αVβ3 Integrin-Targeted Radionuclide Therapy with 64Cu-cyclam-RAFT-c(-RGDfK-)4

Abstract

The transmembrane cell adhesion receptor a V b 3 integrin (a V b 3 ) has been identified as an important molecular target for cancer imaging and therapy. We have developed a tetrameric cyclic RGD (Arg-Gly-Asp) peptide-based radiotracer 64 Cu-cyclam-RAFT-c(-RGDfK-) 4 , which successfully captured a V b 3 -positive tumors and angiogenesis by PET. Here, we subsequently evaluated its therapeutic potential and side effects using an established a

High expression of integrin αvβ3 enables uptake of targeted fluorescent probes into ovarian cancer cells and tumors

“…While SqRGD2 did show higher levels in the lung, skin, and liver compared to SqRGD1, the liver accumulation was actually far lower than in other literature studies. 38,39 Increased retention in non-tumor tissue and organs is an attribute shared by most molecular probes with multiple peptide targeting groups. 40 …”

Novel Linear Peptides with High Affinity to αvβ3 Integrin for Precise Tumor Identification

“…Cyclic RGD peptide is the well-known ligand to αvβ3 and has been extensively exploited for tumor diagnosis and treatment 35, 36, 37. However, the complexity and high-cost of synthesizing cyclic peptides stipulate the development of alternative ligands for targeting αvβ3 integrin.…”

Synthesis and Biological Characterization of Monomeric and Tetrameric RGD‐Cryptophycin Conjugates

“…Additionally, the multimeric ligand efficiently internalizes with the α v β 3 receptor through the clathrin‐mediated endocytic pathway . For this reason, the RAFT‐c(RGDfK) 4 demonstrates improved and more specific integrin α v β 3 ‐targeting and imaging properties for in vitro applications, as well as for the in vivo detection and treatment of solid tumors, compared to the monomeric c (RGDfK) peptide …”

“…[8,9] Many of them have been used as carriers for the tumor selective delivery of cytotoxic payloads and imaging agents. [10][11][12] Significant advances to further increaset he selectivity and binding affinity of the RGD ligands towards integrin a v b 3 have been achieved using multivalent systems [13][14][15][16] or by increasing the size of monomeric RGD peptides. [17] In this context, amultimeric system comprising ar egioselectively addressable functionalized template (RAFT)c yclodecapeptides caffold and four copies of the functionalized cyclopentapeptide c(RGDfK), [RAFT-c(RGDfK) 4 ], specificf or integrin a v b 3 ,i sapromising synthetic vehicle for drug delivery and imaging applications.…”

“…[19] For this reason,t he RAFT-c(RGDfK) 4 demonstrates improved and more specific integrin a v b 3 -targeting and imaging properties fori nv itro applications,a sw ell as for the in vivo detection and treatment of solid tumors,c ompared to the monomeric c(RGDfK) peptide. [14,[20][21][22] Previously,R AFT-c(RGDfK) 4 was conjugated to aB ax proapoptotic protein derived peptide across ad isulfide bridge (RAFT-c[RGD] 4 -S-S-depsi-cgg-Poro2D). This conjugate displayed ad ose-dependentt oxicity against Me275a nd Colo829 human melanoma cell lines and inducedt umor growth inhibition in Me275 xenografts.…”