Biomaterials Translational ›› 2021, Vol. 2 ›› Issue (2): 151-164.doi: 10.12336/biomatertransl.2021.02.005
• RESEARCH ARTICLE • Previous Articles Next Articles
Huoyan Hong1,#, Xiaoyun Wang2,#, Xinran Song1, Gomaa El Fawal1,3, Kaili Wang1, Di Jiang1, Yifei Pei1, Zhe Wang1, Hongsheng Wang1,*(
)
Received:2021-04-17
Revised:2021-06-04
Accepted:2021-06-07
Online:2021-06-28
Published:2021-06-28
Contact:
Hongsheng Wang
E-mail:whs@dhu.edu.cn
About author:#Author equally.
Hong, H.; Wang, X.; Song, X.; El Fawal, G.; Wang, K.; Jiang, D.; Pei, Y.; Wang, Z.; Wang, H. Transdermal delivery of interleukin-12 gene targeting dendritic cells enhances the anti-tumour effect of programmed cell death protein 1 monoclonal antibody. Biomater Transl. 2021, 2(2), 151-164.
| Gene | Sequence (5′ -3′) |
|---|---|
| β-Actin | Forward: GGC TGT ATT CCC CTC CAT CG |
| Reverse: CCA GTT GGT AAC AAT GCC ATG T | |
| IL-12a | Forward: TCC AGC AGC TCC TCT CAG TG |
| Reverse: ACT GGC TAA GAC ACC TGG CA | |
| IL-12b | Forward: GGC TGG ACT GCA TGA TAG CG |
| Reverse: GCC AGG ATG TCT CTG CTC CT |
Table 1 Primer sequences for real-time fluorescence quantitative polymerase chain reaction
| Gene | Sequence (5′ -3′) |
|---|---|
| β-Actin | Forward: GGC TGT ATT CCC CTC CAT CG |
| Reverse: CCA GTT GGT AAC AAT GCC ATG T | |
| IL-12a | Forward: TCC AGC AGC TCC TCT CAG TG |
| Reverse: ACT GGC TAA GAC ACC TGG CA | |
| IL-12b | Forward: GGC TGG ACT GCA TGA TAG CG |
| Reverse: GCC AGG ATG TCT CTG CTC CT |
Figure 1. Characterization of Eths. (A) Infrared spectra of the materials. Arrows indicate the characteristic peaks. (B) Particle size and electric potential. Data are expressed as mean ± SD. The experiments were repeated by three times. (C) Transmission electron microscopy images of Eths. The adsorption of HA made the particle size of Eth increase significantly while the potential greatly reduced. When MC is further adsorbed on the surface of HA, the particle size decreases but is still larger than bare Eth, and the potential increased slightly. Scale bars: 200 nm. (D) Image of agarose gel electrophoresis at different octadecylamine:pIL-12 ratios. Eth: ethosome; HA: hyaluronic acid; MC: mannosylated chitosan; pIL-12: plasmid containing IL-12 gene.
Figure 2. Cytotoxicity of Eths with different modifications as evaluated by Cell Counting Kit-8. (A) Cell viability. Data are expressed as mean ± SD. The experiments were repeated by three times. *P < 0.05, **P < 0.01, ***P < 0.001 (one-way analysis of variance followed with Tukey’s post hoc test). (B) Live and dead staining of Eth-MC-treated cells. There was no significant difference in cell morphology among different groups, but cell proliferation was inhibited to a certain extent when the concentration of Eth-MC is higher than 30 μg/mL. B1-6: 0, 5, 10, 20, 30, and 40 μg/mL. The green fluorescence indicates live cells. Scale bars: 500 μm. Eth: ethosome; HA: hyaluronic acid; MC: mannosylated chitosan.
Figure 3. Performance of Eths targeting dendritic cells. (A) Confocal laser scanning microscopy images of dendritic cells phagocytosing DiI (red)-labelled Eths. The phagocytosis efficiency of Eth-MC was significantly higher than that of others. Scale bars: 20 μm. (B) Fluorescent intensity analysis of A. (C) Relative mRNA expression of IL-12 in different cells transfected with pIL-12@Eths detected by real-time polymerase chain reaction. Data are expressed as mean ± SD. The experiments were repeated by three times. *P < 0.05, **P < 0.01, ***P < 0.001 (one-way analysis of variance followed with Tukey’s post hoc test). DAPI: 4,6-diamino-2-phenylindole dihydrochloride; DiI: 1,1’-dioctadecyl-3,3,3’,3’-tetramethylindocarbocyanine perchlorate; Eth: ethosome; HA: hyaluronic acid; IL-12: interleukin-12; MC: mannosylated chitosan; pIL-12: plasmid containing IL-12 gene.
Figure 4. IL-12 gene-loaded Eths stimulate DCs expression of CD80, CD86 and MHC-II. (A) Flow cytometry histograms. (B) Quantitative analysis of CD80, CD86 and MHC-II. Data are expressed as mean ± SD. The experiments were repeated by three times. **P < 0.01, ***P < 0.001 (one-way analysis of variance followed with Tukey’s post hoc test). Eth: ethosome; HA: hyaluronic acid; IL-12: interleukin-12; LPS: lipopolysaccharide; MC: mannosylated chitosan; MHC-II: major histocompatibility complex-II; PBS: phosphate-buffered saline; pIL-12: plasmid containing IL-12 gene.
Figure 5. Morphology of SF-PVA nanofibrous mats (A1), microspheres (B1) and TCI patch (C1). (A2) Distribution of diameters in A1. (B2) Distribution of diameters in B1. (C2) Fluorescence micrograph of TCI patch. Red represents DiI-labeled Eth-MC. Scale bars: 10 μm in A1, 8 μm in B1 and C1, 500 μm in C2. AD: average diameter; Eth-MC: mannosylated chitosan-modified ethosome; PVA: polyvinyl alcohol; SF: silk fibroin; TCI: transcutaneous immunization.
Figure 6. (A, B) In vitro cumulative transdermal drug release curve (A) and its Steady-state release flux (B). (C, D) Fluorescence images of skin sections (C) and their fluorescent intensity analysis (D) after transdermal administration with pIL-12@Eth-MC. The amount of Eth and DNA that penetrate into the skin tissue increases with time. Scale bar: 200 μm. Data are expressed as mean ± SD. The experiments were repeated by three times. DiI: 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate; Eth: ethosome; IL-12: interleukin-12; MC: mannosylated chitosan; pIL-12: plasmid containing IL-12 gene.
Figure 7. Expression of cytokines in the blood of melanoma-bearing mice given TCI and/or aPD-1 monotherapy treatment. a﹣d: Control, TCI monotherapy, aPD-1 monotherapy, and TCI + aPD-1 groups. Data are expressed as mean ± SD (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001 (one-way analysis of variance followed with Tukey’s post hoc test). aPD-1: programmed cell death protein 1 monoclonal antibody; IFN-γ: interferon-γ; IL-12: interleukin-12; TCI: transcutaneous immunization; TNF-α: tumour necrosis factor-α.
Figure 8. Schematic diagram of animal experiment protocol (A), tumour volume change curves (B), tumour weight at day 24 (C), survival rate (D) and Body weight change curves (E) in melanoma-bearing mice with TCI and/or aPD-1 treatment. a-d: Control, TCI monotherapy, aPD-1 monotherapy, and TCI + aPD-1 groups. Data are expressed as mean ± SD (n = 4). *P < 0.05, **P < 0.01, ***P < 0.001 (one-way analysis of variance followed with Tukey’s post hoc test). aPD-1: programmed cell death protein 1 monoclonal antibody; TCI: transcutaneous immunization.
Figure 9. (A) Different staining images of tumour tissue from the melanoma-bearing mice after receiving different treatments. (B, C) Fluorescent intensity analysis of anti-CD4/CD8 or TUNEL staining. The treatment groups had more tumour cell apoptosis and more cytotoxic T cell infiltration than the control, and the combined treatment group was far better than the other groups. Scale bars: 50 and 400 μm. a-d: Control, TCI monotherapy, aPD-1 monotherapy, and TCI + aPD-1 groups. Data are expressed as mean ± SD (n = 4). *P < 0.05, **P < 0.01, ***P < 0.001 (one-way analysis of variance followed with Tukey’s post hoc test). aPD-1: programmed cell death protein 1 monoclonal antibody; H&E: hematoxylin-eosin; TCI: transcutaneous immunization; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labelling.
Figure 10. Histological characterization (hematoxylin-eosin staining) of the major organs from the melanoma-bearing mice after receiving different treatments. The organs showed little difference among the groups. a-d: Control, TCI monotherapy, aPD-1 monotherapy, and TCI + aPD-1 groups. Scale bar: 400 μm. aPD-1: programmed cell death protein 1 monoclonal antibody; TCI: transcutaneous immunization.
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