Radiohybridization PET imaging of KRAS G12D mRNA expression in human pancreas cancer xenografts with [64Cu]DO3A-peptide nucleic acid-peptide nanoparticles
Autor: | Eric Wickstrom, Christopher Cardi, Mohan R. Aruva, Mathew L. Thakur, Armin W. Opitz, Kaijun Zhang, A. Chakrabarti, Norman J. Wagner |
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Rok vydání: | 2007 |
Předmět: |
Peptide Nucleic Acids
Cancer Research Biology medicine.disease_cause Proto-Oncogene Proteins p21(ras) Heterocyclic Compounds 1-Ring Mice chemistry.chemical_compound medicine Animals Humans RNA Messenger Pharmacology Peptide analog Peptide nucleic acid Oncogene Hybridization probe Cancer medicine.disease Molecular biology digestive system diseases Gene Expression Regulation Neoplastic Pancreatic Neoplasms medicine.anatomical_structure Copper Radioisotopes Oncology chemistry Positron-Emission Tomography Cancer cell Cancer research Nanoparticles Molecular Medicine Female KRAS Peptides Pancreas Neoplasm Transplantation |
Zdroj: | Cancer Biology & Therapy. 6:948-956 |
ISSN: | 1555-8576 1538-4047 |
DOI: | 10.4161/cbt.6.6.4191 |
Popis: | There is a compelling need to image pancreas cancer at an early stage. Human pancreas cancer cells display elevated levels of KRAS protein due to high copy numbers of KRAS mRNA, and elevated levels of insulin-like growth factor 1 receptor (IGF1R) due to overexpression of IGF1R mRNA. Therefore we hypothesized that pancreas cancer could be detected in vivo with a single probe that targets both KRAS mRNA and IGF1R. Because positron emission tomography (PET) is a sensitive imaging technique, we designed a probe incorporating the positron-emitting nuclide (64)Cu. The KRAS-specific hybridization probe consisted of 1,4,7-tris(carboxymethylaza)cyclododecane-10-aza-acetyl (DO3A) on the N-terminus of a peptide nucleic acid (PNA) hybridization sequence (GCCATCAGCTCC) linked to a cyclized IGF1 peptide analog (d-Cys-Ser-Lys-Cys) on the C-terminus, for IGF1R-mediated endocytosis. A series of such KRAS radiohybridization probes with 0, 1, 2 or 3 mismatches to KRAS G12D mRNA, including exact matches to wild type KRAS mRNA and KRAS G12V mRNA, along with a double d(Ala) replacement IGF1 peptide control, were assembled by continuous solid phase synthesis. To test the hypothesis that KRAS-IGF1 dual probes could specifically image KRAS mRNA expression noninvasively in human IGF1R-overexpressing AsPC1 pancreas cancer xenografts in immunocompromised mice, [(64)Cu]PNA radiohybridization probes and controls were administered by tail vein. The [(64)Cu]KRAS-IGF1 radiohybridization probe yielded strong tumor contrast in PET images, 8.6 +/- 1.4-fold more intense in the center of human pancreas cancer xenografts than in the contralateral muscle at 4 h post-injection. Control experiments with single base KRASmismatches, an IGF1 peptide mismatch, and a breast cancer xenograft lacking KRAS activation yielded weak tumor contrast images. These experiments are consistent with our hypothesis for noninvasive PET imaging of KRAS oncogene expression in pancreas cancer xenografts. Imaging oncogene mRNAs with radiolabel-PNA-peptide nanoparticles might provide specific genetic characterization of preinvasive and invasive pancreas cancers for staging and choice of therapy. |
Databáze: | OpenAIRE |
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