Plasmids extravasation

Due to their large molecular weight (> 1,000 kDa) and hydrodynamic diameter in aqueous suspension of 100 nm, plasmids extravasate poorly via continuous capillaries because of tight junctions between the cells. However, plasmids can easily extravasate to sinusoidal capillaries of liver and spleen. Formulating plasmids into unimeric particles of 20-40 nm in diameter may enhance extravasation of plasmids across continuous and fenestrated capillaries. 

The deposition of plasmids after systemic administration is restricted to the intravascular space due to its low microvascular permeability in most organs with continuous capillary bed. Some organs with fenestrated capillaries, such as liver, spleen, and bone marrow, provide some opportunities for extravasation of plasmids. Intravenously injected plasmids initially perfuse the pulmonary vascular beds, maximizing the... 

Figure 14.1. Fate of plasmid DNA in vivo after intravascular (left) or tissue (right) injection. Upon administration, plasmid DNA can be taken up by various cells, including mononuclear phagocytes such as macrophages. It also interacts with plasma proteins and extracellular matrix (ECM) components. In some cases, extravasation (intravascular route) or diffusion (tissue injection) is required for plasmid DNA to reach the target cell. Cellular uptake of DNA occurrs via an endocytotic route (solid lines) as well as a nonendocytotic route (dashed lines), depending on the vector and delivery method used for gene transfer. When endocytosis occurs, a means of endosomal escape is needed. Only plasmid DNA entering the nucleus has a chance to produce therapeutic protein.

Folate-linked liposomes showed efficient FR-dependent cellular uptake and transfection in vitro but have not delivered plasmid DNA successfully in vivo as part of gene therapy experiments (Hofland et al. 2002 Reddy et al. 2002). The major limitation of in vivo gene therapy using liposomes is the low transfection efficiency. A size for gene transfer vectors of less than 300 nm is required for extravasation and intratumoral diffusion, which could be limiting for targeted delivery. 

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