Rapidly responsive silk fibroin hydrogels as an artificial matrix for the programmed tumor cells death

PLoS One. 2018 Apr 4;13(4):e0194441. doi: 10.1371/journal.pone.0194441. eCollection 2018.

Abstract

Timely and spatially-regulated injectable hydrogels, able to suppress growing tumors in response to conformational transitions of proteins, are of great interest in cancer research and treatment. Herein, we report rapidly responsive silk fibroin (SF) hydrogels formed by a horseradish peroxidase (HRP) crosslinking reaction at physiological conditions, and demonstrate their use as an artificial biomimetic three-dimensional (3D) matrix. The proposed SF hydrogels presented a viscoelastic nature of injectable hydrogels and spontaneous conformational changes from random coil to β-sheet conformation under physiological conditions. A human neuronal glioblastoma (U251) cell line was used for screening cell encapsulation and in vitro evaluation within the SF hydrogels. The transparent random coil SF hydrogels promoted cell viability and proliferation up to 10 days of culturing, while the crystalline SF hydrogels converted into β-sheet structure induced the formation of TUNEL-positive apoptotic cells. Therefore, this work provides a powerful tool for the investigation of the microenvironment on the programed tumor cells death, by using rapidly responsive SF hydrogels as 3D in vitro tumor models.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Apoptosis
  • Cell Line
  • Fibroins / therapeutic use*
  • Glioblastoma / drug therapy
  • Glioblastoma / pathology
  • Humans
  • Hydrogels / therapeutic use*
  • Silk / therapeutic use*
  • Tumor Microenvironment / drug effects*

Substances

  • Antineoplastic Agents
  • Hydrogels
  • Silk
  • Fibroins

Grant support

This study was funded by the Portuguese Foundation for Science and Technology (FCT; http://www.fct.pt) project PEst (PEst-C/SAU/LA0026/2013) under POFC and/or FEDER programs, attributed to RLR; Grants under the Investigator FCT program: IF/00423/2012 and IF/01285/2015 (JMO), IF/00411/2013 (ALO) and IF/00115/2015 (JSC); Postdoctoral fellows: SFRH/BPD/94277/2013 (CG), SFRH/BPD/108763/2015 (SP), SFRH/BPD/100957/2014 (HR); PhD scholarship PD/BD/113806/2015 attributed to VPR under the financial support from FCT/MCTES and FSE/POCH, PD/59/2013. An internal R&D grant of Anasys Instruments Corp provided support in the form of salary for author AR, but did not have any additional role in the study design, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the “author contributions” section. The remaining co-authors did not receive any funding from Anasys Instruments Corp.