Abstract 1322: Folate receptor-targeted lipid coated albumin nanoparticles (F-LCAN) for therapeutic delivery of RX-0201 (Archexin®), an antisense oligonucleotide against Akt-1

Abstract

Abstract Akt-1 is a protein kinase that contributes to cancer progression by promoting proliferation and inhibiting apoptosis of tumor cells. RX-0201 (Archexin®), a 20-mer phosphorothioate antisense oligonucleotide that inhibits the expression of Akt-1, is currently in a Phase IIa clinical trial for metastatic renal cancer. To further improve the efficacy of RX-0201, folate receptor-targeted lipid coated albumin nanoparticles containing RX-0201 (F-LCAN-RX-0201) were synthesized and evaluated for Akt-1 inhibition and antitumor activity. These nanoparticles are composed of DOTAP/soyPC/TPGS/folate-PEG-DSPE (25:70:4:1), a cationic human serum albumin-pentaethylenehexamine (HSA-PEHA) conjugate, and RX-0201. F-LCAN-RX-0201 had a particle size of 108.6±5.8 nm, zeta potential of 10.5±3.2 mV and 71.5% antisense loading efficiency. F-LCAN-RX-0201 in folate receptor-expressing KB cells inhibited cell growth at IC50 of 11.9 ± 4.0 μM while free RX-0201 did not show significant cytotoxicity at concentration up to 250 μM. Cellular uptake and Akt-1 inhibition of F-LCAN-RX-0201 was greater than the non-targeted LCAN-RX-0201 and was partially blocked by excess free folate. Pharmacokinetic studies showed that F-LCAN-RX-0201 had a longer half-life than that of free RX-0201 (30 ± 4 min vs 10 ± 2 min). In a KB xenograft tumor model, F-LCAN-RX-0201 exhibited higher tumor suppressive activity compared to the non-targeted LCAN-RX-0201 at 16 mg/kg (as a RX-0201 amount) without body weight changes. Moreover, the antitumor activity of F-LCAN-RX-0201 at a dose of 16mg/kg (as a RX-0201 amount) was similar to free RX-0201 at a dose of 90mg/kg. In conclusion, LCAN is a highly effective formulation for therapeutic delivery of antisense agents and F-LCAN-RX-0201 could be a potential therapeutic agent for tumors with increased folate-receptor expression. Citation Format: Hong Li, Xinwei Cheng, Yang Liu, Young Bok Lee, Deog Joong Kim, Chang-ho Ahn, Robert J. Lee. Folate receptor-targeted lipid coated albumin nanoparticles (F-LCAN) for therapeutic delivery of RX-0201 (Archexin®), an antisense oligonucleotide against Akt-1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1322.