Abstract
Because of the complex mechanisms mediating cancer onset, prognosis, and metastatic behavior, different therapeutic approaches targeting these mechanisms have been investigated. Recent advancements in nanocarrier-based drug and gene delivery methods have encouraged scientific groups to investigate various novel therapeutic techniques. In this study, a poly(amidoamine) (PAMAM) polymer-based gene carrier containing the cathepsin B-enzyme sensitive sequence (glycine-phenylalanine-leucine-glycine, GFLG) was evaluated to determine transfection efficiency. Following the GFLG sequence, the surface of PAMAM generation 4 (G4) was conjugated with histidine (H) and arginine (R) for improved endosomal escape and cellular uptake, respectively. The successful synthesis of G4-GLFG-H-R was confirmed by 1H-nuclear magnetic resonance spectroscopy. The polyplex composed of G4-GLFG-H-R and pDNA was simulated by the enzyme cathepsin B and induced endosomal escape of pDNA, which was confirmed by gel electrophoresis. Compared with the G4 control, enzyme-sensitive G4-GLFG-H-R showed higher transfection efficiency and lower cytotoxicity in HeLa cells. These results demonstrated that G4-GLFG-H-R may be a highly potent and efficient carrier for gene therapy applications.
Highlights
Efficient cancer therapy is urgently needed because of the disease’s complicated onset and growth mechanisms and the increasing incidence rates of various types of cancer
HeLa cells were grown in 89% Dulbecco’s modified Eagle’s medium (DMEM) with 10% fetal bovine serum (FBS) and 1% antibiotic-antimycotic solution and L929 cells were grown in 89% RPMI 1640 with 10% FBS and 1% antibiotic-antimycotic solution
These results indicate that generation 4 (G4)-GLFG-H-R facilitates perinuclear perinuclearsites sitescompared comparedto toother otherpolyplexes
Summary
Efficient cancer therapy is urgently needed because of the disease’s complicated onset and growth mechanisms and the increasing incidence rates of various types of cancer. Non-viral vectors offer various advantages over viral vectors, including low cytotoxicity, tunable size and surface properties, and the ability to condense larger nucleic acids for intracellular delivery [6,7,8]. Despite their low transfection efficiency, novel strategies are still being investigated to maximize efficacy. PAMAM dendrimers have recently emerged as potential gene delivery carriers through chemical modification, such as cationic polymers, cancer-targeting moieties, and enzyme-sensitive linkers. This enzyme-sensitive property of G4-GLFG-H-R can result in enhanced transfection efficiency compared with unmodified G4.
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