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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
| Chemical name: | 64Cu-Labeled bis-1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid conjugated hypericin |
|
| Abbreviated name: | [64Cu]-bis DOTA-hypericin | |
| Synonym: | ||
| Agent Category: | Compound | |
| Target: | Tumor necrosis (cell membranes and subcellular organelle membranes) | |
| Target Category: | Other | |
| Method of detection: | Positron emission tomography (PET) | |
| Source of signal / contrast: | 64Cu | |
| Activation: | No | |
| Studies: |
| Click on the above structure of Hypericin for additional information in PubChem. |
In vitro
Background
[PubMed]
A common problem encountered with the chemotherapy or radiotherapy of cancer is the development of resistance to these treatments resulting in metastasis of the malignancy. Therefore, there is an urgent need to develop new anti-cancer treatments that have a unique mechanism of action and are not prone to the development of drug or radiation resistance (1). Photothermal ablation (PTA) therapy is an emerging technique that uses heat produced from absorbed light to destroy cancer cells. PTA therapy can be performed frequently, has no side effects, and does not promote the development of resistance (1). For PTA therapy, near-infrared (NIR) light is used to deliver a predetermined amount of photothermal energy directly into a tumor, which stimulates photochemical and photothermal reactions within the malignant lesion that are fatal for the cancer cells (2). In addition, the application of PTA in the presence of a light-absorbing nanoparticles (NPs), such as gold NPs (shells, rods, and cages) or copper sulfide (CuS) NPs, has been shown to enhance efficacy of the therapy (3). However, many parameters, such as the dose of NIR required to maximize the efficacy of PTA therapy, the number of NPs required for optimal ablation, or how to monitor the treatment noninvasively, remain to be worked out (1).
Computed tomography, magnetic resonance imaging, and ultrasonography are currently used to monitor morphological changes that occur after PTA therapy, but alterations in the tissue are visible with these techniques for only 2–3 months after initiation of the treatment (1). It is well known that 18F-labeled fluorodeoxyglucose ([18F]-FDG) is often used with positron emission tomography (PET) to assess the response to cancer therapy, but this imaging modality generates reliable results for only 2–3 weeks after initiation of the treatment. In addition, [18F]-FDG can generate false-positive results because it also detects inflammation, sarcoidosis, and fungal and tuberculosis infections (lesions from these conditions show an upregulated glucose metabolism similar to that of cancer cells) (1, 4). Hypericin, a naturally occurring polycyclic quinone that can be isolated from the plant Hypericum perforatum or chemically synthesized, has been investigated for the photodynamic therapy of cancer and other conditions (5). Although the exact mechanism of action of this compound is not known, several reports suggest that multiple cellular pathways participating in the survival, necrosis, or apoptosis of the cell are involved in bringing about the activity of hypericin as discussed elsewhere (5, 6). Hypericin is considered a nonporphyrin agent that binds to necrotic tissues, and 123I-labeled hypericin has been shown to detect tissue necrosis in the liver and the heart [PubMed]. Song et al. synthesized 64Cu-labeled bis-1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid (DOTA)-conjugated hypericin ([64Cu]-bis-DOTA-hypericin) and used it to evaluate the response of xenograft human BT474 breast carcinoma cell tumors in nude mice subjected to PTA treatment in presence of copper sulfide nanoparticles (CuS NPs) (1). The biodistribution of [64Cu]-bis-DOTA-hypericin was also investigated in these animals.
Synthesis
[PubMed]
The synthesis of [64Cu]-bis-DOTA-hypericin has been described by Song et al. (1). The radiochemical yield and purity were reported to be 97.7% and >95%, respectively, as determined with radio-high-performance liquid chromatography. The stability and specific activity of the final product were not reported.
In Vitro Studies: Testing in Cells and Tissues
[PubMed]
A higher number of BT474 cells died when they were exposed to CuS NPs and treated with a NIR laser compared to cells exposed to either the CuS NP alone or the laser alone (1). The PTA-treated cells were reported to have damaged membranes as observed with uptake studies of ethidium homodimer, a red fluorescent dye impermeable to living cells.
In another study, BT474 cells exposed to CuS NPs and treated with a NIR laser showed a significantly higher (P = 0.04) uptake of [64Cu]-bis-DOTA-hypericin compared to cells exposed to the CuS NPs or the NIR laser alone (1). Cell exposed to the CuS NPs and the NIR laser were reported to have a much higher uptake of the red, cell-impermeable EthD-1 dye compared to cells treated with the CuS or the NIR laser alone. This suggested the thermal ablation treatment was more effective (i.e. there was an increased cell death) in presence of the CuS NPs and the CuS NPs or the NIR alone had little effect on the cells. To determine the binding specificity of [64Cu]-bis-DOTA-hypericin, cells were treated with CuS NPs and NIR laser and exposed to [64Cu]-bis-DOTA-hypericin in the presence of excess non-radioactive hypericin. Binding of the labeled compound to these cells was reduced by 54% (P = 0.007) compared to the binding of cells exposed only to [64Cu]-bis-DOTA-hypericin (1). This strongly indicated that the labeled hypericin targeted the same cell membrane components as the native hypericin.
Animal Studies
Rodents
[PubMed]
The biodistribution of [64Cu]-bis-DOTA-hypericin was investigated in nude mice (n = 4–5 animals/time point) bearing BT474 cell tumors as described by Song et al. (1). Animals in the treated group (TG) received an intratumoral injection of CuS NPs (10 μL, 4 × 1013 NP/mL) and were irradiated with NIR laser 24 h later (808 nm, 12 W/cm2 for 3 min). Control animals (non-targeted (N-TG)) were not injected with the NPs or irradiated with the NIR laser. Both groups of mice were injected with [64Cu]-bis-DOTA-hypericin (5.55–7.4 MBq/0.1 mL (150–200 µCi/0.1 mL)) through the tail vein. Small-animal PET scans were subsequently performed on the mice at 2, 6, and 24 h postinjection (p.i.) while the animals were under anesthesia. After the last scan, the mice were euthanized, and major organs (including tumors) were harvested from the animals to determine the amount of radioactivity accumulated in the various tissues. Data were presented as percent of injected dose per gram tissue (% ID/g).
Small-animal PET scans of the animals revealed that tumors on the TG mice were clearly visible from 2 h to 24 h p.i., and tumors on the N-TG mice showed little accumulation of the tracer (1). From quantitative imaging analysis, the amount of radioactivity in tumors of the TG group was reported to be 0.80 ± 0.14% ID/g (P = 0.024), 1.19 ± 0.45% ID/g (P = 0.019), and 1.49 ± 0.68% ID/g (P = 0.039), at 2, 6, and 24 h p.i., respectively, compared to 0.57 ± 0.06% ID/g, 0.50 ± 0.63% ID/g, and 0.53 ± 0.18% ID/g at the same time points for animals in the N-TG group.
Biodistribution data from this study showed that the tumors of the TG and N-TG groups were the only tissues to show a significant difference in the accumulation of radioactivity (1). The uptake of label in tumors of the TG mice (1.71 ± 0.43% ID/g) was significantly higher (P = 0.017) than that observed in tumors of the N-TG mice (0.76 ± 0.19% ID/g). Tissue necrosis and the presence of radioactivity at the tumor site were confirmed with hematoxylin and eosin staining and autoradiography of tumor sections, respectively, as described by Song et al. (1). All other organs from the animals in both groups showed a comparable uptake of the tracer. This suggests that radioactivity derived from [64Cu]-bis-DOTA-hypericin had a binding specificity for necrotic tissue developed in the tumors after the PTA treatment. No blocking studies were reported.
On the basis of results obtained from this study, the investigators concluded that [64Cu]-bis-DOTA-hypericin can be used for the noninvasive assessment of tumor response to CuS NP-mediated PTA in mice.
References
- 1.
- Song, S., C. Xiong, M. Zhou, W. Lu, Q. Huang, G. Ku, J. Zhao, L.G. Flores, Jr., Y. Ni, and C. Li, Small-Animal PET of Tumor Damage Induced by Photothermal Ablation with 64Cu-Bis-DOTA-Hypericin. J Nucl Med, 2011. [PubMed: 21498539]
- 2.
- Vogel A., Venugopalan V. Mechanisms of pulsed laser ablation of biological tissues. Chem Rev. 2003;103(2):577–644. [PubMed: 12580643]
- 3.
- Zhou M., Zhang R., Huang M., Lu W., Song S., Melancon M.P., Tian M., Liang D., Li C. A Chelator-Free Multifunctional [64Cu]CuS Nanoparticle Platform for Simultaneous Micro-PET/CT Imaging and Photothermal Ablation Therapy. Journal of the American Chemical Society. 2010;132(43):15351–15358. [PMC free article: PMC2966020] [PubMed: 20942456]
- 4.
- Culverwell A.D., Scarsbrook A.F., Chowdhury F.U. False-positive uptake on 2-[(1)F]-fluoro-2-deoxy-D-glucose (FDG) positron-emission tomography/computed tomography (PET/CT) in oncological imaging. Clin Radiol. 2011;66(4):366–82. [PubMed: 21356398]
- 5.
- Karioti A., Bilia A.R. Hypericins as potential leads for new therapeutics. Int J Mol Sci. 2010;11(2):562–94. [PMC free article: PMC2852855] [PubMed: 20386655]
- 6.
- Theodossiou T.A., Hothersall J.S., De Witte P.A., Pantos A., Agostinis P. The multifaceted photocytotoxic profile of hypericin. Mol Pharm. 2009;6(6):1775–89. [PubMed: 19739671]
- PMCPubMed Central citations
- PubChem SubstanceRelated PubChem Substances
- PubMedLinks to PubMed
- Small-animal PET of tumor damage induced by photothermal ablation with 64Cu-bis-DOTA-hypericin.[J Nucl Med. 2011]Small-animal PET of tumor damage induced by photothermal ablation with 64Cu-bis-DOTA-hypericin.Song S, Xiong C, Zhou M, Lu W, Huang Q, Ku G, Zhao J, Flores LG Jr, Ni Y, Li C. J Nucl Med. 2011 May; 52(5):792-9. Epub 2011 Apr 15.
- Review (64)Cu-Labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated IRDye 800CW (a near-infrared fluorescence dye) coupled to mAb7, an anti-epithelial cell adhesion molecule monoclonal antibody.[Molecular Imaging and Contrast...]Review (64)Cu-Labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated IRDye 800CW (a near-infrared fluorescence dye) coupled to mAb7, an anti-epithelial cell adhesion molecule monoclonal antibody.Chopra A. Molecular Imaging and Contrast Agent Database (MICAD). 2004
- More advantages in detecting bone and soft tissue metastases from prostate cancer using (18)F-PSMA PET/CT.[Hell J Nucl Med. 2019]More advantages in detecting bone and soft tissue metastases from prostate cancer using (18)F-PSMA PET/CT.Pianou NK, Stavrou PZ, Vlontzou E, Rondogianni P, Exarhos DN, Datseris IE. Hell J Nucl Med. 2019 Jan-Apr; 22(1):6-9. Epub 2019 Mar 7.
- Review Optical diagnostic imaging and therapy for thyroid cancer.[Mater Today Bio. 2022]Review Optical diagnostic imaging and therapy for thyroid cancer.Shao C, Li Z, Zhang C, Zhang W, He R, Xu J, Cai Y. Mater Today Bio. 2022 Dec 15; 17:100441. Epub 2022 Sep 26.
- Review (111)In-Labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-d-Tyr-d-Lys(HSG)-d-Glu-d-Lys(HSG)-NH(2) (IMP-288).[Molecular Imaging and Contrast...]Review (111)In-Labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-d-Tyr-d-Lys(HSG)-d-Glu-d-Lys(HSG)-NH(2) (IMP-288).Chopra A. Molecular Imaging and Contrast Agent Database (MICAD). 2004
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