TY - JOUR

T1 - Stimuli‐Responsive Polypeptide Nanoparticles for Enhanced  DNA Delivery 

AU - Korovkina, Olga

AU - Polyakov , Dmitry

AU - Korzhikov-Vlakh, Viktor

AU - Korzhikova-Vlakh , Evgenia

N1 - Publisher Copyright: © 2022 by the authors.

PY - 2022/12/2

Y1 - 2022/12/2

N2 - The development of non-viral delivery systems for effective gene therapy is one of the current challenges in modern biomedicinal chemistry. In this paper, the synthesis of pH- and redox-responsive amphiphilic polypeptides for intracellular DNA delivery is reported and discussed. Two series of polypeptides consisting of L-lysine, L-phenylalanine, L-histidine, and L-cysteine as well as the same amino acids with L-glutamic acid were synthesized by a combination of copolymerization of N-carboxyanhydrides of α-amino acids and post-polymerization modification of the resulting copolymers. The presence of histidine provided pH-sensitive properties under weakly acidic conditions specific to endosomal pH. In turn, the presence of cysteine allowed for the formation of redox-responsive disulfide bonds, which stabilized the self-assembled nanoparticles in the extracellular environment but could degrade inside the cell. The formation of intraparticle disulfide bonds resulted in their compactization from 200–250 to 55–100 nm. Empty and pDNA-loaded cross-linked nanoparticles showed enhanced stability in various media compared to non-crosslinked nanoparticles. At the same time, the addition of glutathione promoted particle degradation and nucleic acid release. The delivery systems were able to retain their size and surface charge at polypeptide/pDNA ratios of 10 or higher. GFP expression in HEK 293 was induced by the delivery of pEGFP-N3 with the developed polypeptide nanoparticles. The maximal transfection efficacy (70%) was observed when the polypeptide/pDNA ratio was 100.

AB - The development of non-viral delivery systems for effective gene therapy is one of the current challenges in modern biomedicinal chemistry. In this paper, the synthesis of pH- and redox-responsive amphiphilic polypeptides for intracellular DNA delivery is reported and discussed. Two series of polypeptides consisting of L-lysine, L-phenylalanine, L-histidine, and L-cysteine as well as the same amino acids with L-glutamic acid were synthesized by a combination of copolymerization of N-carboxyanhydrides of α-amino acids and post-polymerization modification of the resulting copolymers. The presence of histidine provided pH-sensitive properties under weakly acidic conditions specific to endosomal pH. In turn, the presence of cysteine allowed for the formation of redox-responsive disulfide bonds, which stabilized the self-assembled nanoparticles in the extracellular environment but could degrade inside the cell. The formation of intraparticle disulfide bonds resulted in their compactization from 200–250 to 55–100 nm. Empty and pDNA-loaded cross-linked nanoparticles showed enhanced stability in various media compared to non-crosslinked nanoparticles. At the same time, the addition of glutathione promoted particle degradation and nucleic acid release. The delivery systems were able to retain their size and surface charge at polypeptide/pDNA ratios of 10 or higher. GFP expression in HEK 293 was induced by the delivery of pEGFP-N3 with the developed polypeptide nanoparticles. The maximal transfection efficacy (70%) was observed when the polypeptide/pDNA ratio was 100.

KW - pH и редокс-чувствительные системы доставки

KW - сшитые наночастицы

KW - полипептиды

KW - доставка генов

KW - pH and redox-responsive delivery systems

KW - cross-linked nanoparticles

KW - polypeptides

KW - Gene delivery

KW - gene delivery

UR - http://www.scopus.com/inward/record.url?scp=85143642847&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/affaad70-5d1c-30a5-ac8e-8676a31c2b14/

U2 - 10.3390/molecules27238495

DO - 10.3390/molecules27238495

M3 - Article

VL - 27

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 23

M1 - 8495

ER -