Abstract
The objective of the present study is to conjugate L-thyroxine PEI derivative onto another PEI to compensate the amine content of the whole structure which has been utilized for the ligand conjugation. Since αvβ3 integrin receptors are over-expressed on cancer cells and there is binding site for L-thyroxine on these receptors, PEI conjugation by L-thyroxine along with restoring the PEI amine content might be an efficient strategy for targeted delivery using polymeric nanoparticles. The results demonstrated the ability of the PEI conjugate in the formation of nanoparticles with the size of around 210 nm with higher buffering capacity. The conjugated PEI derivative increased the transfection efficiency in the cell lines over-expressing integrin by up to two folds higher than unmodified PEI, whereas in the cell lines lacking the integrin receptors there was no ligand conjugation-associated difference in gene transfer ability. The specificity of transfection demonstrated the delivery of plasmid DNA through integrin receptors. Also, the results of in vivo imaging of the polyplexes revealed that 99mTc-labeled PEI/plasmid DNA complexes accumulated in kidney and bladder 4 h post injection. Therefore, this PEI derivative could be considered as an efficient targeted delivery system for plasmid DNA.
Highlights
Immunotherapy has been considered as a new paradigm for the treatment of various types of cancers in recent years[1,2]
Among the polymers used as gene carrier, polyethylenimine (PEI) has shown great potential for gene delivery due to its high amine content resulting in the significant proton sponge effect which leads to the early escape of the complexes from endo/lysosomal compartments[12,13]
The Branched polyethylenimine (bPEI) primary amines were conjugated by succinic anhydride to provide the terminal carboxylate group for the formation of the further amide bond
Summary
Immunotherapy has been considered as a new paradigm for the treatment of various types of cancers in recent years[1,2]. Conjugation of targeting ligands via the amines on the surface of PEI has been proposed to direct the PEI/nucleic acid complexes into a specific site of action. These conjugation strategies may reduce the cell-induced toxicity of PEI due the reduction of significant positive charge density on the polymer surface which is responsible for the induction of toxic effects[9,14,15,16]. There are some studies reporting the existence of a recognition site for the thyroid hormone (L-thyroxine, T4) on the extracellular domain of the integrin receptors It seems that this binding site is near or even at the RGD binding site[24]. The radiolabeled complexes were injected to the mice and their biodistribution was studied
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