Trail dr5-b-conjugated polymeric nanoparticles for targeted delivery in tumors
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Mendeleev University of Chemical Technology of Russia, Moscow, Russia
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
Center of Strategic Planning and Management of Medical and Biological Health Risks, Moscow, Russia
Publication date: 2021-09-27
Public Health Toxicol 2021;1(Supplement 1):A22
In current study, polymeric nanoparticles based on poly-N-vinylpyrrolidone amphiphilic derivatives with hydrophilic polymer fragment and one anchor n-alkyl hydrophobic group were obtained, which were covalently conjugated to the antitumor cytokine TRAIL DR5-B. Such system possesses a therapeutic perspective due to the selective induction of apoptosis in tumor cells by specific binding of TRAIL DR5-B to the DR5 receptor, increased stability and apoptotic signal amplification caused by higher local concentration of cytokine.
In this work, we also investigated the effect of the particles composition on the size and sorption capacity, as well as antitumor activity in 3D in vitro models.
A pattern was revealed for an increase in the sorption capacity of particles with an increase in the content of the maleimide-modified polymer in the composition of the particles. It was shown that the particle size depends on the length of the polymer molecules, and the combination of macromolecules with different molecular weight of the polymeric fragment in the composition of the particles affects the steric accessibility of maleimide groups for TRAIL DR5-B/V114C protein molecules, and, thereby, on their sorption capacity.
The cytotoxicity of TRAIL DR5-B-conjugated polymeric nanoparticles with the maximum sorption capacity was tested in 3D models based on multicellular tumor spheroids of various origins in vitro. TRAIL DR5-B-conjugated polymer particles demonstrated enhanced cytotoxicity compared to free TRAIL DR5-B in 3D MCF-7 breast adenocarcinoma tumor spheroids model. At the same time, the absence of cytotoxicity to normal mesenchymal stem cells of the FRSN line was shown.
As a result, a completely novel type of polymeric nanoparticles for targeted delivery of the receptor-selective cytokine TRAIL DR5-B in tumors was obtained. After optimization of the polymer composition, size, and sorption capacity, TRAIL DR5-B-conjugated polymeric nanoparticles based on poly-N-vinylpyrrolidone amphiphilic derivatives can be investigated in xenograft preclinical models in vivo with promising clinical application for the treatment of a wide range of tumors.
The work of Kuskov A.N. was supported by D. Mendeleev University of Chemical Technology of Russia (Project Number K-2020-018).