Intracellular Trafficking, Metabolism and Toxicity of Current Gene Carriers

Abstract

Gene delivery remains to be a very challenging field to efficiently transport the therapeutic gene and to modulate proteins with the desired function at the target site. The physiochemical and biological barriers are the major hurdles that need to be considered, particularly when administered systematically, in order to optimize the therapeutic efficacy. Numerous modifications have been extensively investigated aiming to provide protection from the plasma degradation, enhancement of transfection, target specificity, and most importantly, minimizing the side effects such as cellular toxicity and immune response. This article provides a review with respect to the in vitro and in vivo toxicity, as well as cellular and physiological interactions with the gene delivery system composed from viral vectors, cationic lipids and polymers. Recent progress and development are also addressed, with promising results that may be further adopted for clinical use.

Bolaamphiphiles as carriers for siRNA delivery: From chemical syntheses to practical applications

“…Thus, a sufficient amount of siRNA molecules were not available at the lower concentration of 5 μg/mL to cause the silencing effect due to strong binding of DS RNA with GLH-60, whereas due to lower binding affinity of DS RNA with GLH-58, this bola showed significant silencing activity at lower concentrations compared to GLH-60. The results of this study suggest that our bolaamphiphile carrier is at least as effective as other lipid-based carriers, but the higher stability of bolaamphiphiles of the type described here [17, 31] as compared to amphiphiles with one hydrophilic head group, such as those found in lipoplexes, and the lower toxicity of these types of bolaamphiphiles [17] compared to other cationic lipids used for the delivery of nucleic acids [8], indicate the superiority of bolaamphiphiles over other amphiphiles in delivering nucleic acids.…”

“…Yet, most of these lipid-based carriers have drawbacks that hamper their use in vivo . The most serious problem is toxicity [8], since in order to achieve good complexation with the negatively charged nucleic acids, the lipid carrier should be cationic and cationic lipids have been shown to be toxic [9]. Another problem is stability as nanoparticles made of cationic lipids show very short survival in blood circulation [10] and their head groups may be sensitive to relatively low pHs [11].…”

Triolein-based polycation lipid nanocarrier for efficient gene delivery: characteristics and mechanism

“…24,25 Chlorpromazine could disturb the intracellular clathrin processing and was used to inhibit the clathrin-dependent endocytosis. On the other hand, filipin III could complex with membrane cholesterol and interferes with the cholesterol-sensitive process, thereby blocking the caveolae-mediated endocytosis.…”

“…24,25 To determine the internalization mode of PDC in SPC-A1 cells, transfection of plasmid pGL3-luc was performed in the presence of specific inhibitors of chlorpromazine (Chlor) and filipin III. Because the specificity and toxicity of the endocytic inhibitors varied with the cell lines, the viability of SPC-A1 cells treated with the endocytic inhibitors was over 80%, and their specificity in SPC-A1 cells was also …”

Biocompatible anionic polyelectrolyte for improved liposome based gene transfection

“…However, it has not been widely adopted especially in clinial applications owing to its instability, poor cellular uptake and limited transfection efficiency. Hence, an effective carrier is of vital importance for successful gene therapy.Viral vectors show high efficient gene delivery; however, the drawbacks such as immunogenicity and carcinogenicity restrict their further application (Ferber, 2001;Flotte et al, 2007;Kuo et al, 2009). Thus, non-viral gene delivery systems with less immunotoxic and easier preparation are widely explored (Gargouri et al, 2009;Guo and Huang, 2012;Fortier et al, 2014).…”