Folate receptor-targeted lipid-albumin nanoparticles (F-LAN) for therapeutic delivery of an Akt1 antisense oligonucleotide.

Abstract

BACKGROUND:

RX-0201 is an antisense oligonucleotide (ASO) against Akt1 currently in clinical trial for metastatic renal cancer.

PURPOSE:

To improve the delivery of RX-0201 using folate receptor-targeted lipid-albumin nanoparticles (F-LAN).

METHODS:

F-LAN were synthesized with the composition of DOTAP/soyPC/TPGS/folate-PEG-DSPE (25:70:4:1 m/m), a cationic human serum albumin-pentaethylenehexamine (HSA-PEHA) conjugate and RX-0201. The nanoparticles were evaluated in KB human carcinoma cells in vitro and in a KB murine xenograft tumour model in vivo for pharmacokinetics and antitumor activities.

RESULTS:

The F-LAN-RX-0201 had a mean particle size of 108.6 ± 5.8 nm, zeta potential of 10.5 ± 3.2 mV and ASO loading efficiency of 71.5 ± 4.5%. In KB cells, uptake and Akt1 inhibition by F-LAN-RX-0201 were greater than those of non-targeted LAN-RX-0201 and could be partially blocked by excess free folate. F-LAN-RX-0201 inhibited cell growth with an IC50 of 11.9 μM. In contrast, LAN-RX-0201 showed lower cytotoxicity with an IC50 of 32.0 μM. No significant cytotoxicity was observed with up to 250 µM of free RX-0201. Pharmacokinetic studies showed that F-LAN-RX-0201 had a longer terminal half-life than free RX-0201 (442 vs. 219 min). In a KB xenograft tumour model, F-LAN-RX-0201 exhibited greater tumour inhibition than LAN-RX-0201 at 16 mg/kg. Moreover, F-LAN-RX-0201 at 16 mg/kg showed comparable tumour inhibition compared to free RX-0201 at a much higher dose of 90 mg/kg.

CONCLUSIONS:

F-LAN-RX-0201 showed promise as a therapeutic agent for tumours with elevated folate-receptor expression.

• Authors: Hong Li, Yang Liu, Lihua Chen, Qibing Liu, Shanshan Qi, Xinwei Cheng, Young B Lee, Chang-Ho Ahn, Deog Joong Kim, Robert J Lee
• Journal: Journal of drug targeting (J Drug Target) 2018 Jun - Jul Vol. 26 Issue 5-6 Pg. 466-473 ISSN: 1029-2330 [Electronic] England
• PMID: 29376449 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Albumins
• Fatty Acids, Monounsaturated
• Folate Receptors, GPI-Anchored
• Lipids
• Oligonucleotides
• Oligonucleotides, Antisense
• Phosphatidylethanolamines
• Quaternary Ammonium Compounds
• RX-0201
• polyethylene glycol-distearoylphosphatidylethanolamine
• Vitamin E
• Polyethylene Glycols
• Folic Acid
• AKT1 protein, human
• Proto-Oncogene Proteins c-akt
• 1,2-dioleoyloxy-3-(trimethylammonium)propane
• tocophersolan

Topics

• Albumins (chemistry)
• Animals
• Carcinoma (pathology, therapy)
• Fatty Acids, Monounsaturated (chemistry)
• Folate Receptors, GPI-Anchored (metabolism)
• Folic Acid (chemistry)
• Humans
• KB Cells
• Lipids (chemistry)
• Mice
• Mice, Inbred ICR
• Mice, Nude
• Nanoparticles
• Oligonucleotides (administration & dosage, pharmacology)
• Oligonucleotides, Antisense (administration & dosage, pharmacology)
• Particle Size
• Phosphatidylethanolamines (chemistry)
• Polyethylene Glycols (chemistry)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Quaternary Ammonium Compounds (chemistry)
• Vitamin E (chemistry)
• Xenograft Model Antitumor Assays