD8+ T cells (gray) and CD4+ T cells (red) in spleens after various treatments. Data represent mean ± SD with four replicates. **P<0.01, *P<0.5.

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