RESUMO
High transfection efficiency and low cytotoxicity are the two key factors to be considered in the design of gene carriers. Herein, a novel and versatile gene carrier (PLL-RT) was prepared by introducing "molecular string" RT (i.e., p-toluylsulfonyl arginine) onto the polylysine backbone. The introduction of RT string contributed to the formation of multiple interactions between the polycationic gene carriers and cell membrane or DNA, as well as adopting α-helix conformation, all of which would be beneficial to enhance the gene transfection. In addition, RT string grafted onto other polycations such as hyperbranced PEI25k and dendrimer PAMAM could also acquire improved transfection efficiency and low cytotoxicity. Moreover, PLL-RT presented significant tumor inhibition effect in vivo. This work provided an effective strategy for constructing novel gene carriers with high transfection and low cytotoxicity.
Assuntos
DNA/genética , Técnicas de Transferência de Genes , Polilisina/análogos & derivados , Tosilarginina Metil Éster/análogos & derivados , Animais , Cardiolipinas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA/metabolismo , Endocitose/fisiologia , Endossomos/metabolismo , Feminino , Humanos , Membranas Artificiais , Camundongos Endogâmicos BALB C , Conformação Molecular , Neoplasias/terapia , Tamanho da Partícula , Polilisina/síntese química , Polilisina/metabolismo , Polilisina/toxicidade , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/uso terapêutico , Tosilarginina Metil Éster/síntese química , Tosilarginina Metil Éster/metabolismo , Tosilarginina Metil Éster/toxicidadeRESUMO
Polycationic gene carriers are attracting increasing attention for their use as gene delivery systems. Herein, a novel and high-performance polycationic gene carrier (i.e., Zn-DPPA2) was constructed by introducing a dipicolylamine compound along with zinc ion coordination onto polyethylenimine (PEI1.8k) via Schiff base bonds. Zn-DPPA2 exhibited efficient transfection and negligible cytotoxicity. Zn-DPPA2/DNA complexes possessed significant endocytosis efficiency and excellent endosomal escape ability. Additionally, this polycaitionic gene carrier showed an excellent ability as an antiserum. The nanoscale size and good size stability ensured that Zn-DPPA2/DNA could accumulate in tumor tissue through the enhanced permeability and retention (EPR) effect. Moreover, Zn-DPPA2/DNA complexes exhibited efficient transfection in tumor tissue after intravenous injection. This strategy provided a new idea for polycationic gene carrier construction, which has prospects for widespread application in the field of gene therapy.