[Tc-99m(N)PNP]-moiety: a suitable scaffold for the developmant of radiolabeled probes for SPECT of multidrug resistance. In vitro study (Abstract in rivista)

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Label
  • [Tc-99m(N)PNP]-moiety: a suitable scaffold for the developmant of radiolabeled probes for SPECT of multidrug resistance. In vitro study (Abstract in rivista) (literal)
Anno
  • 2013-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1007/S00259-013-2535-3 (literal)
Alternative label
  • Bolzati, C.; Gandin, V.; Morellato, N.; Salvarese, N.; Marzano, C.; Refosco, F. (2013)
    [Tc-99m(N)PNP]-moiety: a suitable scaffold for the developmant of radiolabeled probes for SPECT of multidrug resistance. In vitro study
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Bolzati, C.; Gandin, V.; Morellato, N.; Salvarese, N.; Marzano, C.; Refosco, F. (literal)
Pagina inizio
  • S424 (literal)
Pagina fine
  • S424 (literal)
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  • 40 (literal)
Rivista
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  • 1 (literal)
Note
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • ICIS CNR; University of Padua (literal)
Titolo
  • [Tc-99m(N)PNP]-moiety: a suitable scaffold for the developmant of radiolabeled probes for SPECT of multidrug resistance. In vitro study (literal)
Abstract
  • Aim. 99mTc(N)-DBODC(5) [DBODC = bis(N -ethoxyethyl)dithiocarbamato; and 5 = bis(dimethoxypropylphosphinoethyl)ethoxyethylamine], is a lipophilic cationic mixed-compound originally investigated as myocardial imaging agent. This compound has been recently identified as a suitable scaffold for the design of new 99mTc-based agents for the noninvasive imaging of P-gp and closely related transporter activities [1]. The possibility to control the hydrophobicity and pharmacological activity of this heterocomplex through the independent variation of the substituents on the two ligand backbones, without affecting the P2S2 coordinating sphere, makes 99mTc(N)-DBODC(5) an appropriate platform for the preparation of different molecular probes for SPECT of MDR. To evaluate the impact of the [99mTc(N)PNP]-moiety on the tumor cell accumulation and on the MDR recognition different 99mTc(N)-DBODC(5) like complexes were synthesized varying the substituents on the PNP ligand and their in-vitro biological behaviors on selected human cancer cell lines and in the corresponding sub-lines were investigated. Method. 99mTc(N)-DBODC(n) complexes were efficiently prepared as previously described [2], [n is PNP3 bis(dimethoxypropylphosphinoethyl)- methoxyethylamine, PNP7 (bis(dimethoxyethylphosphinoethyl)-ethoxyethylamine) and PNP10 (bis(dimethoxyethylphosphinoethyl)-methoxyethylamine). Basic parameters such as the kinetic of uptake, at 4 and 37 °C, of the 99mTc(N)-DBODC(n) complexes were evaluated in-vitro in selected cell lines such us MCF7 (human breast cancer) and 2008 (human ovarian cancer), and in the corresponding sublines by using 99mTc-sestamibi and 99mTc(N)-DBODC(5) as references. Results. In drug-sensitive cell lines a significant increase of the % of cell accumulation of 99mTc(N)-DBODC(7) and 99mTc(N)-DBODC(10) complexes was observed with respect to 99mTc-sestamibi and 99mTc(N)DBODC(5). At steady-state level, this amount was quantified to be two or three times the % of uptake value of the reference compounds. At 4 °C a significant reduction of cellular accumulation was observed for all 99mTc agents. After 60 min, the nonspecific uptake was assessed as around 2 % (p<0.001). A reduction of the net cell uptake between drug-sensitive cells and drug-resistant tumor cells was detected (p< 0.001 for the 99mTc-complexes in all cell lines). Conclusion. Variation of the chemical-physical properties (lipophilicity, dimension, shape, etc.) of [99mTc(N)PNP]-moiety significantly affect the capability of the complexes to cross the plasma membrane increasing their cellular accumulations and their affinity for the MDR transporters. Hence, 99mTc(N)- DBODC(7) and 99mTc(N)-DBODC(10) represent good candidates for the in-vivo exploration of P-gp/MRP functions. This research was supported by the Italian Ministero dell'Istruzione, dell'Università e della Ricerca (PRIN20097FJHPZ-004). [1] Bolzati, C. et al (2013) J Biol Inorg Chem DOI 10.1007/s00775-013-0997-1 [2] Bolzati C, et al (2010) Bioconjug Chem 21:928-939. (literal)
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