Nanocarrier-mediated Delivery Of Small Molecule Modulater Of MiRNA-34a In Therapy Against Hepatocellular Carcinoma

MicroRNAs(miRNAs) are endogenous, evolutionarily conserved, non-coding RNA molecules of approximately 20~23 nucleotides in length that act as the post-transcriptional regulators in eukaryotes. Dysregulation of miRNAs has been broadly reported in a number of cancers, acting as either tumor suppressors or oncogenes. Therefore, miRNAs-based therapeutics provides exciting implications for attractive candidates for the therapeutic gene manipulation of cancers. However,delivery of miRNAs to the designed tumor site and required cellular site of action remains the biggest hurdle to clinical translation. In recent years, small molecule modulators of miRNA expression have been discovered and they could serve as novel therapeutics.Recently, a natural compound 2'-hydroxy-2,4,4',5,6'-pentamethoxychalcone termed Rubone was discovered, which could enhance tumor suppressor miRNA-34 a function and exhibit effective therapeutic activities against hepatocellular carcinoma(HCC). However, its poor aqueous solubility limited its direct application. In the present study, we constructed carboxymethyl dextran(CMD)-coated polyethyleneimine-poly(e-caprolactone)(PEI-PCL) nanoparticles(RC-NPs) to encapsulate Rubone and study its anti-HCC activities in vitro and in vivo.Firstly, Rubone was encapsulated in RC-NPs. The nanoparticle size, surface zeta potential, morphology, Rubone encapsulation and loading efficiency, in vitro release profiles of Rubone, colloidal stability and buffering capability of the nanoparticles were characterized.Secondly, the anti-HCC effects and mechanisms were further investigated by in vitro and in vivo models. It demonstrated that Rubone could be efficiently delivered into HepG-2 cells via RC-NPs, resulting in upregulation of miR-34 a expression,which further induces cell apoptosis and the inhibition of cell proliferation and migration. In addition, RC-NPs are able to targetedly deliver Rubone into tumor sites after intravenous injection and remarkably inhibit tumor growth. The obtained data indicate a great potential for RC-NPs as a promising nanoparticle platform for Rubone delivery that provides a novel strategy for miRNA-assisted therapy against hepatocellular cancer.