Programmed dual targeted lipopolymeric delivery systems for cancer gene therapy

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Gene therapeutic strategies require efficient and safe vector systems. Synthetic delivery systems have been developed to circumvent drawbacks of viral vectors. Based on our most encouraging results of our existing collaboration (since 2008), we will develop lipopolyplex carriers which are inspired by targeting characteristics of natural viruses and take advantage from both polymeric and liposomal carriers, in DNA compaction and endosomal escape, respectively. For tumor targeted delivery, full length proteins or antibodies were used binding cell surface receptors that are overexpressed in tumor cells or tumor vessels. In order to overcome the complexities of proteins, the current design will focus on synthetic short peptide or chemical ligands. Efficient cellular uptake of many natural viruses is based on the utilization of more than one receptor type on target cells. Inspired by viruses, in our previous joint efforts (Nie J. Controlled Release 2011) we developed a gene delivery strategy targeting two different receptors (transferrin receptor and alpha v beta 5 integrin) on prostate cancer cells with dual peptide-ligand containing PEG-PEI polyplexes. We now extend the studies to new combinations of ligands and carriers with better intracellular delivery characteristics. In our collaboration, programmed lipopolyplexes with deshieldable PEGylation were designed (Nie Biomaterials 2011). This intracellularly more effective platform will now be merged with the dual-ligand targeted strategy. Lipopolyplexes will be generated by physical association of polyplexes with targeting peptide-PEG-cholesterol containing liposomes (with or without cleavable PEG linkers). Alternatively, chemical conjugated lipopolymers will be the basis for targeted lipopolyplexes. Established (RGD, B6) and new (such as GE11, folate, TAT) ligands will be evaluated in the lipopolyplexes. The study will explore mechanisms of dual targeting ligand combinations in different cancer types (beyond prostate cancer, such as neuroblastom, hepatocellular carcinoma), especially the effect on cell association and intracellular uptake kinetics, and overall transfection activity. Stable or pH/reductive-deshieldable PEGylation will be compared.