Dual targeting system by supramolecular complex of folate-conjugated methyl-β-cyclodextrin with adamantane-grafted hyaluronic acid for the treatment of colorectal cancer.

Abstract

In our previous study, we demonstrated that folate-appended methyl‑β‑cyclodextrin (FA-M-β-CyD) was a promising antitumor agent for the treatment of folate receptor-α (FR-α)-expressing tumors. In the present study, to enhance the antitumor effect of FA-M-β-CyD against FR-α- and CD44-expressing colorectal cancer cells, we synthesized a dual targeting supramolecular complex composed of FA-M-β-CyD and adamantane-grafted hyaluronic acid (Ad-HA). The supramolecular complex of Ad-HA/FA-M-β-CyD showed higher cytotoxic activity in HCT116 cells (FR-α (+), CD44 (+)), a human colon cancer cell line, than FA-M-β-CyD alone. In addition, the cytotoxic activity of Ad-HA/FA-M-β-CyD was significantly impaired by the addition of FA and HA, as inhibitors of FR-α and CD44, respectively. Furthermore, tetramethylrhodamine isothiocyanate (TRITC)-labeled FA-M-β-CyD was efficiently internalized into HCT116 cells through supramolecular complexation with Ad-HA, compared to that of TRITC-FA-M-β-CyD alone. Additionally, Ad-HA/FA-M-β-CyD induced mitophagy in HCT116 cells. These results suggest that Ad-HA/FA-M-β-CyD targeted HCT116 cells, as well as induced mitophagy-mediated cell death. Notably, an intravenous injection of the Ad-HA/FA-M-β-CyD complex in a mouse model of colorectal cancer significantly ameliorated the growth of tumor polyps. Collectively, these results suggest that Ad-HA/FA-M-β-CyD has antiproliferation effects in tumors, based on the dual targeting activity.

• Authors: Khaled M Elamin, Keiichi Motoyama, Taishi Higashi, Yuki Yamashita, Azumi Tokuda, Hidetoshi Arima
• Journal: International journal of biological macromolecules (Int J Biol Macromol) Vol. 113 Pg. 386-394 (Jul 01 2018) ISSN: 1879-0003 [Electronic] Netherlands
• PMID: 29486262 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• beta-Cyclodextrins
• methyl-beta-cyclodextrin
• Hyaluronic Acid
• Folic Acid
• Adamantane

Topics

• Adamantane (chemistry, metabolism, pharmacology, therapeutic use)
• Animals
• Antineoplastic Agents (chemistry, metabolism, pharmacology, therapeutic use)
• Autophagosomes (drug effects, metabolism)
• Biological Transport
• Colorectal Neoplasms (drug therapy, pathology)
• Folic Acid (chemistry)
• HCT116 Cells
• Humans
• Hyaluronic Acid (chemistry)
• Male
• Mice
• Mitochondria (drug effects, pathology)
• Molecular Targeted Therapy
• Particle Size
• Xenograft Model Antitumor Assays
• beta-Cyclodextrins (chemistry)