Matrix metalloproteinase 9 targeting peptides: syntheses, 68Ga-labeling, and preliminary evaluation in a rat melanoma xenograft model.
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.
Ujula
Tiina
T
Turku PET Centre, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, Turku, Finland.
Huttunen
Merja
M
Luoto
Pauliina
P
Peräkylä
Hannu
H
Simpura
Ilkka
I
Wilson
Ian
I
Bergman
Mathias
M
Roivainen
Anne
A
D000818:Animals; D045744:Cell Line, Tumor; D003553:Cystine / Q000737:chemistry; D004195:Disease Models, Animal; D004341:Drug Evaluation; D005710:Gallium Radioisotopes / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D007700:Kinetics; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000493:pharmacokinetics; D008545:Melanoma / Q000175:diagnosis* / Q000000981:diagnostic imaging; D010455:Peptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D051381:Rats; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D000090324:Tumor Protein, Translationally-Controlled 1
D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D010455:Peptides; C000715649:Tpt1 protein, rat; D000090324:Tumor Protein, Translationally-Controlled 1; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D003553:Cystine; D020780:Matrix Metalloproteinase 9