ICEECE2012 Oral Communications Thyroid Basic (6 abstracts)
Radioiodine therapy of non-thyroidal cancer following systemic sodium iodide symporter (NIS) gene transfer using Transferrin-receptor (Tfr) targeted non-viral gene delivery vectors
K. Klutz 1 , G. Grünwald 1 , M. Willhauck 1 , N. Schwenk 1 , A. Vetter 2 , W. Rödl 2 , M. Hacker 2 , C. Zach 2 , R. Senekowitsch-Schmidtke 3 , E. Wagner 2 , B. Göke 1 , M. Ogris 2 & C. Spitzweg 1
1Campus Grosshadern, University Hospital of Munich, Munich, Germany; 2Ludwig-Maximilians-University, Munich, Germany; 3University Hospital Klinikum rechts der Isar, Munich, Germany.
We have recently demonstrated the high potential of non-viral polyplexes for tumor-specific delivery of the sodium iodide symporter (NIS) after systemic application. In the current study we used novel polymers based on linear polyethylenimine (LPEI), shielded by polyethylene glycol (PEG), and coupled with the synthetic peptide B6 (LPEI-PEG-B6) as a transferrin (Tf)-receptor specific ligand to achieve active tumor targeting to human hepatocellular cancer (HuH7) cells after systemic delivery of NIS DNA.
We complexed LPEI-PEG-B6 with a NIS-expressing plasmid and analyzed levels of functional NIS expression after transfection of HuH7 (high Tf-receptor expression level) as compared to control cancer cells with low Tf-receptor expression level (colon cancer, RKO) in vitro and in vivo.
In vitro incubation of HuH7 cells with LPEI-PEG-B6/NIS resulted in a 9-fold increase in iodide uptake activity as compared to RKO cells. After establishment of subcutaneous HuH7 and RKO tumors in nude mice, NIS-conjugated nanoparticles or control vectors were injected i.v. followed by analysis of radioiodine biodistribution using I-123 scintigraphy. After injection of LPEI-PEG-B6/NIS, a significant perchlorate-sensitive iodide accumulation (8.5–10.9% ID/g I-123; eff. half-life of 5 h) was observed in HuH7 tumors resulting in a tumor absorbed dose of 50 mGy/MBq I-131 after systemic NIS gene transfer using LPEI-PEG-B6/NIS polyplexes. Tumoral iodide uptake activity and NIS mRNA expression were significantly lower in RKO cells confirming the specificity of Tf-receptor targeted nanoparticle vectors. After four cycles of polymer application followed by therapeutic application of I-131 (55.5 MBq), tumor growth was significantly reduced as compared to control groups.
These results clearly demonstrate that systemic in vivo NIS gene transfer using nanoparticle vectors coupled with a Tf-receptor targeting ligand is capable of inducing tumor-specific radioiodide uptake, which represents a promising innovative strategy for the NIS gene therapy approach in metastatic cancer.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.
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Endocrine Abstracts
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