, Volume 33, Issue 4, pp 685-697
Date: 21 Nov 2008

Nonviral Delivery for Genomic Therapy of Cancer

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Abstract

We have developed improved liposomal nanoparticles that efficiently condense nucleic acids, proteins, viruses, drugs, and mixtures of these agents on the interior of bilamellar invaginated structures (BIVs) produced by a novel extrusion procedure. The liposomal complexes have extended half-life in the circulation, serum stability, and broad biodistribution; are targetable to specific organs and cell types; can penetrate through tight barriers in several organs; are fusogenic with cell membranes and avoid endosomes; are optimized for nucleic acid:lipid ratio and colloidal suspension in vivo; can be size fractionated to produce totally homogeneous populations of complexes prior to injection; are nontoxic, nonimmunogenic, and can be repeatedly administered; and they are stable in liquid suspensions and freeze-dried formulations. We can add specific ligands either by ionic interactions or by covalent attachments to the surface of these nucleic acid–liposome complexes to accomplish targeted delivery to specific cell surface receptors. Furthermore, the charge on the surface of these complexes can be modified to avoid uptake by nontarget cells using our novel technology called “reversible masking.” We have also achieved high-dose systemic delivery of these complexes without toxicity in vivo by further purification of plasmid DNA. At present, these complexes are injected intravenously into patients in clinical trials to treat lung cancer and will be used in upcoming trials to treat breast, pancreatic, and head and neck cancers. Notably, BIV complexes are being injected intravenously into patients with non-small-cell lung carcinoma who have failed to respond to chemotherapy. These patients are living longer and have demonstrated objective responses, including tumor regression.

This work was presented at the Molecular Surgeon Symposium on Personalized Genomic Medicine and Surgery at the Baylor College of Medicine, Houston, Texas, on April 12, 2008. The symposium was supported by a grant from the National Institutes of Health (R13 CA132572 to Changyi Chen).