title: Co-administration of succinylated gelatine with a (99m)Tc-bombesin analogue, effects on pharmacokinetics and tumor uptake.
abstract: The bombesin analogue, [(99m)Tc-GGC]-(Ornithine)3-BN(2-14), (99m)Tc-BN-O, targeting gastrin releasing peptide receptors (GRPrs) on the surface of tumors, was pre-clinically investigated as potential imaging agent for single photon emission computed tomography (SPECT). In addition, the improvement of its pharmacokinetic profile (PK) was investigated through the co-administration of a succinylated gelatin plasma expander (Gelofusine), aiming to reduce its kidney accumulation and enhance its tumor-to-normal tissue contrast ratios. Biodistribution data were collected from normal mice and rats, and PC-3 tumor bearing mice, in reference to its PK, metabolism and tumor uptake. Imaging data were also collected from PC-3 tumor bearing mice. Biodistribution and imaging experiments showed that (99m)Tc-BN-O was able to efficiently localize the tumor (5.23 and 7.00% ID/g at 30 and 60min post injection, respectively), while at the same time it was rapidly cleared from the circulation through the kidneys. HPLC analysis of kidney samples, collected at 60min p.i. from normal mice and rats, showed that the majority of radioactivity detected was due to intact peptide i.e. 56% for mice and 73% for rats. Co-administration of (99m)Tc-BN-O with Gelo resulted in the reduction of kidney uptake in both animal models. The integrated area under the curve (AUC30-60 min) from the concentration-time plots of kidneys was decreased in both mice and rats by 25 and 50%, respectively. In PC-3 tumor bearing mice, an increase of tumor uptake (AUCtumor increased by 69%) was also observed with Gelo. An improvement in tumor-to-blood and tumor-to-normal tissue ratios was noted in all cases with the exception of the pancreas, which normally expresses GRPr. The results of this preclinical study may also be extended to other similar peptides, which are utilized in prostate cancer imaging and present similar PK profile.
authors: Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety (I.N.RA.S.T.E.S.), NCSR "Demokritos", 15310, Athens, Greece; Laboratory of Pharmacokinetics, Department of Pharmacy, University of Patras, 26504, Patras, Greece; Department of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany. Electronic address: c.liolios@dkfz-heidelberg.de.
authors: Christos C
authors: CC
authors: Liolios
authors: Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety (I.N.RA.S.T.E.S.), NCSR "Demokritos", 15310, Athens, Greece.
authors: Stavros
authors: S
authors: Xanthopoulos
authors: Deparment of Medical Instruments Technology, Technological Educational Institute, 12210, Athens, Greece.
authors: George
authors: G
authors: Loudos
authors: Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety (I.N.RA.S.T.E.S.), NCSR "Demokritos", 15310, Athens, Greece.
authors: Alexandra D
authors: AD
authors: Varvarigou
authors: Laboratory of Pharmacokinetics, Department of Pharmacy, University of Patras, 26504, Patras, Greece.
authors: Gregory B
authors: GB
authors: Sivolapenko
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001839:Bombesin / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D005780:Gelatin / Q000008:administration & dosage* / Q000494:pharmacology*; D006801:Humans; D007553:Isotope Labeling; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship; D013386:Succinates / Q000008:administration & dosage* / Q000494:pharmacology*; D013667:Technetium / Q000737:chemistry*; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D013386:Succinates; C060085:succinylated gelatin; D013667:Technetium; D005780:Gelatin; D001839:Bombesin
keywords: (99m)Tc; Bombesin; Kidney clearance; Prostate cancer imaging; Succinylated gelatin