Evaluation of the pharmacokinetic effects of various linking group using the 111In-DOTA-X-BBN(7-14)NH2 structural paradigm in a prostate cancer model.
The high incidence of BB2 receptor (BB2r) expression in various cancers has prompted investigators to pursue the development of BB2r-targeted agents for diagnostic imaging, chemotherapy, and radiotherapy. Development of BB2r-targeted agents, based on the bombesin (BBN) peptide, has largely involved the use of the bifunctional chelate approach in which the linking group serves several key roles including pharmacokinetic modification. Understanding the in vivo properties of the various pharmacokinetic modifying linking groups is crucial for developing BB2r-targeted agents with improved targeting and clearance characteristics. The goal of this study was to systematically evaluate the pharmacokinetic profile of aliphatic hydrocarbon, aromatic, and poly(ethylene glycol) (ether) functional groups in order to obtain a better understanding of the in vivo properties of these pharmacokinetic modifiers. Specifically, we synthesized six radioconjugates with the structure 111In-DOTA- X-BBN(7-14)NH2, where X = 8-aminooctanoic acid (8-AOC), 5-amino-3-oxapentyl-succinamic acid (5-ADS), 8-amino-3,6-dioxaoctyl-succinamic acid (8-AOS), p-aminobenzoic acid (AMBA), Gly-AMBA, and Gly- p-aminomethylbenzoic acid (Gly-AM2BA). All of the (nat)In-conjugates demonstrated nanomolar binding affinities to the BB2r. In CF-1 mice, the BB2r uptake in the pancreas of radioconjugates containing aromatic linking groups was found to be significantly higher at 1 h postinjection than the radioconjugates with ether linker moieties. For PC-3 tumor-bearing SCID mice, the tumor uptake was found to be 6.66 +/- 2.00, 6.21 +/- 1.57, 6.36 +/- 1.60, 4.46 +/- 0.81, and 7.76 +/- 1.19 %ID/g for the 8-AOC, 8-ADS, AMBA, Gly-AMBA, and Gly-AM2BA radioconjugates, respectively, at 15 min postinjection. By 24 h postinjection, the radioconjugates containing aromatic groups exhibited the highest percentage tumor retention with 11.4%, 19.8%, 26.6%, 25.8%, and 25.5% relative to the 15 min values remaining in the tumor tissue for the 8-AOC, 8-ADS, AMBA, Gly-AMBA, and Gly-AM2BA radioconjugates, respectively. Fused Micro-SPECT/CT imaging studies performed at 24 h postinjection revealed substantial accumulation of radioactivity in the tumor tissue for all radioconjugates. In both biodistribution and Micro-SPECT/CT imaging studies, the radioconjugates containing aromatic linking groups typically exhibited significantly higher G.I. tract retention than the hydrocarbon or ether linking moieties. In conclusion, our studies indicate that radioconjugates incorporating aromatic linking groups, of the type investigated, generally demonstrated enhanced retention in BB2r expressing tissues in comparison to either the hydrocarbon or ether linking moieties. Furthermore, this investigation clearly demonstrates the significance of the linking group upon not only the in vivo clearance of the radiopharmaceutical, but also on the in vivo uptake and retention of the BB2r-targeted agent in tumor tissue. Future designs of BB2r-targeted agents should include a careful consideration of the effect linking group functionality has upon tumor targeting and retention.
Garrison
Jered C
JC
Research Services, Harry S. Truman Memorial Veterans' Hospital, 800 Hospital Drive, Columbia, Missouri 65201, USA.
Rold
Tammy L
TL
Sieckman
Gary L
GL
Naz
Farah
F
Sublett
Samantha V
SV
Figueroa
Said Daibes
SD
Volkert
Wynn A
WA
Hoffman
Timothy J
TJ
D010129:4-Aminobenzoic Acid / Q000737:chemistry; D000818:Animals; D001667:Binding, Competitive; D001839:Bombesin / Q000031:analogs & derivatives; D002210:Caprylates / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D018377:Neurotransmitter Agents / Q000737:chemistry; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000532:radiotherapy; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics
D002210:Caprylates; D006573:Heterocyclic Compounds, 1-Ring; D018377:Neurotransmitter Agents; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; C046323:omega-aminocaprylic acid; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D001839:Bombesin; D010129:4-Aminobenzoic Acid