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Integrin ?v?3-Targeted [64Cu]CuS Nanoparticles for PET/CT Imaging and Photothermal Ablation Therapy.

ABSTRACT: Copper sulfide (CuS) nanoparticles have been considered one of the most clinical relevant nanosystems because of their straightforward chemistry, small particle size, low toxicity, and intrinsic theranostic characteristics. In our previous studies, radioactive [64Cu]CuS nanoparticles were successfully developed to be used as efficient radiotracers for positron emission tomography and for photothermal ablation therapy of cancer cells using near-infrared laser irradiation. However, the major challenge of CuS nanoparticles as a theranostic platform is the lack of a means for effective targeted delivery to the tumor site. To overcome this challenge, we designed and synthesized angiogenesis-targeting [64Cu]CuS nanoparticles, which are coupled with cyclic RGDfK peptide [c(RGDfK)] through polyethylene glycol (PEG) linkers using click chemistry. In assessing their tumor-targeting efficacy, we found that the tumor uptakes of [64Cu]CuS-PEG-c(RGDfK) nanoparticles at 24 h after intravenous injection were significantly greater (8.6% ± 1.4% injected dose/gram of tissue) than those of nontargeted [64Cu]CuS-PEG nanoparticles (4.3% ± 1.2% injected dose/gram of tissue, p < 0.05). Irradiation of tumors in mice administered [64Cu]CuS-PEG-c(RGDfK) nanoparticles induced 98.7% necrotic areas. In contrast, irradiation of tumors in mice administered nontargeted CuS-PEG nanoparticles induced 59% necrotic areas ( p < 0.05). The angiogenesis-targeting [64Cu]CuS nanoparticles may serve as a promising platform for image-guided ablation therapy with high efficacy and minimal side effects in future clinical translation of this novel class of multifunctional nanomaterials.

SUBMITTER: Cui L

PROVIDER: S-EPMC6693325 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Integrin αvβ3-Targeted [<sup>64</sup>Cu]CuS Nanoparticles for PET/CT Imaging and Photothermal Ablation Therapy.

Cui Lili L Xiong Chiyi C Zhou Min M Shi Sixiang S Chow Diana S-L DS Li Chun C

Bioconjugate chemistry 20181115 12

Copper sulfide (CuS) nanoparticles have been considered one of the most clinical relevant nanosystems because of their straightforward chemistry, small particle size, low toxicity, and intrinsic theranostic characteristics. In our previous studies, radioactive [<sup>64</sup>Cu]CuS nanoparticles were successfully developed to be used as efficient radiotracers for positron emission tomography and for photothermal ablation therapy of cancer cells using near-infrared laser irradiation. However, the ...[more]

PMID: 30404438

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Project description:Current noninvasive imaging methods for monitoring immune response were largely developed for interrogation of the local reaction. This study developed the radiotracer 64Cu-labeled anti-CD11b (64Cu-αCD11b) for longitudinal assessment of local and systemic immune response involving mobilization of CD11b+ myeloid cells by small-animal PET/CT. Methods: Acute or chronic inflammation in the ears of BALB/c mice was induced by 12-o-tetradecanoylphorbol-13-acetate. Acute lung inflammation was induced by intratracheal lipopolysaccharide inoculation. αCD11b was conjugated with p-SCN-Bn-DOTA followed by labeling with 64Cu. PET/CT and biodistribution were evaluated at different times after intravenous injection of 64Cu-αCD11b. Cell populations from bone marrow (BM) and spleen were analyzed by flow cytometry. Results: 64Cu-αCD11b was primarily taken up by BM and spleen in control mice. In comparison, 64Cu-αCD11b uptake was significantly reduced in the BM and spleen of CD11b-knockout mice, indicating that 64Cu-αCD11b selectively homed to CD11b+ myeloid cells in vivo. In mice with ear inflammation, for the local inflammatory response, 64Cu-αCD11b PET/CT revealed significantly higher 64Cu-αCD11b uptake in the inflamed ears in the acute inflammation phase than the chronic phase, consistent with markedly increased infiltration of CD11b+ cells into the inflammatory lesions at the acute phase. Moreover, imaging of 64Cu-αCD11b also showed the difference in mouse systemic response for different inflammatory stages. Compared with uptake in control mice, BM 64Cu-αCD11b uptake in mice with ear inflammation was significantly lower in the acute phase and higher in the chronic phase, reflecting an initial mobilization of CD11b+ cells from the BM to the inflammatory foci followed by a compensatory regeneration of CD11b+ myeloid cells in the BM. Similarly, in mice with lung inflammation, 64Cu-αCD11b PET/CT readily detected acute lung inflammation and recruitment of CD11b+ myeloid cells from the BM. Immunohistochemistry staining and flow cytometry results confirmed the noninvasive imaging of PET/CT. Conclusion: 64Cu-αCD11b PET/CT successfully tracked ear and pulmonary inflammation in mice and differentiated acute from chronic inflammation at the local and systemic levels. 64Cu-αCD11b PET/CT is a robust quantitative method for imaging of local and systemic immune responses.

Project description:PurposeCopper is essential for enzymatic processes throughout the body. [64Cu]copper (64Cu) positron emission tomography (PET) has been investigated as a diagnostic tool for certain malignancies, but has not yet been used to study copper homeostasis in humans. In this study, we determined the hepatic removal kinetics, biodistribution and radiation dosimetry of 64Cu in healthy humans by both intravenous and oral administration.MethodsSix healthy participants underwent PET/CT studies with intravenous or oral administration of 64Cu. A 90 min dynamic PET/CT scan of the liver was followed by three whole-body PET/CT scans at 1.5, 6, and 20 h after tracer administration. PET data were used for estimation of hepatic kinetics, biodistribution, effective doses, and absorbed doses for critical organs.ResultsAfter intravenous administration, 64Cu uptake was highest in the liver, intestinal walls and pancreas; the gender-averaged effective dose was 62 ± 5 μSv/MBq (mean ± SD). After oral administration, 64Cu was almost exclusively taken up by the liver while leaving a significant amount of radiotracer in the gastrointestinal lumen, resulting in an effective dose of 113 ± 1 μSv/MBq. Excretion of 64Cu in urine and faeces after intravenous administration was negligible. Hepatic removal kinetics showed that the clearance of 64Cu from blood was 0.10 ± 0.02 mL blood/min/mL liver tissue, and the rate constant for excretion into bile or blood was 0.003 ± 0.002 min- 1.Conclusion64Cu biodistribution and radiation dosimetry are influenced by the manner of tracer administration with high uptake by the liver, intestinal walls, and pancreas after intravenous administration, while after oral administration, 64Cu is rapidly absorbed from the gastrointestinal tract and deposited primarily in the liver. Administration of 50 MBq 64Cu yielded images of high quality for both administration forms with radiation doses of approximately 3.1 and 5.7 mSv, respectively, allowing for sequential studies in humans.Trial registration numberEudraCT no. 2016-001975-59. Registration date: 19/09/2016.

Project description:The ability to detect and quantify macrophage accumulation can provide important diagnostic and prognostic information for atherosclerotic plaque. We have previously shown that LyP-1, a cyclic 9-amino acid peptide, binds to p32 proteins on activated macrophages, facilitating the visualization of atherosclerotic plaque with PET. Yet, the in vivo plaque accumulation of monomeric [(18)F]FBA-LyP-1 was low (0.31 ± 0.05%ID/g). To increase the avidity of LyP-1 constructs to p32, we synthesized a dendritic form of LyP-1 on solid phase using lysine as the core structural element. Imaging probes (FAM or 6-BAT) were conjugated to a lysine or cysteine on the dendrimer for optical and PET studies. The N-terminus of the dendrimer was further modified with an aminooxy group in order to conjugate LyP-1 and ARAL peptides bearing a ketone. Oxime ligation of peptides to both dendrimers resulted in (LyP-1)4- and (ARAL)4-dendrimers with optical (FAM) and PET probes (6-BAT). For PET-CT studies, (LyP-1)4- and (ARAL)4-dendrimer-6-BAT were labeled with (64)Cu (t1/2 = 12.7 h) and intravenously injected into the atherosclerotic (ApoE(-/-)) mice. After two hours of circulation, PET-CT coregistered images demonstrated greater uptake of the (LyP-1)4-dendrimer-(64)Cu than the (ARAL)4-dendrimer-(64)Cu in the aortic root and descending aorta. Ex vivo images and the biodistribution acquired at three hours after injection also demonstrated a significantly higher uptake of the (LyP-1)4-dendrimer-(64)Cu (1.1 ± 0.26%ID/g) than the (ARAL)4-dendrimer-(64)Cu (0.22 ± 0.05%ID/g) in the aorta. Similarly, subcutaneous injection of the LyP-1-dendrimeric carriers resulted in preferential accumulation in plaque-containing regions over 24 h. In the same model system, ex vivo fluorescence images within aortic plaque depict an increased accumulation and penetration of the (LyP-1)4-dendrimer-FAM as compared to the (ARAL)4-dendrimer-FAM. Taken together, the results suggest that the (LyP-1)4-dendrimer can be applied for in vivo PET imaging of plaque and that LyP-1 could be further exploited for the delivery of therapeutics with multivalent carriers or nanoparticles.

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Integrin ?v?3-Targeted [64Cu]CuS Nanoparticles for PET/CT Imaging and Photothermal Ablation Therapy.

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Integrin αvβ3-Targeted [<sup>64</sup>Cu]CuS Nanoparticles for PET/CT Imaging and Photothermal Ablation Therapy.

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