Hyaluronic acid-mediated multifunctional iron oxide-based MRI nanoprobes for dynamic monitoring of pancreatic cancer

Abstract

Regarded as the most promising technology for an early and precise detection of pancreatic cancer, a sensitive nanoprobe has been developed to enhance the accumulation of contrast agent at the tumor site. Hyaluronic acid (HA)-mediated multifunctional Fe₃O₄ nanoparticles (NPs) were used to target pancreatic cancer cells because on their cytomembrane they overexpress CD44, a receptor protein that has a high affinity to HA. The formation of HA-mediated multifunctional Fe₃O₄ nanoparticles began with the synthesis of polyethyleneimine (PEI·NH₂) stabled Fe₃O₄ NPs by slight reduction. Subsequently, the formed Fe₃O₄@PEI·NH₂ NPs were modified with fluorescein isothiocyanate (FITC), polyethylene glycol (mPEG-COOH) and HA in succession to form the multifunctional Fe₃O₄ NPs denoted as HA-Fe₃O₄ NPs. HA served as a targeting molecule to identify the surface antibody of CD44. As nanoparticles with a diameter of ca. 11.9 nm, the HA-Fe₃O₄ NPs exhibited very high r₂ relaxivity of 321.4 mM⁻¹ s⁻¹ and this has proved that HA-Fe₃O₄ NPs could be efficient T₂-weighted magnetic resonance imaging (MRI) contrast agents. In a CCK8 cell proliferation assay of HA-Fe₃O₄ NPs, there was no toxic response for Fe concentrations up to 100 μg mL⁻¹. Flow cytometry, confocal microscopy observation, and cell MRI results show that the HA-targeted groups had significantly higher cellular uptake than the nontargeted groups. This demonstrates that the HA-Fe₃O₄ NPs are uptaken by pancreatic cells via an HA-mediated targeting pathway. The HA-mediated active targeting strategy could be applied to other biomedical projects.