Lipid-modified cell-penetrating peptide-based self-assembly micelles for co-delivery of narciclasine and siULK1 in hepatocellular carcinoma therapy.

Abstract

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, and one therapeutic approach is to target both the AMPK and autophagy pathways in order to synergistically promote programmed cell death. Here, a series of amphiphilic, lipid-modified cell-penetrating peptides were synthesized and allowed to self-assemble into micelles loaded with the AMPK activator narciclasine (Narc) and short interfering RNA targeting the unc-51-like kinase 1 (siULK1). The size of these micelles, their efficiency of transfection into cells, and their ability to release drug or siRNA cargo in vitro were pH-sensitive, such that drug release was facilitated in the acidic microenvironment of the tumor. Transfecting the micelles into HCC cells significantly inhibited protective autophagy within tumor cells, and delivering the micelles into mice carrying HCC xenografts induced apoptosis, slowed tumor growth, and inhibited autophagy. Our results indicate that co-delivering Narc and siULK1 in biocompatible micelles can safely inhibit tumor growth and protective autophagy, justifying further studies into this promising therapeutic approach against HCC.

STATEMENT OF SIGNIFICANCE:

We have focused on the targeted therapy of HCC via synergistically inhibiting the autophagy and inducing apoptosis. The lipid-modified cell-penetrating peptide can not only aggregate into micelles to load natural product narciclasine and ULK1 siRNA simultaneously, but also facilitate uptake and endosome escape with a pH-sensitive manner in HepG2 cells. HepG2 cell treated with siULK1-M-Narc has increased apoptotic levels and declined autophagy via the targeted regulation of AMPK-ULK1 signaling axis. The in vivo studies have confirmed that siULK1-M-Narc efficiently reduce the growth of tumor on HCC xenograft models with good safety. Thus, we suppose the lipid-modified cell-penetrating peptide has good application prospects in the targeted combinational therapy of HCC.

• Authors: Xiaoyun Wang, Fengbo Wu, Guoyou Li, Nan Zhang, Xiangrong Song, Yu Zheng, Changyang Gong, Bo Han, Gu He
• Journal: Acta biomaterialia (Acta Biomater) Vol. 74 Pg. 414-429 (07 01 2018) ISSN: 1878-7568 [Electronic] England
• PMID: 29787814 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Amaryllidaceae Alkaloids
• Cell-Penetrating Peptides
• Intracellular Signaling Peptides and Proteins
• Lipids
• Micelles
• Neoplasm Proteins
• Phenanthridines
• RNA, Small Interfering
• narciclasine
• Autophagy-Related Protein-1 Homolog
• ULK1 protein, human

Topics

• Amaryllidaceae Alkaloids (chemistry, pharmacokinetics, pharmacology)
• Animals
• Autophagy-Related Protein-1 Homolog (antagonists & inhibitors, genetics)
• Carcinoma, Hepatocellular (drug therapy, enzymology, genetics, pathology)
• Cell-Penetrating Peptides (chemistry, pharmacokinetics, pharmacology)
• Hep G2 Cells
• Humans
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, genetics)
• Lipids (chemistry, pharmacokinetics, pharmacology)
• Liver Neoplasms (drug therapy, enzymology, genetics, pathology)
• Mice
• Mice, Nude
• Micelles
• Neoplasm Proteins (antagonists & inhibitors, genetics)
• Phenanthridines (chemistry, pharmacokinetics, pharmacology)
• RNA, Small Interfering (chemistry, genetics, pharmacokinetics, pharmacology)
• Xenograft Model Antitumor Assays