From a Helix to a Small Cycle: Metadynamics-Inspired αvβ6 Integrin Selective Ligands
Di Leva FS, Tomassi S, Di Maro S, Reichart F, Notni J, Dangi A, Marelli UK, Brancaccio D, Merlino F, Wester HJ, Novellino E, Kessler H, Marinelli L
16.04.2018 [Original Artikel]
The RGD-recognizing αvβ6 integrin has only recently emerged as a major target for cancer diagnosis and therapy. Thus, the development of selective, low-molecular-weight ligands of this receptor is still in great demand. Here, a metadynamics-driven design strategy allowed us to successfully convert a helical nonapeptide into a cyclic pentapeptide (6) showing remarkable potency and αvβ6 specificity. NMR and docking studies elucidated the reasons for the high affinity and selectivity of this compound, setting the ground for the rational design of new αvβ6-specific small peptides or even peptidomimetics. In vivo PET imaging studies demonstrated the potential use of 6 for medical applications.
In vivo characterization of four 68Ga-labeled multimeric RGD peptides to image αvβ3 integrin expression in two human tumor xenograft mouse models
Lobeek D, Franssen GM, Ma MT, Wester HJ, Decristoforo C, Oyen WJG, Boerman OC, Terry SYA, Rijpkema M
06.04.2018 [Original Artikel]
Rationale: αvβ3 integrins play an important role in angiogenesis and cell migration of cancers. They are highly expressed on activated endothelial cells of newly formed blood vessels. Here, we compare the targeting characteristics of four 68Ga-labeled multimeric cyclic arginine-glycine-aspartate RGD-based tracers in an αvβ3 integrin-expressing tumor model and in a tumor model where αvβ3 integrin is expressed solely on the neovasculature. Methods: Female BALB/c nude mice were subcutaneously injected with SK-RC-52 (αvβ3 integrin-positive) or FaDu (αvβ3 integrin-negative) tumor cells. 68Ga-labeled DOTA-(RGD)2, TRAP-(RGD)3, FSC-(RGD)3, or THP-(RGD)3 were intravenously administered to the mice (0.5 nmol per mouse, 10-20 MBq), followed by microPET/CT imaging and ex vivo biodistribution studies one hour post injection. Nonspecific uptake of the tracers in both models was determined by co-injecting an excess of unlabeled DOTA-(RGD)2 (50 nmol) along with the radiolabeled tracers. Results: Imaging and biodistribution data showed specific uptake in the tumors for each tracer in both tumor models. Tumor uptake of [68Ga]Ga-FSC-(RGD)3 was significantly higher than that of [68Ga]Ga-DOTA-(RGD)2, [68Ga]Ga-TRAP-(RGD)3, and [68Ga]Ga-THP-(RGD)3, in the SK-RC-52 model, but not in the FaDu model, where [68Ga]Ga-FSC-(RGD)3 showed significantly higher tumor uptake than [68Ga]Ga-TRAP-(RGD)3 Most importantly, differences were also observed in normal tissues and in tumor-to-blood ratios. Conclusion: All tracers showed sufficient targeting of αvβ3 integrin expression to allow for tumor detection. Although the highest tumor uptake was found for [68Ga]Ga-FSC-(RGD)3 and [68Ga]Ga-THP-(RGD)3 in the SK-RC-52 and FaDu model, respectively, selection of the most optimal tracer for specific diagnostic or therapeutic applications also depends on tumor-to-blood ratio and uptake in normal tissues, and should therefore also be considered.
N-Methylation of isoDGR Peptides: Discovery of a Selective α5β1-Integrin Ligand as a Potent Tumor Imaging Agent
Kapp TG, Di Leva FS, Notni J, Räder AFB, Fottner M, Reichart F, Reich D, Wurzer A, Steiger K, Novellino E, Marelli UK, Wester HJ, Marinelli L, Kessler H
22.03.2018 [Original Artikel]
Specific targeting of the integrin subtype α5β1 possesses high potential in cancer diagnosis and therapy. Through sequential N-methylation, we successfully converted the biselective α5β1/αvβ6 peptide c(phg- isoDGR-k) into a potent peptidic RGD binding α5β1 subtype selective ligand c(phg- isoDGR-( NMe)k). Nuclear magnetic resonance spectroscopy and molecular modeling clarified the molecular basis of its improved selectivity profile. To demonstrate its potential in vivo, c(phg- isoDGR-( NMe)k) was trimerized with the chelator TRAP and used as a positron-emission tomography tracer for monitoring α5β1 integrin expression in a M21 mouse xenograft.
Therapeutic Radiopharmaceuticals Targeting Integrin αvβ6
Färber SF, Wurzer A, Reichart F, Beck R, Kessler H, Wester HJ, Notni J
28.02.2018 [Original Artikel]
The epithelial integrin αvβ6 is expressed by many malignant carcinoma cell types, including pancreatic cancer, and thus represents a promising target for radionuclide therapy. The peptide cyclo(FRGDLAFp(NMe)K) was decorated with different chelators (DOTPI, DOTAGA, and DOTA). The Lu(III) complexes of these conjugates exhibited comparable αvβ6 integrin affinities (IC50 ranging from 0.3 to 0.8 nM) and good selectivities against other integrins (IC50 for αvβ8 >43 nM; for α5β1 >238 nM; and for αvβ3, αvβ5, and αIIbβ3 >1000 nM). Although different formal charges of the Lu(III) chelates (ranging from 0 to 4) resulted in strongly varying degrees of hydrophilicity (log D ranging from -3.0 to -4.1), biodistributions in murine H2009 xenografts of the Lu-177-labeled compounds (except the DOTPI derivative) were quite similar and comparable to our previously reported αvβ6 integrin positron emission tomography tracer Ga-68-avebehexin. Hence, combinations of existing Ga-68- and Lu-177-labeled c(FRGDLAFp(NMe)K) derivatives could be utilized for αvβ6 integrin-targeted theranostics, whereas our data nonetheless suggest that further improvement of pharmacokinetics might be necessary to ensure clinical success.