Functional Polymers for Gene Delivery - Functional Polymers for Nanomedicine - page 73

Huang et al. synthesized a biodegradable PEI-based vector by grafting
branched 800 Da PEI onto poly( L -succinimide) (PSI) backbones (Scheme 4.4B). 27
This compound was considered to ultimately degrade into amino acids in vivo
and help release condensed plasmid DNA in the nucleolus. They further
conjugated methoxy-PEG to this biodegradable vector, which exhibited
remarkably lower cytotoxicity and higher transfection efficiency compared
to 25 kDa PEI. 28 In the study of He et al., biodegradable backbone
polycarbonates, poly[(5-methyl-5-allyloxycarbonyl-trimethylene carbonate)-
co-(5,5-dimethyl-trimethylene carbonate)], were grafted by 1800 kDa PEI
(Scheme 4.4C). 29 This polycation presented better degradability, lower
cytotoxicity, and much higher gene transfection efficacy in comparison with
25 kDa PEI.
Recently, more focus has been placed on the combination of both methods
in one gene delivery system, thereby resulting in better performance. Zhao
et al. synthesized a biodegradable disulfide-containing PEG-PEI by click
chemistry (Scheme 4.4D). 30 PEI (2 kDa) and short chain length PEG
(tetraethylene glycol, TEG) were crosslinked to a HMW PEG-PEI copolymer
(y22 kDa). This PEG-PEI polymer is about 22-fold less toxic than 25 kDa
PEI in the L929 cell line. After coupling of small PEG chains and crosslinking
by disulfide bridges, the transfection efficiency was increased approximately
six-fold in comparison to 2 kDa PEI. This click cluster crosslinked disulfide-
containing PEG-PEI copolymer could be an attractive cationic polymer for
nonviral gene delivery.

d n 4 y 3 n g | 3

4.2.2 Cell-Targeted Polyethylenimine
To develop in vivo suitable gene carriers, the important goal is to increase the
specific uptake efficiency and to decrease the nonspecific uptake efficiency. In
order to promote cell specificity, efforts have been made to combine or even
exchange the nonspecific electrostatic polyplex-cell surface interaction with a
specific receptor-mediated cellular uptake, by the incorporation of cell binding
ligands into the transfection complexes (Figure 4.5). A variety of ligands has
been successfully coupled to PEI, including galactose for hepatocyte targeting,
mannose for enhanced uptake by dendritic cells, epidermal growth factor for
enhanced uptake by epithelial cells, integrin-binding peptides and anti-CD3
antibodies for gene delivery to CD3-expressing cells (Table 4.1).
Much work has been directed to realize this aim by coupling cell-targeting
ligands, such as arginine-glycine-aspartic acid (RGD) peptides and folic acid,
onto cationic polymer vehicles in order to target integrin receptors on the cell
surface. Tian and co-workers modified the hyperbranched PEI with a
hydrophobic poly(c-benzyl L -glutamate) segment (PBLG). 31,32 The biocom-
patible PBLG grafting onto PEI shielded the toxicity of the PEI and condensed
the DNA into small particles (y100 nm). The compound PEI-PBLG exhibited
much higher transfection efficiency than that of 25 kDa PEI. Recently, the
same

group conjugated RGD peptides onto natural anionic polymer