Janus nanocarrier-based co-delivery of doxorubicin and berberine weakens chemotherapy-exacerbated hepatocellular carcinoma recurrence.

Abstract

Despite the rapid progress which has been made in hepatocellular carcinoma (HCC) chemotherapeutics, recurrence of liver cancer still remains a barrier to achieve satisfying prognosis. Herein, we aimed to decipher the role of berberine (BER) in chemotherapy-exacerbated HCC repopulation via developing a nanocarrier co-deliveries doxorubicin (DOX) and BER to achieve a synergic effect in HCC treatment. The underlying fact of chemotherapy that promotes HCC repopulation was firstly examined and corroborated by clinical samples and murine repopulation model. Then, hyaluronic acid (HA)-conjugated Janus nanocarrier (HA-MSN@DB) was developed to load DOX and BER simultaneously. The HCC targeting efficiency, pH-controlled drug-release and anti-cancer property of HA-MSN@DB were assessed in CD44-overexpressed HCCs and normal liver cells. Magnet resonance imaging, bio-distribution, biocompatibility, tumor and recurrence inhibition studies were performed in H22 tumor-bearing mice. BER significantly reduced doxorubicin (DOX)-triggered HCC repopulation in vitro and in vivo through inhibiting Caspase-3-iPLA2-COX-2 pathway. The delivery of HA-MSN@DB into HCCs through CD44 receptor-mediated targeting effect was demonstrated. The controlled release of DOX and BER in response to acidic tumor microenvironment was validated. Importantly, HA-MSN@DB drastically enhanced the antitumor activity of DOX and suppressed DOX-exacerbated HCC repopulation in vitro and in vivo. Furthermore, HA-MSN@DB exhibited enhanced tumor accumulation and biocompatibility. Our findings revealed the pivotal role of BER in overcoming chemotherapy-exacerbated HCC repopulation through Caspase-3-iPLA2-COX-2 pathway, thereby providing a promising and stable nanocarrier integrating DOX and BER for effective HCC chemotherapy without repopulation. STATEMENT OF SIGNIFICANCE: In this work, we have first demonstrated the fact that berberine (Ber) reduces chemotherapy-exacerbated HCC recurrence and studied its mechanism by the aid of a doxorubicin-induced mice HCC relapse model. We then developed a promising strategy that simultaneously inhibits HCC and its recurrence with an HCC-targeted co-delivery nanocarrier HA-MSN@DB and revealed that such an inhibition was related with the suppression of Caspase-3-iPLA2-COX-2 pathway by berberine.

• Authors: Fan Zhang, Yong Jia, Xiao Zheng, Dan Shao, Yawei Zhao, Zheng Wang, Jianati Dawulieti, Wenliang Liu, Madi Sun, Wen Sun, Yue Pan, Lianzhi Cui, Yanan Wang, Kan He, Ming Zhang, Jing Li, Wen-Fei Dong, Li Chen
• Journal: Acta biomaterialia (Acta Biomater) Vol. 100 Pg. 352-364 (12 2019) ISSN: 1878-7568 [Electronic] England
• PMID: 31563690 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Drug Carriers
• Hyaluronan Receptors
• Reactive Oxygen Species
• Berberine
• Silicon Dioxide
• Doxorubicin
• Hyaluronic Acid

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Berberine (therapeutic use)
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Doxorubicin (therapeutic use)
• Drug Carriers (chemistry)
• Drug Delivery Systems
• Drug Liberation
• Hep G2 Cells
• Humans
• Hyaluronan Receptors (metabolism)
• Hyaluronic Acid (chemistry)
• Hydrogen-Ion Concentration
• Liver Neoplasms (drug therapy, pathology)
• Magnetic Resonance Imaging
• Male
• Mice
• Mice, Inbred ICR
• Middle Aged
• NIH 3T3 Cells
• Nanoparticles (chemistry, toxicity, ultrastructure)
• Neoplasm Recurrence, Local (drug therapy)
• Porosity
• Reactive Oxygen Species (metabolism)
• Risk Factors
• Silicon Dioxide (chemistry)
• Tissue Distribution (drug effects)