Sequence-defined cMET/HGFR-targeted Polymers as Gene Delivery Vehicles for the Theranostic Sodium Iodide Symporter (NIS) Gene

Abstract

The sodium iodide symporter (NIS) as well-characterized theranostic gene represents an outstanding tool to target different cancer types allowing noninvasive imaging of functional NIS expression and therapeutic radioiodide application. Based on its overexpression on the surface of most cancer types, the cMET/hepatocyte growth factor receptor serves as ideal target for tumor-selective gene delivery. Sequence-defined polymers as nonviral gene delivery vehicles comprising polyethylene glycol (PEG) and cationic (oligoethanoamino) amide cores coupled with a cMET-binding peptide (cMBP2) were complexed with NIS-DNA and tested for receptor-specificity, transduction efficiency, and therapeutic efficacy in hepatocellular cancer cells HuH7. In vitro iodide uptake studies demonstrated high transduction efficiency and cMET-specificity of NIS-encoding polyplexes (cMBP2-PEG-Stp/NIS) compared to polyplexes without targeting ligand (Ala-PEG-Stp/NIS) and without coding DNA (cMBP2-PEG-Stp/Antisense-NIS). Tumor recruitment and vector biodistribution were investigated in vivo in a subcutaneous xenograft mouse model showing high tumor-selective iodide accumulation in cMBP2-PEG-Stp/NIS-treated mice (6.6 ± 1.6% ID/g (123)I, biological half-life 3 hours) by (123)I-scintigraphy. Therapy studies with three cycles of polyplexes and (131)I application resulted in significant delay in tumor growth and prolonged survival. These data demonstrate the enormous potential of cMET-targeted sequence-defined polymers combined with the unique theranostic function of NIS allowing for optimized transfection efficiency while eliminating toxicity.

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

“…The preconjugation strategy is based on a two‐arm oligomer topology of ligand–PEG–STP/His, which had already proven as effective for receptor targeted gene transfer in vitro as well as in vivo for several receptor/ligand combinations . Four cationizable alternating Stp/histidine repeats provide effective nucleic acid binding and endosomal buffering, a lysine as symmetrical branching point links the dPEG 24 molecule, which is end modified with the targeting ligand.…”

“…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 …”

Imaging and targeted therapy of pancreatic ductal adenocarcinoma using the theranostic sodium iodide symporter (NIS) gene

“…In our previous work, we have extensively investigated the dual reporter/therapy capacity of NIS in various non-thyroidal tumors and have proven the feasibility of extrathyroidal radioiodide therapy after tumor-selective NIS gene transfer [16–26]. Transfection of cancer cells with the NIS gene allows non-invasive monitoring of functional NIS expression and in vivo biodistribution before the application of a therapeutic dose of radioiodide.…”

An Ethylenediamine‐based Switch to Render the Polyzwitterion Cationic at Tumorous pH for Effective Tumor Accumulation of Coated Nanomaterials

“…The present study provides an ovel design of smart switchable polyzwitterion based on aprecise control of the net charge.Thesurfaceofbiomaterialsdeterminestheir interaction with the surrounding biological substances.I np articular, nanomaterials for tumor-targeted therapy,l oading therapeutic molecules such as antitumor drugs and imaging agents, [1][2][3][4][5][6] have to avoid undesired interactions with blood components and normal tissues [7] until reaching the tumor sites; [8] the interactions are often associated with quick elimination from blood stream mostly based on the recognition by reticuloendothelial system (RES). The ethylenediamine moiety in the carboxybetaine enabled stepwise protonation and initiated the di-protonation process around tumorous pH (6.5).…”

“…The net charge of the developed polyzwitterion (PGlu(DET-Car)) was thus neutral at pH 7.4 for antifouling, but was cationic at pH 6.5 for interaction with anionic constituents.Q uantum dots coated with PGlu(DET-Car) exhibited comparable stealth and enhanced tumor accumulation relative to the PEG system. The present study provides an ovel design of smart switchable polyzwitterion based on aprecise control of the net charge.Thesurfaceofbiomaterialsdeterminestheir interaction with the surrounding biological substances.I np articular, nanomaterials for tumor-targeted therapy,l oading therapeutic molecules such as antitumor drugs and imaging agents, [1][2][3][4][5][6] have to avoid undesired interactions with blood components and normal tissues [7] until reaching the tumor sites; [8] the interactions are often associated with quick elimination from blood stream mostly based on the recognition by reticuloendothelial system (RES). [9] To this end, coating by biologically inert polymers,that is,antifouling (or stealth) polymers,such as poly(ethylene glycol) (PEG), endows foreign nanomaterials (for example,q uantum dots (QDs), dendrimers,p olymeric micelles,a nd liposomes) [1][2][3][4] with prolonged blood circulation [9] for effective tumor accumulation through the leaky tumor vasculature.…”