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

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

  • J Drug Target. 2018 Jun-Jul;26(5-6):466-473. doi: 10.1080/1061186X.2018.1433678.
Hong Li 1,  Yang Liu 1,  Lihua Chen 1,  Qibing Liu 1,  Shanshan Qi 1,  Xinwei Cheng 1,  Young B Lee 2,  Chang-Ho Ahn 2,  Deog Joong Kim 2,  Robert J Lee 1
Affiliations

Affiliations

  • 1 a Division of Pharmaceutics , College of Pharmacy, The Ohio State University , Columbus , OH , USA.
  • 2 b Rexahn Pharmaceuticals, Inc. , Rockville , MD , USA.
PMID: 29376449 DOI: 10.1080/1061186X.2018.1433678
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.

Keywords

Akt1; Folate receptor; RX-0201; antisense oligonucleotide; cancer; drug targeting; human serum albumin; nanoparticles.

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