Tumor Environment-Responsive Degradable Branched Glycopolymer Magnetic Resonance Imaging Contrast Agent and Its Tumor-Targeted Imaging

Branched macromolecules have been used as carriers for imaging probes and drug delivery systems because of their tunable molecular structures, as well as their regular nanoscale structures and dimensions. We designed and synthesized two tumor environment-responsive branched and gadolinium (Gd)-based glycopolymer conjugates and investigated their potency as highly effective and safe magnetic resonance imaging (MRI) contrast agents. These branched macromolecules were prepared by one-pot reversible addition fragmentation chain transfer (RAFT) polymerization and conjugating chemistry. A biodegradable GFLG oligopeptide was used to successfully link the branch-chains of the branched macromolecules, finally a conjugate of this branched macromolecule and DOTA-Gd (HB-pGAEMA-Gd) with a molecular weight (MW) of 124 kDa was produced. Meanwhile, to improve the ability of tumor-targeting. we conjugated a tumor-targeting cRGDyK cyclic peptide to the branched molecule to prepare a tumor-targeted branched macromolecule-DOTA-Gd conjugate (HB-pGAEMA-RGD-Gd) with a MW of 136 kDa. The prepared branched macromolecules had a nanoscale hydrodynamic particle size and could be degraded into lower MW fragments with the cathepsin B. The aqueous phase relaxation efficiency of HB-pGAEMA-RGD-Gd (12.3 mM(-1)s(-1)) and HB-pGAEMA-Gd (13.2 mM(-1)s(-1)) was four times higher than that of DTPA-Gd (2.9 mM(-1)s(-1)), a clinically used contrast agent. In comparison with DTPA-Gd, the branched macromolecular contrast agents significantly enhanced the MRI signal intensity at the tumor site in vivo, and the enhancement of MRI signal intensity was up to 6 times that of the DTPA-Gd owing to their high relaxation efficiencies and accumulation at the tumor site. In addition, in vitro and in vivo toxicity studies indicated that the degradable macromolecular contrast agents had no significant toxicity.