Ternary biomolecular nanoparticles for targeting of cancer cells and anti-angiogenesis.

To develop a targeted drug delivery system for cancer therapy and anti-angiogenesis, amphiphilic heparin bioconjugates were synthesized by chemical conjugation of hydrophobic retinoic acid and a targeting ligand, folic acid, to the heparin backbone (HFR). The chemical structure of the HFR conjugates was confirmed by proton nuclear magnetic resonance ((1)H NMR). Various HFR conjugates with different retinoic acid coupling ratios were obtained by modulating the retinoic acid feed molar ratio. The anticoagulant activity of the HFR conjugates decreased to 30% of heparin levels as measured by anti-FXa chromogenic assay. The bioconjugates retained the anti-angiogenic effect, showing a significant decrease in endothelial tubular formation using a Matrigel model. In aqueous solutions, the bioconjugates readily self-assembled to form nanoparticles via the hydrophobic interaction among retinoic acid. The HFR nanoparticles were spherical and ranged from 150 to 300 nm, depending on the degree of retinoic acid coupling. The presence of folic acid efficiently enhanced the cellular uptake of the HFR nanoparticles in folate receptor-positive cells. Furthermore, the internalized HFR nanoparticles demonstrated greater cytotoxicity against folate receptor-positive cells compared to free retinoic acid. These results indicate that specific delivery of retinoic acid with ternary biomolecular nanoparticles targeting folate receptor-positive tumors is a promising strategy to enhance chemotherapy efficacy with minimal side effects. Copyright (c) 2010 Elsevier B.V. All rights reserved.