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Gene delivery intracellular barriers

Several major barriers need to be overcome for the development of nonviral gene delivery systems into true therapeutic products for use in humans. These barriers fall into three classes manufacturing, formulation, and stability (extracellular barriers and intracellular barriers) (85). Cationic lipids and cationic polymers self-assemble with DNA to form small particles that are suitable for cellular uptake. At the therapeutic doses positively charged particles readily aggregate as their concentration increases, and are quickly precipitated above their critical flocculation concentration. [Pg.345]

Gene delivery into eukaryotic cells is commonly performed for research purposes as well as in gene therapy procedures. Cellular membranes do not spontaneously take up ectopic nucleic acid because of the polar nature of the phospholipid bilayer [1] which functions as a natural barrier that prevents entry of most water-soluble molecules such as nucleic acids. In studies of gene or protein function and regulation, manipulation of the intracellular expression level is a fundamental approach. For this reason, multiple methods for delivery of nucleic acids through membranes using chemical, physical, or biological systems have been established in the last 40 years. [Pg.3]

Figure 6 Intracellular barriers to gene delivery include cellular uptake, intracellular transport, endosome escape, vector unpacking, and nuclear uptake. The gene carrier illustrated here has targeting moieties on the vector surface that are specific for cell surface receptors. The dotted arrow represents the prerequisite step of bypassing physiological barriers of the lung, such as the mucosal layer, and reaching the target cell surface. Figure 6 Intracellular barriers to gene delivery include cellular uptake, intracellular transport, endosome escape, vector unpacking, and nuclear uptake. The gene carrier illustrated here has targeting moieties on the vector surface that are specific for cell surface receptors. The dotted arrow represents the prerequisite step of bypassing physiological barriers of the lung, such as the mucosal layer, and reaching the target cell surface.
The need to overcome intracellular barriers may require improved methods of determining rate-limiting steps for specific gene carriers, which will lead to the rational design of new carriers. To this end, our lab uses multiple-particle tracking (MPT) to investigate quantitatively the motion of nanometersized DNA delivery vehicles [170],... [Pg.519]

Steps taken to understand the intracellular barriers to gene delivery have led to the rational modification and improvement of carriers. Quantitative methods, such as multiple-particle tracking, to assess to the intracellular transport of gene carriers promise to add valuable insight that may ultimately lead to nonviral carriers rivaling the efficiencies seen in viral systems. [Pg.523]

Actively transported PEI/DNA nanocomplexes exhibited an average velocity of 0.2 pm/sec [118], a value on the same order of magnitude as motor-protein driven motion. Transport was revealed to be microtubule dependent, because both active transport and perinuclear accumulation were abolished upon microtubule depolymerization. Experiments utilizing MPT to quantify the other intracellular barriers to gene delivery are under way. [Pg.524]

Gene delivery to MSCs requires that DNA overcomes several intracellular barriers that can limit efficiency, including limited cellular internalization, endosomal escape, vector unpacking, and transport into the nucleus. [Pg.401]

Figure 17.2 Extracellular, intracellular and commercial barriers in the sustained brain gene delivery system. Figure 17.2 Extracellular, intracellular and commercial barriers in the sustained brain gene delivery system.
For successful gene delivery, nonviral vectors have to be overcome at a number of extracellular as well as intracellular barriers until the carried DNA reaches its final destination, the nucleus. One strategy for overcoming the extracellular barriers in nonviral gene delivery is receptor-mediated endocytosis to enhance cellular uptake specifically. [Pg.380]

A major effort in the field of gene delivery is the development and evaluation of synthetic vectors to overcome the extra- and intracellular barriers encountered in the gene transfection pathway. The major barriers include... [Pg.3325]

To reach to the cellular nucleus or cytosol, DNA or siRNA has to be delivered aggressively through barriers. There are two barriers to gene delivery one at the extracellular level and the other at the intracellular level, as shown in Table 2 [26]. In this section, we discuss strategies for overcoming these barriers. [Pg.4]


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