Non-viral Gene Therapy - Intracellular Delivery: Fundamentals and Applications - page 628

It has been found that the intranuclear gene delivery is strongly limited by
nuclear pore complexes (NPCs), which are proteins assembled channels that span
the nuclear envelope. The presence of glucocorticoids (GC) such as dexamethasone
(DEX) can lead to the dilation of NPC, which may significantly increase the effi-
ciency of nuclear gene transfection (Shahin 2006 ; Dames et al. 2007 ). The conjuga-
tion of DEX to DNA has been demonstrated to be able to facilitate the uptake of
transfected DNA into the nucleus, taking advantage of steroid receptors as shuttles
(Rebuffat et al. 2001 ). DEX, has been therefore conjugated to PEIs and the obtained
derivatives showed increased transfection efficacy (Bae et al. 2007 ; Kim et al.
2009a, b ). By conjugating five GCs to 1,800 Da bPEI (bPEI-GC), including
betamethasone, dexamethasone, hydrocortisone, methylprednisolone and predniso-
lone, it was found the transfection activity of bPEI-GC polymers correlated with
their GC potency (Ma et al. 2009 ).
A delicately modulated balance between hydrophilic and hydrophobic compo-
nents is crucial for designing more efficient gene vectors based on PEI. Detailed
knowledge about the molecular structure of PEI derivatives is a prerequisite in
order to establish clear structure-function relationships, as well as to optimize cyto-
toxicity and biocompatibility of resulting carriers. In general, the cytotoxicity of
PEI derivatives can be significantly changed by hydrophobic or amphiphilic modi-
fications. In addition, enhanced transfection activities can be implemented in most
cases. Moreover, incorporation of hydrophobic moieties into PEI may influence the
interactions of polyplexes with endo-/lysosomal membranes, resulting in a more
efficient escape from these compartments.

3.3 Cyclodextrin-Containing Polymers

Due to their excellent compatibility and low immunogenicity, multiple sites for
functionalizing as well as their complexation capability with a broad spectrum of
substances including hydrophobic molecules and macromolecules, cyclodextrins
(CDs) are promising candidates for the development of new vectors. There have
been increasing interests in recent years to discover efficient delivery carriers for
gene therapy base on CDs and their derivatives. Table 7 summarizes CD-containing
compounds used for gene transfections.

3.3.1 Cyclodextrin Derivatives

Cationic derivatives were prepared by modifying b-CD with pyridylamino, alky-
limidazole, methoxyethylamino or primary amine groups at 6-positions of the
glucose units (Cryan et al. 2004 ). These compounds could form stable nanoparticu-
late complexes with DNA, while their transfection activities in COS-7 cells were
dependent on the substituents and their sites. The most effective vector, heptak-
ispyridylamino CD, produced a 4,000-fold increase in transfection level over DNA