Levit, Mariia L., Sivtsov, Evgenii V., Sinitsyna, Ekaterina S., Bagaeva, Irina O., Dobrodumov, Anatolii V., Nikolaeva, Alexandra L., Zakharova, Natalia V., Gostev, Alexey I., Silonov, Sergey A., Gofman, Iosif V., and Korzhikova-Vlakh, Evgenia G.
[Display omitted] • Novel gradient-like copolymers were synthesized by RAFT polymerization. • Copolymerization of N -vinylsuccinimide with O-cholesteryl (meth)acrylate was studied. • Amphiphilic poly(vinylsuccinamic acid-co-cholesteryl (meth)acrylate)s were obtained. • Stable nanoparticles of 100–400 nm were produced by several techniques. • Irinotecan delivery systems with high loading and inhibitory activity were developed. Today, biocompatible and bioinspired well-defined copolymers with the ability to form nanoparticles are of great interest as potential drug delivery systems. In this study, we report the synthesis of novel biocompatible copolymers from monomers with different activity and capable of forming gradient copolymers by RAFT polymerization. In particular, the copolymerization of N -vinylsuccinimide (VSI) and O -cholesteryl (meth)acrylate (Ch(M)A) mediated by S,S' -dibenzyl trithiocarbonate (DBTTC) has been thoroughly studied by varying the monomer ratio and the ratio of monomer to RAFT agent. Important dependencies such as molecular weight and monomer conversion versus time, and molar fraction of monomer units as a function of monomer conversion were investigated. The obtained copolymers were thoroughly characterized using a number of physicochemical methods such as 1H NMR, 1H–13C HSQC and ATR-IR-spectroscopy, size-exclusion chromatography, static and dynamic light-scattering, as well as thermogravimetric analysis. In addition, the reactivity ratios of VSI and ChMA were determined and the dyad and triad compositions of the copolymers were calculated from the obtained values. The synthesized P(VSI- co -Ch(M)A) were subjected to selective hydrolysis of succinimide ring to convert it into succinamic acid. This approach yields a set of bioinspired amphiphilic copolymers based on N -vinylsuccinamic acid (VSAA) and Ch(M)A. The synthesized series of P(VSI- co- Ch(M)A) and P(VSAA- co -Ch(M)A) were used to obtain nanoparticles by nanoprecipitation or self-assembly via direct dissolution in aqueous medium. In addition, the method of surface hydrolysis of VSI units in pre-formed P(VSI- co- Ch(M)A) nanoparticles was applied to produce nanoparticles with hydrophilic negatively charged surface and enhanced stability. All techniques were optimized to prepare nanoparticles with characteristics suitable for systems considered for drug delivery. Successful loading of the antitumor drug irinotecan into nanoparticles was achieved with high encapsulation efficacies. The storage stability of empty and irinotecan loaded nanoparticles were studied in various media (water, saline solution, serum containing cell culture medium) under room and refrigerator conditions. The developed empty nanoparticles exhibited low rate of uptake by macrophages and low cytotoxicity to irinotecan-sensitive colon cancer cells (Caco-2). In turn, the irinotecan-loaded nanoparticles demonstrated inhibitory activity against Caco-2 cells comparable to the free drug. [ABSTRACT FROM AUTHOR]