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A pH/MMP-9 smart dual-responsive liposome GBE@LP co-delivers and controls the release of GB1107/BMS1166/Enzalutamide for liver cancer immunotherapy

Lu, Shijia, Zhang, Chenxiao, Wu, Huiru, Wang, Junjie, Wang, Jinglong, Zhao, Limei, Ren, Tianyang, Li, Guofei·2025·Materials Today Bio
DOI 10.1016/j.mtbio.2025.101801PMC PMC12139023
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Graphical abstract CC BY-NC-ND · PubMed Central
Scheme 1 Graphical illustration of the immunization strategy of GBE@LP for liver cancer treatment. GBE@LP has prolonged circulation in the bloodstream due to surface PEG and selectively accumulates in liver cancer tissues through EPR effect. Meanwhile, DOPE and TGMS give it the property to be released in response to low pH and MMP-9 overexpression in liver cancer microenvironment. GBE@LP delivers drugs into liver cancer, converting uninfiltrated "cold" tumors into highly infiltrated "hot" tumors, while reversing CD8+ T-cell depletion and enhancing cytotoxicity. These effects ultimately enhance immunotherapy for liver cancer.
Scheme 1 Graphical illustration of the immunization strategy of GBE@LP for liver cancer treatment. GBE@LP has prolonged circulation in the bloodstream due to surface PEG and selectively accumulates in liver cancer tissues through EPR effect. Meanwhile, DOPE and TGMS give it the property to be released in response to low pH and MMP-9 overexpression in liver cancer microenvironment. GBE@LP delivers drugs into liver cancer, converting uninfiltrated "cold" tumors into highly infiltrated "hot" tumors, while reversing CD8+ T-cell depletion and enhancing cytotoxicity. These effects ultimately enhance immunotherapy for liver cancer.CC BY-NC-ND · PubMed Central
Fig. 1 Liver cancer is a "cold" tumor with high Gal-3 expression. (A) Immunofluorescence images of CD8+ T cells (red) and DAPI (blue) in liver cancer tissues of tumor-bearing mice. (B) Immunohistochemical images of cd8+T cells in patients with hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and lung cancer (LC) from the HPA database. (C) Expression of Gal-3 in different human cancers was analyzed by HPA database. (D) The expression of Gal-3 in mouse liver cancer tissues and paracancerous tissues was detected by western blotting. (E) The expression of CD8 in the control group and GB1107 treatment group was detected by western blotting. (F) Immunofluorescence images of CD8+ T cells (green), PD-1 (red), and DAPI (blue) in liver cancer tissues and paracancerous tissues of tumor-bearing mice. (G) Immunofluorescence images of CD8+ T cells (green), AR (red), and DAPI (blue) in liver cancer tissues and paracancerous tissues of tumor-bearing mice.
Fig. 1 Liver cancer is a "cold" tumor with high Gal-3 expression. (A) Immunofluorescence images of CD8+ T cells (red) and DAPI (blue) in liver cancer tissues of tumor-bearing mice. (B) Immunohistochemical images of cd8+T cells in patients with hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and lung cancer (LC) from the HPA database. (C) Expression of Gal-3 in different human cancers was analyzed by HPA database. (D) The expression of Gal-3 in mouse liver cancer tissues and paracancerous tissues was detected by western blotting. (E) The expression of CD8 in the control group and GB1107 treatment group was detected by western blotting. (F) Immunofluorescence images of CD8+ T cells (green), PD-1 (red), and DAPI (blue) in liver cancer tissues and paracancerous tissues of tumor-bearing mice. (G) Immunofluorescence images of CD8+ T cells (green), AR (red), and DAPI (blue) in liver cancer tissues and paracancerous tissues of tumor-bearing mice.CC BY-NC-ND · PubMed Central
Fig. 2 Preparation and characterization of GBE@LP. (A) TEM images of GBE@LP co-loaded with GB1107, BMS1166 and enzalutamide at different scales. (B) Size of GBE@LP. (C) Charge of GBE@LP series liposomes. (D) In vitro drug release in PBS (pH = 4.0, 6.0, 7.4). (E) In vitro drug release in PBS (pH = 4.0, 6.0, 7.4) containing 100 ng MMP-9. (F) Mean size and zeta potential of GBE@LP under different storage conditions over 6 months.
Fig. 2 Preparation and characterization of GBE@LP. (A) TEM images of GBE@LP co-loaded with GB1107, BMS1166 and enzalutamide at different scales. (B) Size of GBE@LP. (C) Charge of GBE@LP series liposomes. (D) In vitro drug release in PBS (pH = 4.0, 6.0, 7.4). (E) In vitro drug release in PBS (pH = 4.0, 6.0, 7.4) containing 100 ng MMP-9. (F) Mean size and zeta potential of GBE@LP under different storage conditions over 6 months.CC BY-NC-ND · PubMed Central
Fig. 3 In vivo pharmacokinetic study and biodistribution of GBE@LP. (A) In vivo pharmacokinetics of BMS1166, GB1107 and enzalutamide after formulation into liposomes. -S is the drug solution group, -L is the liposome group with single-loaded drug, and -M is the liposome GBE@LP group with co-loaded three drugs. (B) Biodistribution of GBE@LP in major organs and tumors in subcutaneous liver cancer mice 12 h after intravenous injection. -S is the concentration of different drugs in the solution group, -L is the concentration of different drugs in the GBE@LP group. (C) Fluorescence images of H22 tumor-bearing mice after intravenous injection for 2, 6, 12, and 24 h. (D) Ex vivo fluorescence imaging and. (E) corresponding radiant efficiency of tumors and main organs at 24-h post intravenous injection (n = 3,p∗∗∗∗ < 0.0001).
Fig. 3 In vivo pharmacokinetic study and biodistribution of GBE@LP. (A) In vivo pharmacokinetics of BMS1166, GB1107 and enzalutamide after formulation into liposomes. -S is the drug solution group, -L is the liposome group with single-loaded drug, and -M is the liposome GBE@LP group with co-loaded three drugs. (B) Biodistribution of GBE@LP in major organs and tumors in subcutaneous liver cancer mice 12 h after intravenous injection. -S is the concentration of different drugs in the solution group, -L is the concentration of different drugs in the GBE@LP group. (C) Fluorescence images of H22 tumor-bearing mice after intravenous injection for 2, 6, 12, and 24 h. (D) Ex vivo fluorescence imaging and. (E) corresponding radiant efficiency of tumors and main organs at 24-h post intravenous injection (n = 3,p∗∗∗∗ < 0.0001).CC BY-NC-ND · PubMed Central
Fig. 4 In vivo anti-liver cancer effects of GBE@LP. (A) Treatment regimen of subcutaneous H22-bearing mice model. (B) Tumor images of tumor-bearing mice. (C) Tumor final volume of tumor-bearing mice. (D) Tumor final weight of tumor-bearing mice. (E) Tumor growth curves of individual mice in different groups of the tumor-bearing mice. (F) Tumor growth curves of tumor-bearing mice. (G) Body weight growth curves of tumor-bearing mice. (n = 6, p∗ < 0.05, p∗∗ < 0.01, p∗∗∗ < 0.001, p∗∗∗∗ < 0.0001).
Fig. 4 In vivo anti-liver cancer effects of GBE@LP. (A) Treatment regimen of subcutaneous H22-bearing mice model. (B) Tumor images of tumor-bearing mice. (C) Tumor final volume of tumor-bearing mice. (D) Tumor final weight of tumor-bearing mice. (E) Tumor growth curves of individual mice in different groups of the tumor-bearing mice. (F) Tumor growth curves of tumor-bearing mice. (G) Body weight growth curves of tumor-bearing mice. (n = 6, p∗ < 0.05, p∗∗ < 0.01, p∗∗∗ < 0.001, p∗∗∗∗ < 0.0001).CC BY-NC-ND · PubMed Central
Fig. 5 GBE@LP remodeling the immunosuppressive microenvironment of liver cancer. (A) Flow cytometry scatter graph and (C) Flow cytometry statistical plot of CD8+T cells infiltration in the tumors of different treatment groups. (B) Flow cytometry histogram and (D) Flow cytometry statistical plot of CD3+T cells infiltration in the spleen of different treatment groups. (n = 3, p∗ < 0.05, p∗∗ < 0.01, p∗∗∗ < 0.001, p∗∗∗∗ < 0.0001).
Fig. 5 GBE@LP remodeling the immunosuppressive microenvironment of liver cancer. (A) Flow cytometry scatter graph and (C) Flow cytometry statistical plot of CD8+T cells infiltration in the tumors of different treatment groups. (B) Flow cytometry histogram and (D) Flow cytometry statistical plot of CD3+T cells infiltration in the spleen of different treatment groups. (n = 3, p∗ < 0.05, p∗∗ < 0.01, p∗∗∗ < 0.001, p∗∗∗∗ < 0.0001).CC BY-NC-ND · PubMed Central
Fig. 6 (A) Immunofluorescence images of CD8+ T cells (green) and DAPI (blue) in different treatment groups. Scale bars, 1000 μm (top), 50 μm (bottom).
Fig. 6 (A) Immunofluorescence images of CD8+ T cells (green) and DAPI (blue) in different treatment groups. Scale bars, 1000 μm (top), 50 μm (bottom).CC BY-NC-ND · PubMed Central
Fig. 7 (A) Concentrations of IFN-γ, CXCL10, TGF-β and TNF-α in tumor tissues of H22-bearing mice. (B) Flow cytometry histogram and (C) Flow cytometry statistical plot of M1 TAMs infiltration in the tumors of different treatment groups. (n = 3, p∗ < 0.05, p∗∗ < 0.01, p∗∗∗ < 0.001, p∗∗∗∗ < 0.0001).
Fig. 7 (A) Concentrations of IFN-γ, CXCL10, TGF-β and TNF-α in tumor tissues of H22-bearing mice. (B) Flow cytometry histogram and (C) Flow cytometry statistical plot of M1 TAMs infiltration in the tumors of different treatment groups. (n = 3, p∗ < 0.05, p∗∗ < 0.01, p∗∗∗ < 0.001, p∗∗∗∗ < 0.0001).CC BY-NC-ND · PubMed Central

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Authors
Lu, S., Zhang, C., Wu, H., Wang, J., Wang, J., Zhao, L., Ren, T., & Li, G.
Venue
Materials Today Bio
Publisher
Elsevier BV
Published
2025-06
Volume
32
Pages
101801
ISSN
2590-0064
DOI
10.1016/j.mtbio.2025.101801
PMC
PMC12139023
Cited by
8
References
1
Language
en
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