PURPOSE: Prostate cancer (PCa) is the most widespread tumor affecting males in Western countries. We propose a novel MRI molecular tetrameric probe based on the heptadentate gadolinium (Gd)-AAZTA (6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid) that is able to in vivo detect PCa through the recognition of the fibrin-fibronectin (FB-FN) complex. METHODS: The peptide CREKA (Cys-Arg-Glu-Lys-Ala), targeting the FB-FN complex in the reactive stroma of the tumor, was synthesized by solid phase peptide synthesis (SPPS) and conjugated to the tetramer dL-(Gd-AAZTA)4 . The resulting probe was characterized by 1 H relaxometry, tested in vitro on FB clots and in vivo on an orthotopic mouse model of PCa. RESULTS: CREKA-dL-(Gd-AAZTA)4 showed a remarkable relaxivity of 18.2 m M−1Gd s-1 (0.47 T, 25°C) because of the presence of 2 water molecules (q = 2) in the inner coordination sphere of each Gd3+ ion, whose rotational motion (τR ) is lengthened as the result of the relatively high molecular weight. The probe displayed a detectable affinity for plasma-derived FB clots. On intravenous injection of the probe in an orthotopic mouse model of PCa, a significant increase in the prostate T1 contrast (~40%) was observed. The MRI signal appears statistically higher either with respect to the one observed for the control probes and to the one detected when CREKA-dL-(Gd-AAZTA)4 was administered to healthy animals. CONCLUSIONS: This study demonstrated the ability of the CREKA-dL-(Gd-AAZTA)4 probe to specifically localize in prostate tumor after injection. The high relaxivity of the probe allows the reduction of the injected dose to 20 µmolGd /kg, yielding a good in vivo contrast enhancement in the region of prostate tumor.

An efficient MRI agent targeting extracellular markers in prostate adenocarcinoma

Pagoto A.;Tripepi M.;Lanzardo S.;Garello F.;Porpiglia F.;Manfredi M.;Aime S.;Terreno E.
Last
;
LONGO, Dario Livio
2019-01-01

Abstract

PURPOSE: Prostate cancer (PCa) is the most widespread tumor affecting males in Western countries. We propose a novel MRI molecular tetrameric probe based on the heptadentate gadolinium (Gd)-AAZTA (6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid) that is able to in vivo detect PCa through the recognition of the fibrin-fibronectin (FB-FN) complex. METHODS: The peptide CREKA (Cys-Arg-Glu-Lys-Ala), targeting the FB-FN complex in the reactive stroma of the tumor, was synthesized by solid phase peptide synthesis (SPPS) and conjugated to the tetramer dL-(Gd-AAZTA)4 . The resulting probe was characterized by 1 H relaxometry, tested in vitro on FB clots and in vivo on an orthotopic mouse model of PCa. RESULTS: CREKA-dL-(Gd-AAZTA)4 showed a remarkable relaxivity of 18.2 m M−1Gd s-1 (0.47 T, 25°C) because of the presence of 2 water molecules (q = 2) in the inner coordination sphere of each Gd3+ ion, whose rotational motion (τR ) is lengthened as the result of the relatively high molecular weight. The probe displayed a detectable affinity for plasma-derived FB clots. On intravenous injection of the probe in an orthotopic mouse model of PCa, a significant increase in the prostate T1 contrast (~40%) was observed. The MRI signal appears statistically higher either with respect to the one observed for the control probes and to the one detected when CREKA-dL-(Gd-AAZTA)4 was administered to healthy animals. CONCLUSIONS: This study demonstrated the ability of the CREKA-dL-(Gd-AAZTA)4 probe to specifically localize in prostate tumor after injection. The high relaxivity of the probe allows the reduction of the injected dose to 20 µmolGd /kg, yielding a good in vivo contrast enhancement in the region of prostate tumor.
2019
81
3
1935
1946
http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1522-2594
AAZTA; fibrin–fibronectin complex; prostate cancer; T ; 1; -weighted MRI ; targeting peptide
Pagoto A.; Tripepi M.; Stefania R.; Lanzardo S.; Livio Longo D.; Garello F.; Porpiglia F.; Manfredi M.; Aime S.; Terreno E.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1705194
Citazioni
  • ???jsp.display-item.citation.pmc??? 1
  • Scopus 6
  • ???jsp.display-item.citation.isi??? 6
social impact