Polymer Based Antiangiogenic Gene Therapy

Anti-angiogenic gene therapy strategies against several human tumors have shown encouraging results in animal models.160,161 A number of strategies to deliver therapeutic genes to angiogenic endothelial cells using RGD guided viral162,163 and non-viral systems (cationic polymers, cationic lipids,165 and cationic peptides166) have been investigated. The cationic polymer poly-ethylenimine (PEI) has been extensively used as a non-viral gene carrier.167 PEI has also been investigated as an RGD guided transfection system for angiogenic endothelial cells (Table 9.4). Broadly, these systems can be divided into two classes: those that are direct conjugates of PEI-RGD168,169 and those where RGD is conjugated onto PEI via a hydrophilic PEG spacer (PEI-PEG-RGD).164,168,170-172 Because of their reduced non-specific interaction with normal tissues, the charge-shielded pegylated systems have shown more efficient targeting and gene transfection.171,172

The PEI-PEG-RGD conjugate architecture has been used to deliver siRNA as a means to inhibit VEGFR-2 expression.170 Specific tumor accumulation was observed in a murine neuroblastoma model, and there was lower non-specific uptake in lung and liver as compared to aqueous siRNA and non-targeted conjugate. With a 40 mg treatment dose repeated every three days, there

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