Design of functional peptide-assembled polymer nanoparticles with uniform dispersion for oligonucleotide delivery to the brain and spinal cord via the nose-to-brain route

The physicochemical properties of nanoparticles influence their biodistribution and pharmacological effects, and for reproducibility, it is necessary to design nanoparticles of stable quality with good dispersion uniformity. In this study, we prepared assembled nanoparticles (AsNPs) with good dispersion uniformity using methoxy-polyethylene glycol-polycaprolactone (mPEG-PCL) and a stearic acid-modified functional peptide (STR-CH2R4H2C). The physicochemical properties and storage stability of the AsNPs were evaluated. Furthermore, we loaded antisense oligonucleotides (ASOs) onto AsNPs using electrostatic interactions and investigated their usefulness as drug delivery systems for the central nervous system (CNS) via the nose-to-brain route. The most stable and reproducible AsNPs were prepared using mPEG5k-PCL10k, with a particle size of 29.7 +/- 0.8 nm, polydispersity index (PDI) of 0.0401 +/- 0.0175, and zeta potential of 9.2 +/- 1.5 mV. The composition and molar ratio of the block copolymer to the functional peptide in the AsNPs affected the mean particle size, PDI, and zeta potential. It was also suggested that increasing the molecular weights of the PEG and PCL chains improved the PDI and storage stability of the nanoparticles. Evaluation of the knockdown (KD) activity of CNS target genes by the intranasal administration of ASO-loaded AsNPs (PDI<0.1) showed that ASO-loaded AsNPs tended to show KD in a wider region of the CNS than ASOs alone. These results showed that stable AsNPs with good dispersion uniformity were successfully prepared, which may be useful for oligonucleotide delivery via the nose-to-brain route.