EGFR-homing dsRNA activates cancer-targeted immune response and eliminates disseminated EGFR-overexpressing tumors in mice.

Purpose: The cause of most cancer deaths is incurable dissemination of cancer cells into vital organs. Current systemic therapies for disseminated cancers provide limited efficacy and are often accompanied by toxic side effects. We have recently shown that local application of epidermal growth factor receptor (EGFR)-targeted polyinosine-cytosine (polyIC) eradicates preestablished EGFR-overexpressing tumors.

Induction of apoptosis in murine neuroblastoma by systemic delivery of transferrin-shielded siRNA polyplexes for downregulation of Ran.

The polymer, OEI-HD, based on beta-propionamide-cross-linked oligoethylenimine and its chemical transferrin conjugate were evaluated for siRNA delivery into murine Neuro2A neuroblastoma cells in vitro and in vivo. An 80% silencing of luciferase expression in neuroblastoma cells, stably transfected with a luciferase gene, was obtained using standard OEI-HD polyplexes or transferrin-conjugated shielded OEI-HD polyplexes. The Ras-related nuclear protein Ran was selected as a therapeutically relevant target protein.

Nitric oxide--a novel therapeutic for cancer.

Much research over the past two decades has focussed on understanding the complex interactions of nitric oxide (NO(.)) in both physiological and pathological processes. As with many other aspects of NO(.

DNA polyplexes based on degradable oligoethylenimine-derivatives: combination with EGF receptor targeting and endosomal release functions.

Combination of the degradable polymeric gene carriers OEI-HD-1 and LT- OEI-HD-1 with an EGF targeting conjugate resulted in strongly (up to 900-fold) enhanced polyplex activity in EGF-receptor rich HUH7 hepatocellular carcinoma cells. The targeting ligand effect was DNA dose dependent, could be blocked by competitive receptor binding with unbound EGF ligand, and was not observed in receptor-negative control cells. Measures which enhance intracellular endosomal escape, either photochemically enhanced intracellular release (PCI) or the incorporation of a novel membrane-active melittin analog NMA-3, further enhanced gene transfer activity of EGF/OEI-HD-1 polyplexes.

Melittin analogs with high lytic activity at endosomal pH enhance transfection with purified targeted PEI polyplexes.

Melittin-polyethylenimine (PEI) conjugates have been shown to enhance gene transfer efficiency of polyplexes due to their membrane-destabilizing properties. Inherent lytic activity at neutral pH however also provokes high cytotoxicity due to plasma membrane damage. In order to shift the lytic activity towards the endosomal membrane, several melittin analogs were designed.