title: Delivery of mitogen-activated protein kinase inhibitor for hepatocellular carcinoma stem cell therapy.
abstract: Hepatocellular carcinoma (HCC) is one of the most common malignant human tumors worldwide, but no effective therapeutic options are currently available. The cancer stem cell (CSC) has proven to play a central role in the development, metastasis, and recurrence of HCC. In this study, we report a dual functional mitogen-activated protein kinase inhibitor (U0126)-based therapy for treating both bulk HCC and HCC CSCs, using poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-PLA) nanoparticles as the drug carrier. It is demonstrated that nanoparticle encapsulation enhanced the cell uptake of U0126 in HCC CSCs and that enhanced endocytosis lead to augmented cytotoxicity of U0126 in HCC CSCs. Moreover, the nanoparticle encapsulation increased the inhibition of self-renewal capability, prolonged the circulation time, and increased the tumor accumulation of U0126 when compared with the use of the free inhibitor. The systemic delivery of U0126 remarkably enhanced the suppression of tumor development with decreased CSCs in the HepG2 xenograft simultaneously with reduced systemic toxicity.
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China , Hefei, Anhui 230027, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Chun-Yang
authors.initials: CY
authors.lastname: Sun
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D002070:Butadienes / Q000737:chemistry; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D004337:Drug Carriers; D004705:Endocytosis; D004791:Enzyme Inhibitors / Q000737:chemistry; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009368:Neoplasm Transplantation; D009570:Nitriles / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D033581:Stem Cell Transplantation / Q000379:methods*
chemical_list: D002070:Butadienes; D004337:Drug Carriers; D004791:Enzyme Inhibitors; D009570:Nitriles; C113580:U 0126; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; D011092:Polyethylene Glycols; D020928:Mitogen-Activated Protein Kinases
keywords: CSC; U0126; hepatocellular carcinoma; mitogen-activated protein kinase; nanoparticle