title: Lipid-Albumin Nanoparticles (LAN) for Therapeutic Delivery of Antisense Oligonucleotide against HIF-1α.
abstract: Lipid-albumin nanoparticles (LAN) were synthesized for delivery of RX-0047, an antisense oligonucleotide (ASO) against the hypoxia inducible factor-1 alpha (HIF-1α) to solid tumor. These lipid nanoparticles (LNs) incorporated a human serum albumin-pentaethylenehexamine (HSA-PEHA) conjugate, which is cationic and can form electrostatic complexes with negatively charged oligonucleotides. The delivery efficiency of LAN-RX-0047 was investigated in KB cells and a KB murine xenograft model. When KB cells were treated with LAN-RX-0047, significant HIF-1α downregulation and enhanced cellular uptake were observed compared to LN-RX-0047. LN-RX-0047 and LAN-RX-0047 showed similar cytotoxicity against KB cells with IC50 values of 19.3 ± 3.8 and 20.1 ± 4.2 μM, respectively. LAN-RX-0047 was shown to be taken up by the cells via the macropinocytosis and caveolae-mediated endocytosis pathways while LN-RX-0047 was taken up by cells via caveolae-mediated endocytosis. In the KB xenograft tumor model, LAN-RX-0047 exhibited tumor suppressive activity and significantly reduced intratumoral HIF-1α expression compared to LN-RX-0047. Furthermore, LAN-RX-0047 greatly increased survival time of mice bearing KB-1 xenograft tumors at doses of either 3 mg/kg or 16 mg/kg. These results indicated that LAN-RX-0047 is a highly effective vehicle for therapeutic delivery of antisense agents to tumor.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Jishan
authors.initials: J
authors.lastname: Quan
authors.affiliation: Molecular, Cellular and Developmental Biology Program, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Mengzi
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Bryant C
authors.initials: BC
authors.lastname: Yung
authors.affiliation: Department of Biomedical Engineering, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Xinwei
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Rexahn Pharmaceuticals, Inc. , Rockville, Maryland 20850, United States.
authors.forename: Young B
authors.initials: YB
authors.lastname: Lee
authors.affiliation: Rexahn Pharmaceuticals, Inc. , Rockville, Maryland 20850, United States.
authors.forename: Chang-Ho
authors.initials: CH
authors.lastname: Ahn
authors.affiliation: Rexahn Pharmaceuticals, Inc. , Rockville, Maryland 20850, United States.
authors.forename: Deog Joong
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
mesh_terms: D000418:Albumins; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D009841:Oligonucleotides / Q000737:chemistry* / Q000627:therapeutic use*; D016376:Oligonucleotides, Antisense / Q000737:chemistry*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000418:Albumins; D004337:Drug Carriers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008055:Lipids; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; C531306:RX 0047
keywords: RX-0047; antisense oligonucleotide; human serum albumin−pentaethylenehexamine conjugate; hypoxia inducible factor-1 alpha; lipid−albumin nanoparticle; therapeutic delivery