Scandium-44 Radiolabeled Peptide and Peptidomimetic Conjugates Targeting Neuropilin-1 Co-Receptor as Potential Tools for Cancer Diagnosis and Anti-Angiogenic Therapy

Abstract

Pathological angiogenesis, resulting from an imbalance between anti- and pro-angiogenic factors, plays a pivotal role in tumor growth, development and metastasis. The inhibition of the angiogenesis process by the VEGF/VEGFR-2/NRP-1 pathway raises interest in the search for such interaction inhibitors for the purpose of the early diagnosis and treatment of angiogenesis-dependent diseases. In this work we designed and tested peptide-based radiocompounds that selectively bind to the neuropilin-1 co-receptor and prevent the formation of the pro-angiogenic VEGF-A165/NRP-1 complex. Three biomolecules, A7R and retro-inverso DR7A peptides, and the branched peptidomimetic Lys(hArg)-Dab-Pro-Arg (K4R), conjugated with macrocyclic chelator through two linkers’ types, were labeled with theranostic scandium-44 radionuclide, and studied in vitro as potential targeted radiopharmaceuticals. ELISA (enzyme-linked immunosorbent assay) studies showed no negative effect of the introduced biomolecules’ changes and high NRP-1 affinity in the case of A7R- and K4R-radiocompounds and a lack affinity for DR7A-radiocompounds. All radiopeptides showed a hydrophilic nature as well as high stability against ligand exchange reactions in cysteine/histidine solutions. Unfortunately, all radiocompounds showed unsatisfactory nano-scale stability in human serum, especially for use as therapeutic radioagents. Further work is ongoing and focused on the search for angiogenesis inhibitors that are more human serum stable.

Towards Clinical Development of Scandium Radioisotope Complexes for Use in Nuclear Medicine: Encouraging Prospects with the Chelator 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic Acid (DOTA) and Its Analogues

“…A series of three 44 Sc-DOTA-type radiotracer candidates with different linear or branched peptides (A7R, the retro-reverse D R7A, and K4R) as the targeting moieties (Figure 8D) were tested for site-specific action on neuropilin-1 (NRP-1) co-receptor (entry 4, Table 5), a key component of a pro-angiogenic protein complex involving VEGF-A165, responsible for inducing an angiogenesis signaling pathway in tumors [63]. Apart from serving as imaging agents for NPR-1, the peptides were also designed to inhibit the angiogenesis pathway promoted by this complex.…”

“…Additionally, with Sc-43/Sc-44, images could be recorded over longer periods of time [ 58 ]. Moreover, because scandium is stable when bound to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), combinations of radiopharmaceuticals can be used for both diagnostic and treatment options [ 63 ]. Sc-43/Sc-44 can, therefore, be used for diagnosis and, in combination with radionuclides Lu-177 and Y-90, to monitor targeted therapy, as Lu-177 and Y-90 are beta-emitting radionuclides, which release beta particles during radioactive decay.…”

“…Studies have also been carried out to produce the isotopes in an accelerator using α-particles, protons, and deuterons from calcium and titanium nuclei ( Table 1 ) [ 3 , 29 , 37 , 75 , 76 , 77 , 78 ]. Depending on the beam current and irradiation time, it has been demonstrated that the use of calcium and titanium can produce activities of the two isotopes in the order of GBq and hundreds of MBq [ 63 ]. However, the production of Sc-44 by these reactions is accompanied by the undesired co-production of its nuclear isomer, Sc-44m (t 1/2 = 558.6 h).…”

Scandium-44: Diagnostic Feasibility in Tumor-Related Angiogenesis

“…Although no previous in vivo experiments that investigated 44 Sc-labelled VEGF-VEGFR-NRP-1-directed radiopharmaceuticals have been published so far, Masłowska et al examined the potential diagnostic and therapeutic feasibility of such molecules under in vitro circumstances [ 79 ].…”

“…With the aim of inhibiting the formation of the vascular endothelial growth factor/neuropilin-1 co-receptor complex VEGF-A 165 /NRP-1, Masłowska et al developed NRP-1-targeting radiotracers [ 79 ]. In their study, three NRP-1-affine molecules were labelled with 44 Sc: Ala-Thr-Trp-Leu-Pro-Pro-Arg (A7R) heptapeptide, branched peptidomimetic Lys(hArg)-Dab-Pro-Arg (K4R), and the retro–inverso isomer of A7R (dArg-dPro-dPro-dLeu-dTrp-dThr-dAla) named D R7A.…”