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Targeted delivery of microRNA‐199a‐3p using self‐assembled dipeptide nanoparticles efficiently reduces hepatocellular carcinoma in mice
Author(s) -
Varshney Aditi,
Panda Jiban J.,
Singh Avishek K.,
Yadav Nitin,
Bihari Chhagan,
Biswas Subhrajit,
Sarin Shiv K.,
Chauhan Virander S.
Publication year - 2018
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.29643
Subject(s) - hepatocellular carcinoma , cancer research , microrna , apoptosis , asialoglycoprotein receptor , downregulation and upregulation , chemistry , gene delivery , cell growth , in vitro , microbiology and biotechnology , biology , transfection , biochemistry , gene , hepatocyte
Hepatocellular carcinoma (HCC) is an aggressive tumor with limited systemic and locoregional modalities of treatment. Although microRNA (miRNA) based therapies have significant potential, their targeted delivery remains a major challenge. miR‐199a‐3p functions as an important tumor suppressor in HCC, which regulates various cellular processes. Recently, peptide‐based nanoparticles (NPs) have been developed to deliver oligonucleotides including miRNA. Here, we describe the synthesis and characterization of arginine α,β‐dehydrophenylalanine (RΔF) nanoparticles for the selective delivery of miR‐199a‐3p to restore dysregulated gene expression in HCC. Targeted delivery was achieved by conjugating lactobionic acid (LA) with RΔF NPs (RΔF‐LA NPs), a ligand for the asialoglycoprotein receptor known to be overexpressed in HCC cell lines. RΔF‐LA NPs condensed miR‐199a‐3p had an average size of ∼60nm and a zeta potential of ∼+2.54 mV. RΔF‐LA/miR NPs were found to be stable in serum as well as against RNase attack. RΔF‐LA/miR NPs showed an enhanced cellular uptake and an efficient delivery of miR‐199a‐3p leading to a significant increase in miR‐199a‐3p levels (over 500 fold). The increased miR‐199a‐3p levels remarkably suppressed cell proliferation and migration as well as induced cellular apoptosis and downregulation of the specific target gene (mTOR) in vitro . RΔF‐LA/miR NPs showed high tumor/ low organ ratios after intravenous injection into HCC tumor bearing nude mice. RΔF‐LA/miR NPs treated mice demonstrated>50% decline in tumor growth, which also corresponded well with suppression of mTOR protein expression, tumor cell proliferation and increased survival rate ( P < 0.05). Conclusion : RΔF‐LA/miR NPs showed significantly enhanced delivery of the miRNA which underscores their potential for further development as a therapeutic approach for HCC. (H epatology 2018;67:1392‐1407)