Lipid–Albumin Nanoparticles (LAN) for Therapeutic Delivery of Antisense Oligonucleotide against HIF-1α
| Autor: | Bryant C. Yung, Hong Li, Young Bok Lee, Deog Joong Kim, Robert J. Lee, Jishan Quan, Yang Liu, Xinwei Cheng, Mengzi Zhang, Chang-Ho Ahn |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Blotting Western Oligonucleotides Mice Nude Pharmaceutical Science Alpha (ethology) 02 engineering and technology Biology Endocytosis Mice 03 medical and health sciences Hypoxia-Inducible Factor 1-Alpha Downregulation and upregulation Albumins Cell Line Tumor Drug Discovery Animals Humans Cytotoxicity Drug Carriers Reverse Transcriptase Polymerase Chain Reaction Oligonucleotide Pinocytosis Oligonucleotides Antisense Hypoxia-Inducible Factor 1 alpha Subunit 021001 nanoscience & nanotechnology Lipids Xenograft Model Antitumor Assays Molecular biology 030104 developmental biology Nanoparticles Molecular Medicine 0210 nano-technology HeLa Cells Conjugate |
| Zdroj: | Molecular Pharmaceutics. 13:2555-2562 |
| ISSN: | 1543-8392 1543-8384 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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