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

<bold>Background:</bold> RX-0201 is an antisense oligonucleotide (ASO) against Akt1 currently in clinical trial for metastatic renal cancer. <bold>Purpose:</bold> To improve the delivery of RX-0201 using folate receptor-targeted lipid-albumin nanoparticles (F-LAN). <bold>Methods:</bold> 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 <italic>in vitro</italic> and in a KB murine xenograft tumour model <italic>in vivo</italic> for pharmacokinetics and antitumor activities. <bold>Results:</bold> 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. <bold>Conclusions:</bold> F-LAN-RX-0201 showed promise as a therapeutic agent for tumours with elevated folate-receptor expression. [ABSTRACT FROM AUTHOR]