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Polymers based on amphiphilic derivatives of N-vinylpyrrolidone are able to form nanoparticles in water solutions and to immobilize water insoluble drugs. Chemically linking of the antitumor receptor-selective variant TRAIL DR5-B to the polymer-based nanoparticles will increase the protein stability and support the hypothesis that increase of the cytokine local concentration enhances the clustering of the DR5 death receptor on the surface of tumor cells and improves the efficiency of the apoptotic signal. Amphiphilic copolymers of N-vinyl-2-pyrrolidone and acrylic acid (the content of acrylic units is 5 mol%) were synthesized by a one-stage method by polymerizing monomers of N-vinyl-2- pyrrolidone and acrylic acid in the presence of the initiator of radical polymerization (azobisisobutylonitrile), transmitter and regulator of chain growth (octadecylmercaptan). TRAIL DR5-B protein was produced in E. coli cells and purified on the affinity sorbent Ni-NTA followed by cation-exchange sorbent SP Sepharose. The TRAIL DR5-B protein was linked to the amphiphilic copolymer by the selective covalent interaction of the protein amino groups with activated carboxyl groups of the amphiphilic copolymer. Resulting conjugates were purified by gel filtration on a Sephadex sorbent using FPLC. Obtained polymers were characterized by the following parameters: the average size of the particles, ζ-potential, and the amount of the attached protein. As a result, we obtained polymeric nanoparticles with a hydrophobic core and a hydrophilic surface based on amphiphilic N-vinyl-2- pyrrolidone, and developed optimal conditions for its conjugation with antitumor cytokine TRAIL DR5-B. The work is supported by the RFBR grant No. 18-34-00812.