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Cited by 24Extracellular vesicles in diseaseNanoplatforms for cancer theranosticsNanoparticle-Based Drug Delivery

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Tumor-derived extracellular vesicle drug delivery system for chemo-photothermal-immune combination cancer treatment

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Bi, Yanghui, Chen, Jieya, Li, Qing, Li, Yan, Zhang, Ling, Zhida, Liu, Yuan, Fajia, Zhang, Ruiping·2024·iScience
DOI 10.1016/j.isci.2024.108833PMC PMC10850737
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Abstract

Tumor extracellular vesicles (EVs) demonstrate considerable promise for medication delivery and tumor targeting owing to their natural long-term blood circulation and tissue targeting capabilities. We extracted EVs from mouse breast cancer cell 4T1 using UV stimulation and differential centrifugation. To create a new nano-drug delivery system, the vesicle delivery system (EPM) loaded with melanin and paclitaxel albumin (PA), the collected EVs were repeatedly compressed on a 200 nm porous polycarbonate membrane with melanin and PA. Our findings suggest that EPM is readily absorbed by breast cancer and dendritic cells. EPM generates significant photoacoustic signals and photothermal effects when exposed to near-infrared light and can enhance the infiltration of CD8 + T cells in mouse tumor tissues. EPM is more cytotoxic than PA in in vivo and in vitro investigations. The efficacy of EPM in clinical transformation when paired with chemotherapy/photothermal/immunotherapy treatment is demonstrated in this study.

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Graphical abstract CC BY-NC-ND · PubMed Central
Figure 1 Characterization of EPM (A) TEM images of EVs and EPM. Scale bars, 0.5 μm. (B) Overall distribution of hydrodynamic diameters of EVs and EPM (DLS). (C) Zeta potential of EVs, melanin, EPM. (D) The protein expression of CD63, ALIX cytochrome c, and Annexin V in EVs, EPM, and 4T1 cells. (E) Stability analysis of EPM: average hydrodynamic diameter of EPM.
Figure 1 Characterization of EPM (A) TEM images of EVs and EPM. Scale bars, 0.5 μm. (B) Overall distribution of hydrodynamic diameters of EVs and EPM (DLS). (C) Zeta potential of EVs, melanin, EPM. (D) The protein expression of CD63, ALIX cytochrome c, and Annexin V in EVs, EPM, and 4T1 cells. (E) Stability analysis of EPM: average hydrodynamic diameter of EPM.CC BY-NC-ND · PubMed Central
Figure 2 Evaluation of photoacoustic, photothermal performance of EPM (A) Photoacoustic signal of EPM and EVs solution. Data are represented as mean ± SEM. ∗ ∗ ∗p < 0.001. (B) Concentration-dependent thermal infrared images of EPM solutions within 5 min under 808 nm laser irradiation (1 W/cm2). (C) Temperature change curves of a series of EPM solutions with different concentrations recorded with 808 nm laser irradiation (1 W/cm2). (D) Power density-dependent thermal infrared images of EPM solutions (100 μg/mL) within 5 min under 808 nm laser irradiation. (E) Temperature change curves of EPM solution (100 μg/mL) under 808 nm laser irradiation with different power densities. (F) The heating and cooling curves of EPM solution (100 μg/mL) measured with irradiation of 808 nm laser (1 W/cm2). (G) Photothermal stability of EPM (100 μg/mL) solution upon irradiation for six cycles (808 nm, 1W/cm2).
Figure 2 Evaluation of photoacoustic, photothermal performance of EPM (A) Photoacoustic signal of EPM and EVs solution. Data are represented as mean ± SEM. ∗ ∗ ∗p < 0.001. (B) Concentration-dependent thermal infrared images of EPM solutions within 5 min under 808 nm laser irradiation (1 W/cm2). (C) Temperature change curves of a series of EPM solutions with different concentrations recorded with 808 nm laser irradiation (1 W/cm2). (D) Power density-dependent thermal infrared images of EPM solutions (100 μg/mL) within 5 min under 808 nm laser irradiation. (E) Temperature change curves of EPM solution (100 μg/mL) under 808 nm laser irradiation with different power densities. (F) The heating and cooling curves of EPM solution (100 μg/mL) measured with irradiation of 808 nm laser (1 W/cm2). (G) Photothermal stability of EPM (100 μg/mL) solution upon irradiation for six cycles (808 nm, 1W/cm2).CC BY-NC-ND · PubMed Central
Figure 3 EPM uptake by 4T1 cells, evaluation of internalization mechanism, and EPM lethal impact on 4T1 cells (A) Flow cytometry was used to quantify 4T1 cell EPM uptake at 0.5 h, 1.0 h, and 3 h. (B) Laser confocal images of 4T1 cells uptake EPM at the above time points. Orange-red fluorescence represents Dir-labeled EPM, blue fluorescence (DAPI) represents cell nuclei, and the merge image shows the combination of orange-red and blue fluorescence. Scale bar, 100 μm. Data are represented as mean ± SEM. ∗ ∗ ∗p < 0.001. (C) Flow cytometry was used to quantify 4T1 cell EPM uptake under different conditions, including 4°C, 37°C, chlorpromazine (100 μM), and amiloride hydrochloride (25 μM). Data are represented as mean ± SEM. ∗ ∗ ∗p < 0.001. (D and E) Flow cytometry was used to detect the effect of EPM on 4T1 cell apoptosis. ∗∗p < 0.01, ∗∗∗p < 0.001.
Figure 3 EPM uptake by 4T1 cells, evaluation of internalization mechanism, and EPM lethal impact on 4T1 cells (A) Flow cytometry was used to quantify 4T1 cell EPM uptake at 0.5 h, 1.0 h, and 3 h. (B) Laser confocal images of 4T1 cells uptake EPM at the above time points. Orange-red fluorescence represents Dir-labeled EPM, blue fluorescence (DAPI) represents cell nuclei, and the merge image shows the combination of orange-red and blue fluorescence. Scale bar, 100 μm. Data are represented as mean ± SEM. ∗ ∗ ∗p < 0.001. (C) Flow cytometry was used to quantify 4T1 cell EPM uptake under different conditions, including 4°C, 37°C, chlorpromazine (100 μM), and amiloride hydrochloride (25 μM). Data are represented as mean ± SEM. ∗ ∗ ∗p < 0.001. (D and E) Flow cytometry was used to detect the effect of EPM on 4T1 cell apoptosis. ∗∗p < 0.01, ∗∗∗p < 0.001.CC BY-NC-ND · PubMed Central
Figure 4 In vivo imaging and evaluation of therapeutic effect (A) Representative time-dependent photoacoustic images in orthotopic breast cancer mice treated with EPM at predetermined time points during 24 h. (B) The quantitative analysis intensities of tumor tissue (n = 3) determined by photoacoustic imaging at selected time intervals. Data are represented as mean ± SEM. ∗ ∗ ∗p < 0.001. (C) Schematic depicting the experimental approach. (D) Photographs of excised tumors (n = 5 per group) at day 26 after different treatments. (E) Relative tumors growth curves (n = 5 per group). p values were obtained using ANOVA. ∗∗∗p < 0.001 by Student’s t test. (F) Body weight curves (n = 5 per group). (G–J) Detection of biomarkers of liver (ALT and AST) and kidney function (Scr and BUN) in mice (n = 3) with high-dose EPM injection. (K) Representative pictures of H&E staining of major organ tissues in mice with high-dose EPM injection. Scale bar, 100 μm.
Figure 4 In vivo imaging and evaluation of therapeutic effect (A) Representative time-dependent photoacoustic images in orthotopic breast cancer mice treated with EPM at predetermined time points during 24 h. (B) The quantitative analysis intensities of tumor tissue (n = 3) determined by photoacoustic imaging at selected time intervals. Data are represented as mean ± SEM. ∗ ∗ ∗p < 0.001. (C) Schematic depicting the experimental approach. (D) Photographs of excised tumors (n = 5 per group) at day 26 after different treatments. (E) Relative tumors growth curves (n = 5 per group). p values were obtained using ANOVA. ∗∗∗p < 0.001 by Student’s t test. (F) Body weight curves (n = 5 per group). (G–J) Detection of biomarkers of liver (ALT and AST) and kidney function (Scr and BUN) in mice (n = 3) with high-dose EPM injection. (K) Representative pictures of H&E staining of major organ tissues in mice with high-dose EPM injection. Scale bar, 100 μm.CC BY-NC-ND · PubMed Central
Figure 5 Evaluation of immune effects of EPM (A and B) The proportion of CD80 and CD86 double-positive cells in CD11c+ DCs was detected by flow cytometry. Data are represented as mean ± SEM. ∗ ∗ ∗p < 0.001. (C) Assessment of EPM uptake by macrophages. Flow cytometry was used to quantify by CD80+CD86+ DCs EPM uptake at 0.5 h, 1.0 h, and 3 h. Data are represented as mean ± SEM. ∗ ∗ ∗p < 0.001. (D and E) Flow cytometry was used to detect CD3+CD8+ T cell infiltration in tumor tissues (n = 5 per group). Data are represented as mean ± SEM. ∗p < 0.05, ∗∗∗p < 0.001.
Figure 5 Evaluation of immune effects of EPM (A and B) The proportion of CD80 and CD86 double-positive cells in CD11c+ DCs was detected by flow cytometry. Data are represented as mean ± SEM. ∗ ∗ ∗p < 0.001. (C) Assessment of EPM uptake by macrophages. Flow cytometry was used to quantify by CD80+CD86+ DCs EPM uptake at 0.5 h, 1.0 h, and 3 h. Data are represented as mean ± SEM. ∗ ∗ ∗p < 0.001. (D and E) Flow cytometry was used to detect CD3+CD8+ T cell infiltration in tumor tissues (n = 5 per group). Data are represented as mean ± SEM. ∗p < 0.05, ∗∗∗p < 0.001.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Bi, Y., Chen, J., Li, Q., Li, Y., Zhang, L., Zhida, L., Yuan, F., & Zhang, R.
Affiliations
Shanxi Medical University (CN)
Corresponding author
Zhang, Ruiping
ORCID
Venue
iScience
Publisher
Elsevier BV
Published
2024-02
Volume
27
Issue
2
Pages
108833
ISSN
2589-0042 (ISSN-L)
DOI
10.1016/j.isci.2024.108833
PMC
PMC10850737
OpenAlex
W4390661715
Cited by
24
References
1
Citations by year
2026: 3 · 2025: 17 · 2024: 4
FWCI
3.27
Type
journal article
Language
en
Open access
Licence
Locations
  • iScience (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Shaanxi Key Science and Technology Innovation Team Project (202204051001024)
  • National Key Research and Development Program of China (202104010910010, 2023YFC3402800, 2021YZ17)
  • National Natural Science Foundation of China (82002606, 82071987, 82120108016)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords
tumor-derived extracellular vesicles, melanin, photothermal therapy, near-infrared light, photoacoustic imaging, combination cancer therapy, chemotherapy, immunotherapy, CD8+ T cell infiltration, breast cancer, 4T1 cells, dendritic cells

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