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3D bioprinted breast tumor model for structure–activity relationship study

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Abstract

In this paper, we present a 3D printed tumor spheroidal model suitable for drug discovery. This model is based on a hydroxyethyl cellulose/alginate/gelatin (HCSG) composite biomaterial that has three distinct properties: (1) the HCSG is similar to the commercial basement membrane extract in Ki67, MUC1, and PARP1 expressions of MCF-7 cells for embedding culture; (2) the HCSG is printable at room temperature; and (3) the HCSG can be large-scale manufactured at an ultralow cost. We printed a 3D MCF-7 spheroid model with HCSG and characterized it in terms of cell viability, spheroid size, key protein expression, and mitochondrial metabolic activity. We used the 3D MCF-7 spheroid model to evaluate the anti-breast cancer activity of 13 amino acid-based flavone phosphoramidates and found that the alanine structure induced a stronger drug resistance, whereas phenylalanine hardly caused drug resistance in the MCF-7 cells. This is the first time that 3D bioprinting technology has been used in a structure–activity relationship study.

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References

  1. Rohall SL, Auch L, Gable J, Gora J, Jansen J, Lu Y, Martin E, Pancost-Heidebrecht M, Shirley B, Stiefl N, Lindvall M (2020) An artificial intelligence approach to proactively inspire drug discovery with recommendations. J Med Chem. https://doi.org/10.1021/acs.jmedchem.9b02130

    Article  Google Scholar 

  2. Li F, Cao L, Parikh S, Zuo R (2020) Three-dimensional spheroids with primary human liver cells and differential roles of kupffer cells in drug-induced liver injury. J Pharm Sci 109(6):1912–1923. https://doi.org/10.1016/j.xphs.2020.02.021

    Article  Google Scholar 

  3. Beaurivage C, Naumovska E, Chang YX, Elstak ED, Nicolas A, Wouters H, van Moolenbroek G, Lanz HL, Trietsch SJ, Joore J, Vulto P, Janssen RAJ, Erdmann KS, Stallen J, Kurek D (2019) Development of a gut-on-a-chip model for high throughput disease modeling and drug discovery. Int J Mol Sci 20(22):5661. https://doi.org/10.3390/ijms20225661

    Article  Google Scholar 

  4. Marotta N, Kim S, Krainc D (2020) Organoid and pluripotent stem cells in Parkinson’s disease modeling: an expert view on their value to drug discovery. Expert Opin Drug Discov 15(4):427–441. https://doi.org/10.1080/17460441.2020.1703671

    Article  Google Scholar 

  5. Gardin C, Ferroni L, Latremouille C, Chachques JC, Mitrecic D, Zavan B (2020) Recent applications of three dimensional printing in cardiovascular medicine. Cells. https://doi.org/10.3390/cells9030742

    Article  Google Scholar 

  6. Zhao Y, Yao R, Ouyang L, Ding H, Zhang T, Zhang K, Cheng S, Sun W (2014) Three-dimensional printing of Hela cells for cervical tumor model in vitro. Biofabrication 6(3):035001. https://doi.org/10.1088/1758-5082/6/3/035001

    Article  Google Scholar 

  7. King SM, Presnell SC, Nguyen DG (2014) Development of 3D bioprinted human breast cancer for in vitro drug screening. Cancer Res 74(19):5. https://doi.org/10.1158/1538-7445.am2014-2034

    Article  Google Scholar 

  8. Brancato V, Oliveira JM, Correlo VM, Reis RL, Kundu SC (2020) Could 3D models of cancer enhance drug screening? Biomaterials 232:119744. https://doi.org/10.1016/j.biomaterials.2019.119744

    Article  Google Scholar 

  9. Salib JY, El-Toumy SA, Hassan EM, Shafik NH, Abdel-Latif SM, Brouard I (2014) New quinoline alkaloid from Ruta graveolens aerial parts and evaluation of the antifertility activity. Nat Prod Res 28(17):1335–1342. https://doi.org/10.1080/14786419.2014.903395

    Article  Google Scholar 

  10. Cos P, Ying L, Calomme M, Hu JP, Cimanga K, Van Poel B, Pieters L, Vlietinck AJ, Vanden Berghe D (1998) Structure–activity relationship and classification of flavonoids as inhibitors of xanthine oxidase and superoxide scavengers. J Nat Prod 61(1):71–76. https://doi.org/10.1021/np970237h

    Article  Google Scholar 

  11. Wang J, Zhang X, Li X, Zhang Y, Hou T, Wei L, Qu L, Shi L, Liu Y, Zou L, Liang X (2016) Anti-gastric cancer activity in three-dimensional tumor spheroids of bufadienolides. Sci Rep 6:24772. https://doi.org/10.1038/srep24772

    Article  Google Scholar 

  12. Albritton JL, Miller JS (2017) 3D bioprinting: improving in vitro models of metastasis with heterogeneous tumor microenvironments. Dis Model Mech 10(1):3–14. https://doi.org/10.1242/dmm.025049

    Article  Google Scholar 

  13. Knowlton S, Onal S, Yu CH, Zhao JJ, Tasoglu S (2015) Bioprinting for cancer research. Trends Biotechnol 33(9):504–513. https://doi.org/10.1016/j.tibtech.2015.06.007

    Article  Google Scholar 

  14. Meng F, Meyer CM, Joung D, Vallera DA, McAlpine MC, Panoskaltsis-Mortari A (2019) 3D bioprinted in vitro metastatic models via reconstruction of tumor microenvironments. Adv Mater 31:e1806899. https://doi.org/10.1002/adma.201806899

    Article  Google Scholar 

  15. Zhang YS, Duchamp M, Oklu R, Ellisen LW, Langer R, Khademhosseini A (2016) Bioprinting the cancer microenvironment. ACS Biomater Sci Eng 2(10):1710–1721. https://doi.org/10.1021/acsbiomaterials.6b00246

    Article  Google Scholar 

  16. Guestini F, Ono K, Miyashita M, Ishida T, Ohuchi N, Nakagawa S, Hirakawa H, Tamaki K, Ohi Y, Rai Y, Sagara Y, Sasano H, McNamara KM (2018) Impact of Topoisomerase IIalpha, PTEN, ABCC1/MRP1, and KI67 on triple-negative breast cancer patients treated with neoadjuvant chemotherapy. Breast Cancer Res Treat 173(2):275–288. https://doi.org/10.1007/s10549-018-4985-6

    Article  Google Scholar 

  17. Zhang L, Wang L, Dong D, Wang Z, Ji W, Yu M, Zhang F, Niu R, Zhou Y (2018) MiR-34b/c-5p and the neurokinin-1 receptor regulate breast cancer cell proliferation and apoptosis. Cell Prolif 52(1):e12527. https://doi.org/10.1111/cpr.12527

    Article  Google Scholar 

  18. Kaushal N, Tiruchinapally G, Durmaz YY, Bao L, Gilani R, Merajver SD, ElSayed MEH (2018) Synergistic inhibition of aggressive breast cancer cell migration and invasion by cytoplasmic delivery of anti-RhoC silencing RNA and presentation of EPPT1 peptide on “smart” particles. J Control Release 289:79–93. https://doi.org/10.1016/j.jconrel.2018.07.042

    Article  Google Scholar 

  19. Islam F, Gopalan V, Lam AK, Kabir SR (2018) Pea lectin inhibits cell growth by inducing apoptosis in SW480 and SW48 cell lines. Int J Biol Macromol 117:1050–1057. https://doi.org/10.1016/j.ijbiomac.2018.06.021

    Article  Google Scholar 

  20. Zhong C, Xie H-Y, Zhou L, Xu X, Zheng S-S (2016) Human hepatocytes loaded in 3D bioprinting generate mini-liver. Hepatobiliary Pancreat Dis Int 15(5):512–518. https://doi.org/10.1016/s1499-3872(16)60119-4

    Article  Google Scholar 

  21. Pimentel CR, Ko SK, Caviglia C, Wolff A, Emneus J, Keller SS, Dufva M (2018) Three-dimensional fabrication of thick and densely populated soft constructs with complex and actively perfused channel network. Acta Biomater 65:174–184. https://doi.org/10.1016/j.actbio.2017.10.047

    Article  Google Scholar 

  22. Li YQ, Yang F, Wang L, Cao Z, Han TJ, Duan ZA, Li Z, Zhao WJ (2016) Phosphoramidate protides of five flavones and their antiproliferative activity against HepG2 and L-O2 cell lines. Eur J Med Chem 112:196–208. https://doi.org/10.1016/j.ejmech.2016.02.012

    Article  Google Scholar 

  23. Benton G, Kleinman HK, George J, Arnaoutova I (2011) Multiple uses of basement membrane-like matrix (BME/Matrigel) in vitro and in vivo with cancer cells. Int J Cancer 128(8):1751–1757. https://doi.org/10.1002/ijc.25781

    Article  Google Scholar 

  24. Zehnder T, Sarker B, Boccaccini AR, Detsch R (2015) Evaluation of an alginate-gelatine crosslinked hydrogel for bioplotting. Biofabrication 7(2):025001. https://doi.org/10.1016/j.biomaterials.2015.05.031

    Article  Google Scholar 

  25. Neufurth M, Wang X, Schroder HC, Feng Q, Diehl-Seifert B, Ziebart T, Steffen R, Wang S, Muller WEG (2014) Engineering a morphogenetically active hydrogel for bioprinting of bioartificial tissue derived from human osteoblast-like SaOS-2 cells. Biomaterials 35(31):8810–8819. https://doi.org/10.1016/j.biomaterials.2014.07.002

    Article  Google Scholar 

  26. Ouyang L, Yao R, Chen X, Na J, Sun W (2015) 3D printing of HEK 293FT cell-laden hydrogel into macroporous constructs with high cell viability and normal biological functions. Biofabrication 7(1):015010. https://doi.org/10.1088/1758-5090/7/1/015010

    Article  Google Scholar 

  27. Saito M, Shinbo T, Saito T, Kato H, Otagiri H, Karaki Y, Tazawa K, Fujimaki M (1990) Temperature sensitivity on proliferation and morphologic alteration of human esophageal carcinoma cells in culture. Vitro Cell Dev Biol 26(2):181–186. https://doi.org/10.1007/BF02624110

    Article  Google Scholar 

  28. Sugasawa T, Mukai N, Tamura K, Tamba T, Mori S, Miyashiro Y, Yamaguchi M, Nissato S, Ra S, Yoshida Y, Hoshino M, Ohmori H, Kawakami Y, Takekoshi K (2016) Effects of cold stimulation on mitochondrial activity and VEGF expression in vitro. Int J Sports Med 37(10):766–778. https://doi.org/10.1055/s-0042-102659

    Article  Google Scholar 

  29. Yasuhara R, Kushida R, Ishii S, Yamanoha B, Shimizu A (2013) Effects of pressure and temperature on the survival rate of adherent A-172 cells. High Press Res 33(2):322–327. https://doi.org/10.1080/08957959.2013.780054

    Article  Google Scholar 

  30. Kamel S, Ali N, Jahangir K, Shah SM, El-Gendy AA (2008) Pharmaceutical significance of cellulose: a review. Express Polym Lett 2(11):758–778. https://doi.org/10.3144/expresspolymlett.2008.90

    Article  Google Scholar 

  31. Zulkifli FH, Hussain FS, Rasad MS, Mohd Yusoff M (2014) Nanostructured materials from hydroxyethyl cellulose for skin tissue engineering. Carbohydr Polym 114:238–245. https://doi.org/10.1016/j.carbpol.2014.08.019

    Article  Google Scholar 

  32. Chahal S, Hussain FSJ, Yusoff MM, Abdull Rasad MSB, Kumar A (2016) Nanohydroxyapatite-coated hydroxyethyl cellulose/poly (vinyl) alcohol electrospun scaffolds and their cellular response. Int J Polym Mater Polym Biomater 66(3):115–122. https://doi.org/10.1080/00914037.2016.1190926

    Article  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 21675017), State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products (KF20190108), and the National Key Research and Development Program of China (No. 2017YFC1702001). And we thanked Prof. Yueqing Li for the synthesis of the isoflavone derivatives and useful discussions.

Author information

Author notes

  1. Yong Luo

    Present address: State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian, China

  2. Xiuli Zhang

    Present address: College of Pharmaceutical Sciences, Soochow University, Soochow, China

  3. Bingcheng Lin

    Present address: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China

  4. Xiaorui Li and Quanfeng Deng have contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian, China

    Xiaorui Li, Tiantian Zhuang & Weijie Zhao

  2. College of Pharmaceutical Sciences, Soochow University, Soochow, China

    Quanfeng Deng

  3. Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China

    Yao Lu

  4. Section of Oral Pathology, College of Stomatology, Dalian Medical University, Dalian, China

    Tingjiao Liu

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  1. Xiaorui Li
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Contributions

Y. Luo and X.L. Zhang conceived this study. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. X.R. Li and Q.F. Deng contributed equally to this work.

Corresponding authors

Correspondence to Bingcheng Lin, Yong Luo or Xiuli Zhang.

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This study does not contain any studies with human or animal subjects performed by any of the authors.

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Li, X., Deng, Q., Zhuang, T. et al. 3D bioprinted breast tumor model for structure–activity relationship study. Bio-des. Manuf. 3, 361–372 (2020). https://doi.org/10.1007/s42242-020-00085-5

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  • DOI: https://doi.org/10.1007/s42242-020-00085-5

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