Delivery of miR-375 and doxorubicin hydrochloride by lipid-coated hollow mesoporous silica nanoparticles to overcome multiple drug resistance in hepatocellular carcinoma.

Abstract

Multidrug resistance (MDR) due to overexpression of P-glycoprotein (P-gp) is a major obstacle that hinders the treatment of hepatocellular carcinoma (HCC). It has been shown that miR-375 inhibits P-gp expression via inhibition of astrocyte elevated gene-1 (AEG-1) expression in HCC, and induces apoptosis in HCC cells by targeting AEG-1 and YAP1. In this study, we prepared lipid-coated hollow mesoporous silica nanoparticles (LH) containing doxorubicin hydrochloride (DOX) and miR-375 (LHD/miR-375) to deliver the two agents into MDR HCC cells in vitro and in vivo. We found that LHD/miR-375 overcame drug efflux and delivered miR-375 and DOX into MDR HepG2/ADR cells or HCC tissues. MiR-375 delivered by LHD/miR-375 was taken up through phagocytosis and clathrin- and caveolae-mediated endocytosis. Following release from late endosomes, it repressed the expression of P-gp in HepG2/ADR cells. The synergistic effects of miR-375 and hollow mesoporous silica nanoparticles (HMSN) resulted in a profound increase in the uptake of DOX by the HCC cells and prevented HCC cell growth. Enhanced antitumor effects of LHD/miR-375 were also validated in HCC xenografts and primary tumors; however, no significant toxicity was observed. Mechanistic studies also revealed that miR-375 and DOX exerted a synergistic antitumor effect by promoting apoptosis. Our study illustrates that delivery of miR-375 using HMSN is a feasible approach to circumvent MDR in the management of HCC. It, therefore, merits further development for potential clinical application.

• Authors: Huiying Xue, Zhaoyang Yu, Yong Liu, Weigang Yuan, Tan Yang, Jia You, Xingxing He, Robert J Lee, Lei Li, Chuanrui Xu
• Journal: International journal of nanomedicine (Int J Nanomedicine) Vol. 12 Pg. 5271-5287 ( 2017) ISSN: 1178-2013 [Electronic] New Zealand
• PMID: 28769563 (Publication Type: Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antibiotics, Antineoplastic
• Lipids
• MIRN375 microRNA, human
• MicroRNAs
• Silicon Dioxide
• Doxorubicin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Animals
• Antibiotics, Antineoplastic (administration & dosage, chemistry, pharmacokinetics)
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (drug therapy, metabolism)
• Cell Line, Tumor
• Doxorubicin (administration & dosage, pharmacokinetics)
• Drug Delivery Systems (methods)
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Lipids (chemistry)
• Liver Neoplasms (drug therapy, metabolism)
• Mice, Inbred BALB C
• MicroRNAs (administration & dosage, pharmacokinetics)
• Nanoparticles (administration & dosage, chemistry)
• Silicon Dioxide (chemistry)
• Tissue Distribution
• Xenograft Model Antitumor Assays