Systemic tumor‐targeted sodium iodide symporter (NIS) gene therapy of hepatocellular carcinoma mediated by B6 peptide polyplexes

Abstract

These results clearly demonstrate that systemic in vivo NIS gene transfer using nanoparticle vectors coupled to B6 tumor targeting ligand is capable of inducing tumor-specific radioiodide uptake. This promising gene therapy approach opens the exciting prospect of NIS-mediated radionuclide therapy in metastatic cancer, together with the possibility of combining several targeting ligands to enhance selective therapeutic efficacy in a broad field of cancer types with various receptor expression profiles.

EGFR Targeting and Shielding of pDNA Lipopolyplexes via Bivalent Attachment of a Sequence‐Defined PEG Agent

“…NIS features the beneficial dual characteristic as diagnostic and therapeutic gene . This theranostic function gives the possibility of exact determination of tumoral NIS gene expression in vivo by noninvasive imaging modalities as well as therapeutic investigation by application of cytotoxic radionuclides …”

“…[60,62] This theranostic function gives the possibility of exact determination of tumoral NIS gene expression in vivo by noninvasive imaging modalities as well as therapeutic investigation by application of cytotoxic radionuclides. [48,59,61,64,65,[84][85][86][87][88][89][90] In cell culture studies, NIS gene expression after lipopolyplex-mediated delivery can be detected by measuring iodide ( 125 I) uptake activity of transfected cells by gamma-counter analysis. To verify NIS-dependent 125 I cell uptake, cells were pretreated with the NIS-specific inhibitor perchlorate (NaClO 4 ) that results in a blockade of NIS-mediated iodide uptake.…”

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

“…Polymers with LPEI-PEG 2kDa -backbone were synthesized by coupling heterobifunctional (poly)ethylene glycol (NHS-PEG-OPSS, 2 kDa, Rapp Polymere GmbH, Tübingen, Germany) to amine groups of linear polyethylene imine (LPEI) via N-hydroxy succiniminyl ester followed by a cation exchange chromatography purification step as described previously [7,18]. Specific targeting was achieved by coupling peptide ligands to the polymer backbone.…”

“…Most importantly for specific tumor targeting, incorporation of active targeting ligands provides the mechanistic rationale to enhance tumor-specific binding, cellular uptake and transfection efficiency. Various ligands that bind receptors that are highly expressed in a wide range of tumors, including epidermal growth factor receptor (EGFR), cMET/hepatocyte growth factor receptor (HGFR), transferrin receptor, integrin receptors and folate receptor, have served as promising candidates for molecularly targeted cancer gene therapy [5,[7][8][9][10][17][18][19]. Nevertheless, efficacy of nanoparticle-based carriers often varies after translation from in vitro conditions to in vivo models and between different tumor models [20], which is most likely attributable to tumor heterogeneity.…”

“…The transduction efficiency in vitro and in vivo can be monitored by taking advantage of the reporter function of NIS that allows determination of radionuclide uptake in transfected cells and consequently gives the possibility of monitoring the gene delivery function. This further enables exact localization of tumorous tissue by noninvasive bioimaging as well as quantification of trapped radionuclides ( 125 I, 123 I, 124 I, 18 F-TFB). At the same time, NIS provides the basis for an effective treatment strategy by application of 131 I, 188 Re, and 211 At [29,30].…”