Matrix metalloproteinase 9 targeting peptides: syntheses, 68Ga-labeling, and preliminary evaluation in a rat melanoma xenograft model
| Autor: | Merja Huttunen, Mathias Bergman, Hannu Peräkylä, Pauliina Luoto, Ian Wilson, Ilkka Simpura, Anne Roivainen, Tiina Ujula |
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| Rok vydání: | 2010 |
| Předmět: |
Pathology
medicine.medical_specialty Transplantation Heterologous Biomedical Engineering Pharmaceutical Science Bioengineering Peptide Gallium Radioisotopes Biopanning chemistry.chemical_compound Heterocyclic Compounds 1-Ring In vivo Cell Line Tumor medicine Distribution (pharmacology) DOTA Animals Tissue Distribution neoplasms Melanoma Pharmacology chemistry.chemical_classification Organic Chemistry Tumor Protein Translationally-Controlled 1 medicine.disease Rats Disease Models Animal Kinetics chemistry Matrix Metalloproteinase 9 Positron-Emission Tomography Lactam Cancer research Cystine Drug Evaluation Peptides Ex vivo Biotechnology |
| Zdroj: | Bioconjugate chemistry. 21(9) |
| ISSN: | 1520-4812 |
| Popis: | Biopanning of tumor cells was used in order to identify matrix metalloproteinase 9 (MMP-9) targeting peptides. The tumor cell targeting peptide (TCTP-1) and two modified versions thereof were evaluated as imaging agents for positron emission tomography (PET) using a rat melanoma xenograft model. For the PET imaging purposes, the 3 peptides were 1,4,7,10-tetraazacyclo-dodecane-N',N'',N''',N''''-tetraacetic acid (DOTA) conjugated and labeled with Gallium-68 ((68)Ga) and preliminarily evaluated: (1) cyclic (68)Ga-DOTA-TCTP-1 with cystine bridge, (2) cyclic (68)Ga-DOTA-lactam-TCTP-1 with a lactam bridge, and (3) linear (68)Ga-DOTA-lin-TCTP-1. The whole-body distribution kinetics and tumor targeting of the intravenously administered (68)Ga-DOTA-peptides were evaluated in vivo by PET and ex vivo by measuring the radioactivity of excised tissues. In addition, the in vivo stability of the radiolabeled peptides in rat plasma, tumor tissue, and urine was studied. All (68)Ga-DOTA-peptides were cleared via the liver and kidneys, and approximately 44% of injected radioactivity was excreted in urine during 120 min after injection. Ex vivo biodistribution studies showed a tumor-to-muscle ratio of 5.5 ± 1.3 (mean ± SD) for (68)Ga-DOTA-TCTP-1, 3.2 ± 0.2 for (68)Ga-DOTA-lactam-TCTP-1, and 3.2 ± 0.6 for (68)Ga-DOTA-lin-TCTP-1 at 120 min after injection. The (68)Ga-DOTA-lactam-TCTP-1 peptide appeared to be the most stable in vivo. The fraction of intact (68)Ga-DOTA-lactam-TCTP-1 in tumor was 59 ± 4.2% at 120 min after injection. The stability was moderate for (68)Ga-DOTA-TCTP-1 and poor for (68)Ga-DOTA-lin-TCTP-1. The possibility of imaging tumors that overexpress MMP-9, such as melanoma, by using radiolabeled TCTP peptides in PET imaging makes these peptides highly attractive for diagnostic and therapeutic applications. However, further modifications to improve the stability and affinity of the peptides are needed. |
| Databáze: | OpenAIRE |
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