Dual-targeted NIS polyplexes-a theranostic strategy toward tumors with heterogeneous receptor expression.

Abstract

Tumor heterogeneity, within and between tumors, may have severe implications for tumor therapy, especially for targeted gene therapy, where single-targeted approaches often result in limited efficacy and therapy resistance. Polymer-formulated nonviral vectors provide a potent delivery platform for cancer therapy. To improve applicability for future clinical use in a broad range of patients and cancer types, a dual-targeting approach was performed. Synthetic LPEI-PEG2kDa-based polymer backbones were coupled to two tumor-specific peptide ligands GE11 (EGFR-targeting) and cMBP (cMET-targeting). The dual-targeting approach was used to deliver the theranostic sodium iodide symporter (NIS) gene to hepatocellular cancer. NIS as auspicious theranostic gene allows noninvasive imaging of functional NIS gene expression and effective anticancer radioiodide therapy. Enhanced tumor-specific transduction efficiency of dual-targeted polyplexes compared to single-targeted polyplexes was demonstrated in vitro using tumor cell lines with different EGFR and cMET expression and in vivo by 124I-PET-imaging. Therapeutic efficacy of the bispecific concept was mirrored by significantly reduced tumor growth and perfusion, which was associated with prolonged animal survival. In conclusion, the dual-targeting approach highlights the benefits of a bifunctional strategy for a future clinical translation of the bioimaging-based NIS-mediated radiotherapy allowing efficient targeting of heterogeneic tumors with variable receptor expression levels.

• Authors: Sarah Urnauer, Kathrin A Schmohl, Mariella Tutter, Christina Schug, Nathalie Schwenk, Stephan Morys, Sibylle Ziegler, Peter Bartenstein, Dirk-André Clevert, Ernst Wagner, Christine Spitzweg
• Journal: Gene therapy (Gene Ther) Vol. 26 Issue 3-4 Pg. 93-108 (04 2019) ISSN: 1476-5462 [Electronic] England
• PMID: 30683895 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ligands
• Peptides
• Polymers
• EGFR protein, human
• ErbB Receptors
• MET protein, human
• Proto-Oncogene Proteins c-met

Topics

• Animals
• Carcinoma, Hepatocellular (genetics, therapy)
• Cell Line, Tumor
• Drug Delivery Systems (methods)
• ErbB Receptors (analysis, genetics)
• Female
• Gene Expression (genetics)
• Gene Transfer Techniques
• Genetic Heterogeneity
• Genetic Therapy (methods)
• Heterografts
• Humans
• Ligands
• Liver Neoplasms (genetics)
• Mice
• Mice, Nude
• Peptides (chemical synthesis, genetics)
• Polymers
• Proto-Oncogene Proteins c-met (analysis, genetics)
• Theranostic Nanomedicine (methods)