Extracellular barriers

Burke RS, Pun SH (2008) Extracellular barriers to in vivo PEI and PEGylated PEI polyplex-mediated gene delivery to the liver. Bioconjug Chem 19 693-704... 

Between the free CSF space and the extracellular space there is a diffusion equilibrium for macromolecules. The intra/extracellular barrier and the blood-brain barrier are essentially lipid barriers, retaining small hydrophilic molecules but allowing the passage of lipophilic molecules up to approximately 500 Da... 

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. 

Extracellular barriers (DNA, enzymes, mucus) Paucity of receptors Proteosome-mediated degradation Inhibition of second-strand synthesis Airway clearance, anti-inflammatory, anti-protease pre-treatments Alternate serotypes, targeted capsid mutants Proteosome inhibitors (tripeptides, anthracyclines) Tyrosine kinase inhibitors... 

Helminths are multicellular parasites, often a millimeter or more in length. With rare exceptions (see Trichinella), invasion of and seclusion within host cells is not feasible. When speaking of host invasion by helminth parasites, one considers tissue invasion or, more specifically, migration through extracellular barriers. 

Delivery of DNA in vivo faces additional extracellular barriers posed by specific tissues and the immune system (Fig. 6.38). The blood-brain barrier, connective tissue, and epithelial cell linings are particular examples of cellular... 

Polyplexes face various extracellular as well as intraeellular barriers. Most of the extracellular barriers are the factors that influence biodistribution of the administered polyplexes from the point of delivery to the site of interest and they will vary profoundly between routes of delivery. 

Extracellular barriers in systemic delivery involve hurdles to nucleic acid delivery encountered from the point of injection to the surface of the cellular target. For cationic polymer-based systems, these barriers typically include the toxicity of the nanoparticles, interactions with semm proteins, extracellular matrices, and nonspecific cell surfaces, clearance by the innate immune system, aggregation due to physiological salt conditions, and evasion of the adaptive immune response. Ideally, the nanoparticle should (1) remain nontoxic, small, and dis-aete, (2) bypass the immune system, and (3) interact only with the cells of interest. Efforts to prepare polymer systems that endow nanoparticles with these characteristics are discussed below. 

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. 

The challenge is not limited to bringing the polyplex inside cells even if the polyplexes overcome the extracellular barriers, it is not useful if, due do its intrinsic toxicity, the polyplex kills cells after uptake. This is in many cases the reason why the overall transfection efficiency of a polyplex is rather low, despite a high value for its cellular uptake. Thus, it is of prime importance to study the intracellular uptake, for example with fluorescence imaging, as well as the toxicity of both the... 

Biological Barriers in the Delivery of Nucleic Acid Drugs 2.1 Extracellular Barriers... 

Fig. 1 Extracellular barriers to nucleic acid drug delivery...

---