title: Synthesis and exploration of novel radiolabeled bombesin peptides for targeting receptor positive tumor.
abstract: Increasing evidence of peptide receptor overexpression in various cancer cells, warrant the development of receptor specific radiolabeled peptides for molecular imaging and therapy in nuclear medicine. Gastrin-releasing-peptide (GRP) receptor, are overexpressed in a variety of human cancer cells. The present study report the synthesis and biological evaluation of new bombesin (BBN) analogs, HYNIC-Asp-[Phe13]BBN(7-13)-NH-CH2-CH2-CH3:BA1, HYNIC-Pro-[Tyr13Met14]BBN(7-14)NH2:BA2 as prospective tumor imaging agent with compare to BBN(7-14)NH2:BS as standard. The pharmacophores were radiolabeled in high yields with99mTc, characterized for their stability in serum and saline, cysteine/histidine and were found to be substantially stable. Internalization/externalization and receptor binding studies were assessed using MDA-MB-231 cells and showed high receptor binding-affinity and favourable internalization. Fluorescence studies revealed that BA1 changed the morphology of the cells and could localize in the nucleus more effectively than BA2/BS. Cell-viability studies displayed substantial antagonistic and nuclear-internalization effect of BA1. BA1 also exhibited antiproliferative effect on MDA-MB-231 cell by inducing apoptosis. In vivo behaviour of the radiopeptides was evaluated in GRP receptor positive tumor bearing mice. The99mTc-BA1/99mTc-BA2 demonstrated rapid blood/urinary clearance through the renal pathway and comparatively more significant tumor uptake image and favourable tumor-to-non-target ratios provided by99mTc-BA1. The specificity of the in vivo uptake was confirmed by co-injection with BS. Moreover,99mTc-BA1 provided a much clearer tumor image in scintigraphic studies than others. Thus the combination of favourable in vitro and in vivo properties renders BA1 as more potential antagonist bombesin-peptide for targeting GRP-receptor positive tumor. These properties are encouraging to carry out further experiments for non-invasive receptor targeting potential diagnostinc and therapeutic agent for tumors.
authors.affiliation: Infectious Diseases and Immunology Division (Nuclear Medicine Laboratory), CSIR-Indian Institute of Chemical Biology, 4 Raja S C Mullick Road, Kolkata, 700032, West Bengal, India. Electronic address: kakalide@yahoo.com.
authors.forename: Kakali
authors.initials: K
authors.lastname: De
authors.affiliation: Infectious Diseases and Immunology Division (Nuclear Medicine Laboratory), CSIR-Indian Institute of Chemical Biology, 4 Raja S C Mullick Road, Kolkata, 700032, West Bengal, India.
authors.forename: Indranil
authors.initials: I
authors.lastname: Banerjee
authors.affiliation: Regional Radiation Medicine Center, Thakurpukur Cancer Center and Welfare Home Campus, Kolkata, 700 063, India.
authors.forename: Samarendu
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Regional Radiation Medicine Center, Thakurpukur Cancer Center and Welfare Home Campus, Kolkata, 700 063, India.
authors.forename: Shantanu
authors.initials: S
authors.lastname: Ganguly
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001839:Bombesin / Q000008:administration & dosage / Q000138:chemical synthesis / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000235:genetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000138:chemical synthesis; D018004:Receptors, Bombesin / Q000008:administration & dosage / Q000235:genetics*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D010455:Peptides; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D001839:Bombesin
keywords: Bombesin; GRP; MDA-MB-231 cell; Radiopeptide; Scintigraphic