Reversing activity of cancer associated fibroblast for staged glycolipid micelles against internal breast tumor cells

Yun Zhu, Fangying Yu, Yanan Tan, Yun Hong, Tingting Meng, Yupeng Liu, Suhuan Dai, Guoxi Qiu, Hong Yuan, Fuqiang Hu, Yun Zhu, Fangying Yu, Yanan Tan, Yun Hong, Tingting Meng, Yupeng Liu, Suhuan Dai, Guoxi Qiu, Hong Yuan, Fuqiang Hu

Abstract

Rationale: Nano-carrier based combinational therapies for tumor cells hold great potential to improve the outcomes of patients. However, cancer associated fibroblasts (CAFs) in desmoplastic tumors and the derived pathological tumor stroma severely impede the access and sensitibity of tumor cells to antitumor therapies. Methods: Glycolipid-based polymeric micelles (GLPM) were developed to encapsulate an angiotensin II receptor I inhibitor (telmisartan, Tel) and a cytotoxic drug (doxorubicin, DOX) respectively, which could exert combinational antitumor efficacy by reprogramming tumor microenvironment to expose the vulnerability of internal tumor cells. Results: As demonstrated, α-SMA positive CAFs significantly decreased after the pre-administration of GLPM/Tel in vitro, which accordingly inhibited the secretion of the CAFs derived stroma. The tumor vessels were further decompressed as a result of the alleviated solid stress inside the tumor masses, which promoted more intratumoral drug delivery and penetration. Ultimately, staged administration of the combined GLPM/Tel and GLPM/DOX at the screened molar ratio not only inhibited the stroma continuously, but also achieved a synergistic antitumor effect through the apoptosis-related peroxisome proliferator-activated receptor-gamma (PPAR-γ) pathway. Conclusion: In summary, the strategy of suppressing tumor stroma for subsequent combinational therapies against internal breast tumor cells could provide avenues for management of intractable desmoplastic tumors.

Keywords: cancer associated fibroblasts; doxorubicin; glycolipid micelles; stroma; telmisartan..

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

© The author(s).

Figures

Figure 1
Figure 1
Schematic illustration of the mechanism of remodeling the tumor microenvironment for enhanced synergistic antitumor therapy against breast tumor cells. Pre-administered GLPM/Tel primarily decreased the tumor stroma by reversing the activity of CAFs to alleviate solid stress and facilitate drug penetration in desmoplastic breast tumors. The subsequent administration of combined GLPM/Tel and GLPM/DOX enhanced antitumor efficacy collaboratively through the PPAR-γ signal pathway.
Figure 2
Figure 2
Pharmacological action evaluation of GLPM/Tel in activated NIH/3T3 cells. A) Images of GLPM/Tel and GLPM/DOX visualized by TEM. B) Immunofluorescence staining analysis of α-SMA expression after different drugs treatment for 48h. C) Western blot analysis of the α-SMA and CTGF proteins after PBS, Tel and GLPM/Tel incubation for 48h. D) The intracellular uptake of Tel and GLPM/Tel on normal NIH/3T3 and activated NIH/3T3 cell lines. *p

Figure 3

The evaluation of synergistic antitumor…

Figure 3

The evaluation of synergistic antitumor efficiency between GLPM/Tel and GLPM/DOX in MCF-7 cells…

Figure 3
The evaluation of synergistic antitumor efficiency between GLPM/Tel and GLPM/DOX in MCF-7 cells in vitro. A) Intracellular uptake of Tel and GLPM/Tel on MCF-7 cells. B) Western blot analysis of apoptosis related PPAR-γ and cleaved-caspase 3 proteins after drugs treatment for 48h. The combination index (CI) vs Fa plots of C) combinational Tel and DOX, D) GLPM/Tel and GLPM/DOX was calculated according to the MTT assays. E) Evaluation of antitumor efficacy by Annexin V-FITC/PI staining after different drugs treatments. **p < 0.01, ***p < 0.001 as determined by two-tailed student's t-test.

Figure 4

Enhanced drugs penetration by pre-administrated…

Figure 4

Enhanced drugs penetration by pre-administrated GLPM/Tel in vitro and in vivo . A)…

Figure 4
Enhanced drugs penetration by pre-administrated GLPM/Tel in vitro and in vivo. A) Z-stack images of penetration of GLPM/DOX in MCTSs were visualized by confocal microscopy after PBS, Tel and GLPM/Tel treatment for 2 days. Scale bar: 200μm. B) Curves of fluorescence intensity vs different depth in MCTSs calculated by ImageJ software. C) Fluorescent images of ICG labelled GLPM distribution on breast xenografts at determined time intervals after saline, Tel and GLPM/Tel treatments for three times. The tumor position is circled by the red lines. D) Semi-quantitative analysis of fluorescence intensity from the excised tumor masses. E) Distribution patterns of ICG labelled GLPM in vivo. Bar: 50μm. F) Graphic illustration of changed distribution patterns in breast tumors after drug treatments. T: tumor cells area, S: stromal area, red line: blood vessel, blue dots: accumulated drugs.

Figure 5

The remodeled tumor microenvironment at…

Figure 5

The remodeled tumor microenvironment at pre-administration of GLPM/Tel. A) Changes in the drug…

Figure 5
The remodeled tumor microenvironment at pre-administration of GLPM/Tel. A) Changes in the drug penetration capacity of breast tumors with saline, Tel and GLPM/Tel post-injection. Green fluorescence indicates α-SMA positive CAFs, and purple fluorescence indicates CD31 positive vessels, and red fluorescence indicates subsequently administered GLPM/DiI. Bar: 100μm. Semi-quantitative analysis of B) α-SMA positive CAFs, C) diameter of tumor vessels and D) penetrated DiI. E) Images of immunohistochemical staining and semi-quantitative analysis for F) TGF-β and G) CCL2 (n=5). *p < 0.05, **p < 0.01, ***p < 0.001 as determined by two-tailed Student's t-test.

Figure 6

Investigation of alleviated solid stress…

Figure 6

Investigation of alleviated solid stress at post-administration of GLPM/Tel. A) Estimation of solid…

Figure 6
Investigation of alleviated solid stress at post-administration of GLPM/Tel. A) Estimation of solid stress in breast tumors surgically excised from mice after saline, Tel and GLPM/Tel treatment. B) Images and semi-quantitative analysis of HIF-α stained by immunofluorescent staining (n=5). Bar: 100μm. *p

Figure 7

Antitumor efficacy of combination administration…

Figure 7

Antitumor efficacy of combination administration strategy. a) Scheme of the strategy for combinational…

Figure 7
Antitumor efficacy of combination administration strategy. a) Scheme of the strategy for combinational therapies in vivo. b) In vivo tumor inhibition evaluation of different drug treatments. The results are shown as the means ± SD. c) The weights of excised tumor masses and d) the weight of mice was monitored during drug treatment (n=5). *p < 0.05, **p < 0.01, ***p < 0.001 as determined by two-tailed Student's t-test. e) HE staining and TUNEL staining for tumor mass were adopted after different drugs treatments to study the efficacy of remodelingthe tumor microenvironment and subsequent synergistic antitumor efficacy. Scale bar: 100μm. I: saline, II: Tel, III: DOX, IV: Tel+combination (Tel+DOX); I': GLPM/Tel, II': GLPM/DOX, III': GLPM/Tel+GLPM/DOX, IV': GLPM/Tel+combined NPs (GLPM/Tel+GLPM/DOX).
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References
    1. Peng H, Chen B, Huang W, Tang Y, Jiang Y, Zhang W. et al. Reprogramming Tumor-Associated Macrophages To Reverse EGFR(T790M) Resistance by Dual-Targeting Codelivery of Gefitinib/Vorinostat. Nano Lett. 2017;17:7684–90. - PubMed
    1. Greco F, Vicent MJ. Combination therapy: opportunities and challenges for polymer-drug conjugates as anticancer nanomedicines. Adv Drug Deliv Rev. 2009;61:1203–13. - PubMed
    1. Mura S, Nicolas J, Couvreur P. Stimuli-responsive nanocarriers for drug delivery. Nature Materials. 2013;12:991–1003. - PubMed
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    1. Zhang B, Jin K, Jiang T, Wang L, Shen S, Luo Z. et al. Celecoxib normalizes the tumor microenvironment and enhances small nanotherapeutics delivery to A549 tumors in nude mice. Sci Rep. 2017;7:10071. - PMC - PubMed
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Figure 3
Figure 3
The evaluation of synergistic antitumor efficiency between GLPM/Tel and GLPM/DOX in MCF-7 cells in vitro. A) Intracellular uptake of Tel and GLPM/Tel on MCF-7 cells. B) Western blot analysis of apoptosis related PPAR-γ and cleaved-caspase 3 proteins after drugs treatment for 48h. The combination index (CI) vs Fa plots of C) combinational Tel and DOX, D) GLPM/Tel and GLPM/DOX was calculated according to the MTT assays. E) Evaluation of antitumor efficacy by Annexin V-FITC/PI staining after different drugs treatments. **p < 0.01, ***p < 0.001 as determined by two-tailed student's t-test.
Figure 4
Figure 4
Enhanced drugs penetration by pre-administrated GLPM/Tel in vitro and in vivo. A) Z-stack images of penetration of GLPM/DOX in MCTSs were visualized by confocal microscopy after PBS, Tel and GLPM/Tel treatment for 2 days. Scale bar: 200μm. B) Curves of fluorescence intensity vs different depth in MCTSs calculated by ImageJ software. C) Fluorescent images of ICG labelled GLPM distribution on breast xenografts at determined time intervals after saline, Tel and GLPM/Tel treatments for three times. The tumor position is circled by the red lines. D) Semi-quantitative analysis of fluorescence intensity from the excised tumor masses. E) Distribution patterns of ICG labelled GLPM in vivo. Bar: 50μm. F) Graphic illustration of changed distribution patterns in breast tumors after drug treatments. T: tumor cells area, S: stromal area, red line: blood vessel, blue dots: accumulated drugs.
Figure 5
Figure 5
The remodeled tumor microenvironment at pre-administration of GLPM/Tel. A) Changes in the drug penetration capacity of breast tumors with saline, Tel and GLPM/Tel post-injection. Green fluorescence indicates α-SMA positive CAFs, and purple fluorescence indicates CD31 positive vessels, and red fluorescence indicates subsequently administered GLPM/DiI. Bar: 100μm. Semi-quantitative analysis of B) α-SMA positive CAFs, C) diameter of tumor vessels and D) penetrated DiI. E) Images of immunohistochemical staining and semi-quantitative analysis for F) TGF-β and G) CCL2 (n=5). *p < 0.05, **p < 0.01, ***p < 0.001 as determined by two-tailed Student's t-test.
Figure 6
Figure 6
Investigation of alleviated solid stress at post-administration of GLPM/Tel. A) Estimation of solid stress in breast tumors surgically excised from mice after saline, Tel and GLPM/Tel treatment. B) Images and semi-quantitative analysis of HIF-α stained by immunofluorescent staining (n=5). Bar: 100μm. *p

Figure 7

Antitumor efficacy of combination administration…

Figure 7

Antitumor efficacy of combination administration strategy. a) Scheme of the strategy for combinational…

Figure 7
Antitumor efficacy of combination administration strategy. a) Scheme of the strategy for combinational therapies in vivo. b) In vivo tumor inhibition evaluation of different drug treatments. The results are shown as the means ± SD. c) The weights of excised tumor masses and d) the weight of mice was monitored during drug treatment (n=5). *p < 0.05, **p < 0.01, ***p < 0.001 as determined by two-tailed Student's t-test. e) HE staining and TUNEL staining for tumor mass were adopted after different drugs treatments to study the efficacy of remodelingthe tumor microenvironment and subsequent synergistic antitumor efficacy. Scale bar: 100μm. I: saline, II: Tel, III: DOX, IV: Tel+combination (Tel+DOX); I': GLPM/Tel, II': GLPM/DOX, III': GLPM/Tel+GLPM/DOX, IV': GLPM/Tel+combined NPs (GLPM/Tel+GLPM/DOX).
All figures (7)
Figure 7
Figure 7
Antitumor efficacy of combination administration strategy. a) Scheme of the strategy for combinational therapies in vivo. b) In vivo tumor inhibition evaluation of different drug treatments. The results are shown as the means ± SD. c) The weights of excised tumor masses and d) the weight of mice was monitored during drug treatment (n=5). *p < 0.05, **p < 0.01, ***p < 0.001 as determined by two-tailed Student's t-test. e) HE staining and TUNEL staining for tumor mass were adopted after different drugs treatments to study the efficacy of remodelingthe tumor microenvironment and subsequent synergistic antitumor efficacy. Scale bar: 100μm. I: saline, II: Tel, III: DOX, IV: Tel+combination (Tel+DOX); I': GLPM/Tel, II': GLPM/DOX, III': GLPM/Tel+GLPM/DOX, IV': GLPM/Tel+combined NPs (GLPM/Tel+GLPM/DOX).

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