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Chelator-Free Copper-64-Incorporated Iron Oxide Nanoparticles for PET/MR Imaging: Improved Radiocopper Stability and Cell Viability.

ABSTRACT: We have developed chelator-free copper-64-incorporated iron oxide (IO) nanoparticle (NPs) which have both magnetic and radioactive properties being applied to positron emission tomography (PET)-magnetic resonance imaging (MRI). We have found that the IO nanoparticles composed of radioactive isotope ⁶⁴Cu may act as a contrast agent being a diagnostic tool for PET as well as a good T₂ MRI nanoprobe due to their good r₂/r₁ ratio. Furthermore, we demonstrate that the ⁶⁴Cu incorporation at the core of core-shell-structured IO NPs exhibits a good in vivo stability, giving us an insightful strategy for the design of a contrast agent for the PET-MRI system.

SUBMITTER: Jang HM

PROVIDER: S-EPMC9416411 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Chelator-Free Copper-64-Incorporated Iron Oxide Nanoparticles for PET/MR Imaging: Improved Radiocopper Stability and Cell Viability.

Jang Hye Min HM Jung Myung Hwan MH Lee Jae Sang JS Lee Jun Sig JS Lim In-Cheol IC Im Hyunsik H Kim Sang Wook SW Kang Sung-A SA Cho Won-Je WJ Park Jun Kue JK

Nanomaterials (Basel, Switzerland) 20220814 16

We have developed chelator-free copper-64-incorporated iron oxide (IO) nanoparticle (NPs) which have both magnetic and radioactive properties being applied to positron emission tomography (PET)-magnetic resonance imaging (MRI). We have found that the IO nanoparticles composed of radioactive isotope 64Cu may act as a contrast agent being a diagnostic tool for PET as well as a good T2 MRI nanoprobe due to their good r2/r1 ratio. Furt ...[more]

PMID: 36014656

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Project description:BackgroundProgrammed cell death ligand 1 (PD-L1) plays a critical role in the tumor microenvironment and overexpression in several solid cancers has been reported. This was associated with a downregulation of the local immune response, specifically of T-cells. Immune checkpoint inhibitors showed a potential to break this localized immune paralysis, but only 30% of patients are considered responders. New diagnostic approaches are therefore needed to determine patient eligibility. Small molecule radiotracers targeting PD-L1, may serve as such diagnostic tools, addressing the heterogeneous PD-L1 expression between and within tumor lesions, thus aiding in therapy decisions.ResultsFour biphenyl-based small-molecule PD-L1 ligands were synthesized using a convergent synthetic route with a linear sequence of up to eleven steps. As a chelator NODA-GA, CB-TE2A or DiAmSar was used to allow radiolabeling with copper-64 ([64Cu]Cu-14-[64Cu]Cu-16). In addition, a dimeric structure based on DiAmSar was synthesized ([64Cu]Cu-17). All four radioligands exhibited high proteolytic stability (> 95%) up to 48 h post-radiolabeling. Saturation binding yielded moderate affinities toward PD-L1, ranging from 100 to 265 nM. Real-time radioligand binding provided more promising KD values around 20 nM for [64Cu]Cu-14 and [64Cu]Cu-15. In vivo PET imaging in mice bearing both PC3 PD-L1 overexpressing and PD-L1-mock tumors was performed at 0-2, 4-5 and 24-25 h post injection (p.i.). This revealed considerably different pharmacokinetic profiles, depending on the substituted chelator. [64Cu]Cu-14, substituted with NODA-GA, showed renal clearance with low liver uptake, whereas substitution with the cross-bridged cyclam chelator CB-TE2A resulted in a primarily hepatobiliary clearance. Notably, the monomeric DiAmSar radioligand [64Cu]Cu-16 demonstrated a higher liver uptake than [64Cu]Cu-15, but was still renally cleared as evidenced by the lack of uptake in gall bladder and intestines. The dimeric structure [64Cu]Cu-17 showed extensive accumulation and trapping in the liver but was also cleared via the renal pathway. Of all tracer candidates and across all timepoints, [64Cu]Cu-17 showed the highest accumulation at 24 h p.i. in the PD-L1-overexpressing tumor of all timepoints and all radiotracers, indicating drastically increased circulation time upon dimerization of two PD-L1 binding motifs.ConclusionsThis study shows that chelator choice significantly influences the pharmacokinetic profile of biphenyl-based small molecule PD-L1 radioligands. The NODA-GA-conjugated radioligand [64Cu]Cu-14 exhibited favorable renal clearance; however, the limited uptake in tumors suggests the need for structural modifications to the binding motif for future PD-L1 radiotracers.

Dataset Information

Chelator-Free Copper-64-Incorporated Iron Oxide Nanoparticles for PET/MR Imaging: Improved Radiocopper Stability and Cell Viability.

Publications

Chelator-Free Copper-64-Incorporated Iron Oxide Nanoparticles for PET/MR Imaging: Improved Radiocopper Stability and Cell Viability.

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