title: Synthesis, physicochemical and biological evaluation of technetium-99m labeled lapatinib as a novel potential tumor imaging agent of Her-2 positive breast cancer.
abstract: Tumors that are Her-2-positive tend to grow and spread more quickly than other types of breast cancer. Overexpression of Her-2 can be a predictive biomarker for stratification of patients for therapy with Herceptin (containing humanized IgG1 monoclonal antibody trastuzumab) or Tykerb (containing lapatinib di-p-toluenesulfonate) drug. Usually, Her-2 status is determined by immunohistochemical (IHC) as well as fluorescent or chromogenic in situ hybridisation (FISH or CISH) analysis of biopsy material. The objective of the present work was to standardize the conjugation of anti-cancer drug lapatinib (which recognizes selectively the Her-2 extracellular domain) with technetium-99m complex, of type '4+1', to obtain (99m)Tc(NS3)(CN-lapatinib) conjugate for use as in vivo tracer of the Her-2 expression in breast cancer. The conjugate (99m)Tc(NS3)(CN-lapatinib) was formed with high yield, high radiochemical purity and specific activity within the range 25-30 GBq/μmol. The biological in vitro and in vivo studies of the conjugate showed its high affinity to Her-2 receptor (Kd = 3.5 ± 0.4 nM, Ki = 2.9 ± 0.5 nM, Bmax = 2.4 ± 0.3 nM, approximate number of 2.4 × 10(6) binding sites per cell, IC50 = 41.2 ± 0.4 nM) and also pointed out to the clearance through the hepatic and renal route in comparable degree. Basing on these results one can conclude that (99m)Tc(NS3)(CN-lapatinib) conjugate could be a promising radiopharmaceutical for in vivo diagnosis of the Her-2 status in breast with impact on treatment planning.
authors.affiliation: Centre for Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, 16 Dorodna Street, 03-195 Warsaw, Poland. Electronic address: e.gniazdowska@ichtj.waw.pl.
authors.forename: Ewa
authors.initials: E
authors.lastname: Gniazdowska
authors.affiliation: Centre for Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, 16 Dorodna Street, 03-195 Warsaw, Poland.
authors.forename: Przemysław
authors.initials: P
authors.lastname: Koźmiński
authors.affiliation: Pharmaceutical Research Institute, 8 Rydygiera Street, 01-793 Warsaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Bańkowski
authors.affiliation: Pharmaceutical Research Institute, 8 Rydygiera Street, 01-793 Warsaw, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Łuniewski
authors.affiliation: Nuclear Medicine Department, Medical University of Warsaw, 1a Banacha Street, 02-097 Warsaw, Poland.
authors.forename: Leszek
authors.initials: L
authors.lastname: Królicki
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D000077341:Lapatinib; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D015609:Organotechnetium Compounds / Q000737:chemistry; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry; D011877:Radionuclide Imaging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D000077341:Lapatinib; D015609:Organotechnetium Compounds; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: Her-2 receptor; Lapatinib; Radiopharmaceutical; SKOV-3; Technetium