FGF2 engineered SPIONs attenuate tumor stroma and potentiate the effect of chemotherapy in 3D heterospheroidal model of pancreatic tumor

Nanotheranostics. 2020 Jan 1;4(1):26-39. doi: 10.7150/ntno.38092. eCollection 2020.

Abstract

Pancreatic ductal adenocarcinoma (PDAC), characterized with abundant tumor stroma, is a highly malignant tumor with poor prognosis. The tumor stroma largely consists of cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM), and is known to promote tumor growth and progression as well as acts as a barrier to chemotherapy. Inhibition of tumor stroma is highly crucial to induce the effect of chemotherapy. In this study, we delivered fibroblast growth factor 2 (FGF2) to human pancreatic stellate cells (hPSCs), the precursors of CAFs, using superparamagnetic iron oxide nanoparticles (SPIONs). FGF2 was covalently conjugated to functionalized PEGylated dextran-coated SPIONs. FGF2-SPIONs significantly reduced TGF-β induced hPSCs differentiation (α-SMA and collagen-1 expression) by inhibiting pSmad2/3 signaling and inducing ERK1/2 activity, as shown with western blot analysis. Then, we established a stroma-rich self-assembling 3D heterospheroid model by co-culturing PANC-1 and hPSCs in 3D environment. We found that FGF2-SPIONs treatment alone inhibited the tumor stroma-induced spheroid growth. In addition, they also potentiated the effect of gemcitabine, as shown by measuring the spheroid size and ATP content. These effects were attributed to the reduced expression of the hPSC activation and differentiation marker, α-SMA. Furthermore, to demonstrate an application of SPIONs, we applied an external magnetic field to spheroids while incubated with FGF2-SPIONs. This resulted in an enhanced effect of gemcitabine in our 3D model. In conclusion, this study presents a novel approach to target FGF2 to tumor stroma using SPIONs and thereby enhancing the effect of gemcitabine as demonstrated in the complex 3D tumor spheroid model.

Keywords: cancer-associated fibroblasts; fibroblast growth factor 2; pancreatic cancer; pancreatic stellate cells; superparamagnetic iron oxide nanoparticles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / metabolism
  • Antineoplastic Agents* / pharmacology
  • Cancer-Associated Fibroblasts / drug effects
  • Cancer-Associated Fibroblasts / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Drug Synergism
  • Fibroblast Growth Factor 2* / metabolism
  • Fibroblast Growth Factor 2* / pharmacology
  • Humans
  • Magnetite Nanoparticles / chemistry*
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Stellate Cells* / drug effects
  • Pancreatic Stellate Cells* / metabolism
  • Spheroids, Cellular / cytology
  • Spheroids, Cellular / drug effects

Substances

  • Antineoplastic Agents
  • Magnetite Nanoparticles
  • Deoxycytidine
  • Fibroblast Growth Factor 2
  • gemcitabine