Cationic Graft Copolymers as Carriers for Delivery of Antisense‐Oligonucleotides

Abstract

Abstract Self‐assembling systems based on ionic complexes of DNA fragments (36 base pairs), bcl‐2 antisense oligonucleotides (octadecamer), oligophosphates (25 phosphate groups) or acrylic oligomers (18 groups of phosphonic acid) with poly( L ‐lysine) (PLL) ( $\overline M _{\rm w}$ = 130 000 and 88 000) grafted with short poly[ N ‐(2‐hydroxypropyl)methacrylamide] (PHPMA) chains ( $\overline M _{\rm n}$ = 4 300 or 8 600) were studied by static and dynamic light scattering methods as systems suitable for gene therapy applications. The graft copolymers (GPLLs) with shorter PHPMA grafts ( $\overline M _{\rm n}$ = 4 300) provide polyelectrolyte complexes (PECs) with smaller $\overline M _{\rm w}$ and R H than the corresponding GPLLs with longer grafts ( $\overline M _{\rm n}$ = 8 600) and the same content of PLL. The lowest aggregation number of 2 was observed for PECs prepared from the GPLL with short grafts and 40 wt.‐% of PLL. The complexes of oligonucleotides and DNA fragments with GPLLs showed quite similar behavior to that with oligophosphates and acrylic oligomer. The complexes prepared from GPLLs containing 40 wt.‐% of PLL and at excess of oligophosphate were stable for at least 48 h under physiological conditions (0.15 M NaCl) and in bovine serum albumin solutions (1 mg · mL −1 ). Additionally, polyanion exchange reactions of the PECs in contact with poly(styrenesulfonate) and DNA were studied in 0.15 M NaCl solutions. The oligophosphates in complexes were at least partially substituted with high‐molecular‐weight polyanions. The structure of the initial PECs dominated the PEC structure after the exchange reaction. The dependence of the molecular weight $\overline M _{\rm w}$ (a) and the hydrodynamic radius R H (b) of complexes of the oligophosphate (OPP) and four graft copolymers (GPLLi, i = 0–3) on the mixing ratio X . magnified image The dependence of the molecular weight $\overline M _{\rm w}$ (a) and the hydrodynamic radius R H (b) of complexes of the oligophosphate (OPP) and four graft copolymers (GPLLi, i = 0–3) on the mixing ratio X .