Non-viral Gene Therapy - Intracellular Delivery: Fundamentals and Applications - page 643

(Fig. 6b ) (Rigby 1969 ). Domb's group has developed a series of oligoamines
conjugated dextrans for gene delivery recently, which were synthesized by oxidizing
dextran with periodate followed by reductive amination with various oligoamines
(Azzam et al. 2002 ). In this polycation library, spermine-conjugated dextran
(DEX-SP) is the most effective vector (Fig. 6c ). DEX-SP showed the transfection
efficiency as higher as DOTAP-based lipoplexes. High local gene expression was
observed post-intramuscular injection of DEX-SP/pDNA polyplexes, while no
expression was observed after intravenous injection of the same nano-formulation
(Hosseinkhani et al. 2004 ). PEGylation of DEX-SP led to a polymer with high
transfection yield in serum-rich medium. Furthermore, this dextran derivation can
high efficiently mediate the gene expression in the liver of mice post-intravenous
injection. Targeting studies suggested that the preferential binding to galactose
receptor of liver parenchymal cells rather than the mannose receptor of liver non-
parenchymal cells was responsible for the liver specific gene expression mediated
by PEGylated DEX-SP. In addition, the gene transfer capability of DEX-SP
in vitro and in vivo could be further enhanced by chemical modification using
hydrophobic moieties such as oleic acid, fatty acid, and cholesterol (Azzam et al.
2004 ; Eliyahu et al. 2005 ).

3.7.3 Vectors Derived from Proteins

Natural proteins such as collagen and gelatin as well as their derivatives have been
extensively studied for gene delivery applications. Methylated collagen could
mediate a gene transfection significantly higher than that of native collagen in HEK
293 cells (Wang et al. 2004c ). The transfection efficiency of this formulation was
dramatically affected by the collagen/pDNA weight ratio. Different from in vitro
result, the complexes based on native collagen showed a higher transfection level
than that of methylated collagen. Gelatin and its derivatives have also been demon-
strated to be effective vehicles for gene delivery. High level of gene transfection in
human tracheal epithelial cells was achieved using gelatin-DNA nanoparticles
(Truong-Le et al. 1999 ). Tabata and coworkers synthesized cationized gelatin,
which could effectively deliver a pDNA (expressing siRNA for TGF-b type II
receptor) to the interstitium of renal tissue, after the polyplexes were injected to the
left kidney of mice via the ureter (Kushibiki et al. 2005a, b ).

3.8 Biodegradable Hydrophobic Polymers

In addition to polycations, biodegradable polymers that are essentially hydrophobic
can also serve as carriers for gene therapy. Due to their degradation profile at a long
time scale, these polymers have been extensively employed for sustained or local
delivery of genetic payload. Polyesters, such as polylactide (PLA), poly(lactide-co-
glycolide) (PLGA), and poly(ortho esters) are among the most prominent materials
examined for these purposes.