Challenges and Opportunities in Gene Delivery - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 49

No. Barrier Significance Methods to Overcome the Barrier Reference

1. Extracellular barriers to naked DNA delivery

1.1 DNA stability against

serum nuclease

Complete degradation of DNA by serum
nuclease is observed

Complexation with polycation
decreases DNA degradation

[22]

1.2 Hepatic metabolism of

DNA

80% to 90 % of DNA is hepatically
metabolized during the first pass

Direct tissue or cell delivery avoids
hepatic metabolism

[22]

1.3 DNA charge, shape, and

size

Strong negative charge, supercoiled or linear
threadlike structure, and size around 2-8 kbp
hinder cell membrane permeation

Complexing the DNA with polycation
helps to decrease the size and
neutralizes the negative charge

[22]

2. Extracellular barriers to the DNA delivery system

2.1 Partial DNA degradation

against serum nuclease

Partially condensed DNA is degraded to a
significant extent by serum nuclease, resulting
in little or no transfection efficiency

Complete complexation and
condensation of DNA with the vector
partially protects DNA against
nuclease

[22,42]

2.2 Physical stability of DNA

delivery system

Colloidal instability during in vivo ionic
environment causes adhesion, aggregation, and
immobilization of the delivery system

Steric stabilization by PEGylation of
lipidic and polymeric cation improves
colloidal stability

[43]

2.3 RES and hepatic clearance Significant RES uptake after opsonization and

hepatic first-pass metabolism leads to systemic
clearance of the DNA delivery system

Steric stabilization by PEGylation of
lipidic and polymeric cation avoids
hepatic and RES clearance

[22]

2.4 Extravasation Extravasation to target tissue via small gaps of

endothelial cells of capillary membrane is very
difficult

Direct tissue injection of the DNA-
polycation system results

[22]

2.5 Biodistribution and organ

and cellular targeting

Systemic delivery results in unwanted
biodistribution of the delivery system, with
reduced cellular delivery at target site

Ligand-attached DNA delivery
systems for target cells having certain
overexpressed receptors alter the
pharmacokinetics favorably

[43]