Melanoma Therapy via Peptide-Targeted α-Radiation

Miao, Yubin; Hylarides, Mark D.; Fisher, Darrell R.; Shelton, Tiffani; Moore, Herbert; Wester, D. W.; Fritzberg, Alan R.; Winkelmann, Christopher T.; Hoffman, Timothy J.; Quinn, Thomas P.

doi:10.1158/1078-0432.ccr-05-0619

Cited by 121 publications

(127 citation statements)

References 25 publications

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“…Several α-MSH analogs which can recognize the MC1R have been labeled with different radionuclides for melanoma detection and radiotherapy (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(26)(27)(28). The most promising melanoma-targeting peptides are linear peptide NAPamide (16) and rhenium-cyclized CCMSH peptides (9,11,15).…”

Section: Discussionmentioning

confidence: 99%

⁶⁴Cu-Labeled Alpha-Melanocyte-Stimulating Hormone Analog for MicroPET Imaging of Melanocortin 1 Receptor Expression

et al. 2007

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The alpha-melanocyte-stimulating hormone (α-MSH) receptor (melanocortin type 1 receptor, or MC1R) plays an important role in the development and growth of melanoma cells. It was found that MC1R was overexpressed on most murine and human melanoma, making it a promising molecular target for melanoma imaging and therapy. Radiolabeled α-MSH peptide and its analogs that can specifically bind with MC1R have been extensively explored for developing novel agents for melanoma detection and radionuclide therapy. The goal of this study was to evaluate a 64 Culabeled α-MSH analog, Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-Lys(DOTA)-NH 2 (DOTANAPamide), as a potential molecular probe for microPET imaging of melanoma and MC1R expression in melanoma xenografted mouse models. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugated NAPamide was synthesized and radiolabeled with 64 Cu (t 1/2 =12 h) in NH 4 OAc (0.1 M; pH 5.5) buffered solution for 60 min at 50 °C. Cell culture studies reveal rapid and high uptake and internalization of 64 Cu-DOTA-NAPamide in B16F10 cells. Over 90% of receptor-bound tracer is internalized at 3 h incubation. A cellular retention study demonstrates that the receptor-bound 64 Cu-DOTA-NAPamide is slowly released from the B16F10 cells into the medium; 66% of the radioactivity is still associated with the cells even after 3 h incubation. The biodistribution of 64 Cu-DOTA-NAPamide was then investigated in C57BL/6 mice bearing subcutaneous murine B16F10 melanoma tumors with high capacity of MC1R and Fox Chase Scid mice bearing human A375M melanoma with a relatively low number of MC1R receptors. Tumor uptake values of 64 Cu-DOTA-NAPamide are found to be 4.63 ± 0.45% and 2.49 ± 0.31% ID/g in B16F10 and A375M xenografted melanoma at 2 h postinjection (pi), respectively. The B16F10 tumor uptake at 2 h pi is further inhibited to 2.29 ± 0.24% ID/g, while A375M tumor uptake at 2 h pi remains 2.20 ± 0.41% ID/g with a coinjection of excess α-MSH peptide. MicroPET imaging of 64 Cu-DOTA-NAPamide in B16F10 tumor mice clearly shows good tumor localization. However, low A375M tumor uptake and poor tumor to normal tissue

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Section: Discussionmentioning

confidence: 99%

⁶⁴Cu-Labeled Alpha-Melanocyte-Stimulating Hormone Analog for MicroPET Imaging of Melanocortin 1 Receptor Expression

et al. 2007

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“…Peptide-targeted a-particle therapy for melanoma using 212 Pb-[1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-ReO-[Cys 3,4,10 ,D-Phe 7 ,Arg 11 ]a-MSH 3-13 ( 212 Pb-DOTARe(Arg 11 )CCMSH) was reported in our previous publication (10). The results demonstrated that the peptide-targeted a-particle therapy was effective in increasing the mean survival times of mice initially bearing melanoma tumors.…”

mentioning

confidence: 99%

²⁰³Pb-Labeled α-Melanocyte–Stimulating Hormone Peptide as an Imaging Probe for Melanoma Detection

Miao¹,

Figueroa²,

Fisher³

et al. 2008

J Nucl Med

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Peptide-targeted a-therapy with 7.4 MBq of 212 Pb-[1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-ReO-[Cys 3,4,10 , D-Phe 7 ,Arg 11 ]a-MSH 3-13 ( 212 Pb-DOTA-Re(Arg 11 )CCMSH) cured 45% of B16/F1 murine melanoma-bearing C57 mice in a 120-d study, highlighting its melanoma treatment potential. However, there is a need to develop an imaging surrogate for patientspecific dosimetry and to monitor the tumor response to 212 Pb-DOTA-Re(Arg 11 )CCMSH therapy. The purpose of this study was to evaluate the potential of 203 Pb-DOTA-Re(Arg 11 )CCMSH as a matched-pair SPECT agent for 212 Pb-DOTA-Re(Arg 11 ) CCMSH. Methods: DOTA-Re(Arg 11 )CCMSH was labeled with 203 Pb in 0.5 M NH 4 OAc buffer at pH 5.4. The internalization and efflux of 203 Pb-DOTA-Re(Arg 11 )CCMSH were determined in B16/F1 melanoma cells. The pharmacokinetics of 203 Pb-DOTARe(Arg 11 )CCMSH was examined in B16/F1 melanoma-bearing C57 mice. A micro-SPECT/CT study was performed with 203 Pb-DOTA-Re(Arg 11 )CCMSH in a B16/F1 melanoma-bearing C57 mouse at 2 h after injection. Results: 203 Pb-DOTARe(Arg 11 )CCMSH was easily prepared in NH 4 OAc buffer and completely separated from the excess nonradiolabeled peptide by reversed-phase high-performance liquid chromatography (RP-HPLC). 203 Pb-DOTA-Re(Arg 11 )CCMSH displayed fast internalization and extended retention in B16/F1 cells. Approximately 73% of 203 Pb-DOTA-Re(Arg 11 )CCMSH activity internalized after a 20-min incubation at 25°C. After incubation of the cells in culture medium for 20 min, 78% of internalized activity remained in the cells. 203 Pb-DOTA-Re(Arg 11 )CCMSH exhibited a biodistribution pattern similar to that of 212 Pb-DOTA-Re(Arg 11 )CCMSH in B16/ F1 melanoma-bearing mice. 203 Pb-DOTA-Re(Arg 11 )CCMSH exhibited a peak tumor uptake of 12.00 6 3.20 percentage injected dose per gram (%ID/g) at 1 h after injection. The tumor uptake gradually decreased to 3.43 6 1.12 %ID/g at 48 h after injection. 203 Pb-DOTA-Re(Arg 11 )CCMSH exhibited a peak tumor-to-kidney uptake ratio of 1.53 at 2 h after injection. The absorbed doses to the tumor and kidneys were 4.32 and 4.35 Gy, respectively, per 37 MBq. Whole-body clearance of 203 Pb-DOTA-Re(Arg 11 )CCMSH was fast, with approximately 89% of the injected activity cleared through the urinary system by 2 h after injection. 203 Pb showed 1.6-mm SPECT resolution, which was comparable to 99m Tc. Melanoma lesions were visualized through SPECT/CT images of 203 Pb-DOTA-Re(Arg 11 )CCMSH at 2 h after injection. Conclusion: 203 Pb-DOTA-Re(Arg 11 )CCMSH exhibited favorable pharmacokinetic and tumor imaging properties, highlighting its potential as a matched-pair SPECT agent for 212 Pb-DOTA-Re(Arg 11 )CCMSH melanoma treatment.

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“…The procedure for coordinating lead to the peptide has been published (Miao et al, 2005). A solution of Pb-203 was substituted for Pb-212 to make the Pb-203-labeled peptide.…”

Section: Research Approachmentioning

confidence: 99%

“…Because of the short range of alpha particles (40 to 70 micrometers in soft tissue), and to be effective in cell killing, the alpha-emitters need to be delivered directly to cancer cells using cell-targeted radioimmunotherapy. Miao et al (2005) treated laboratory mice with rhenium-186-and lead-212-labeled-[DOTA]-Re(arg 11 )CCMSH, a novel class of metal-cyclized melanotropin peptide analogues for melanoma imaging and therapy that target the melanocortin-1 receptor on melanoma cells. Alpha-particles from bismuth-212, the first decay daughter of lead-212 complexed with DOTA]-Re(arg 11 )CCMSH were used to treat mice inoculated with melanoma cells.…”

Section: Introductionmentioning

confidence: 99%

“…Alpha-particles from bismuth-212, the first decay daughter of lead-212 complexed with DOTA]-Re(arg 11 )CCMSH were used to treat mice inoculated with melanoma cells. Miao et al (2005) showed that treatment significantly decreased tumor growth, resulting in extended survival times and in many cases (45%), complete remission of disease. However, laboratory techniques must be further developed, tested, and verified for successful commercialization and Food and Drug Administration approval.…”

Section: Introductionmentioning

confidence: 99%

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Development and Testing of a 212Pb/212Bi Peptide for Targeting Metastatic Melanoma

Fisher¹

2012

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Project Roles and ResponsibilitiesThis project addressed several difficult technical issues and challenges, including radioisotope production, safe handling and transportation, protein synthesis, protein labeling, radiolabeled protein safety characterization and safety analysis, and pre-clinical biodistribution in laboratory animals. The team assembled, as described below for this project, provided each of the scientific and technical work elements needed for project success: V.G. Khlopin Radium Institute, St. Petersburg, Russia conducted research in nuclear physical, radiochemical, geochemical, and ecological fields, associated with the problems of nuclear power engineering, radioecology, and isotope production and represents one of Russian and world-wide leaders in these directions. The Khlopin Radium Institute actively participates in federal programs and international projects related to nuclear physics, radiochemistry, radioecology, and radiogeochemistry. On this study, Khlopin prepared Pb-203 and performed peptide-labeling and purification studies. Khlopin also managed work involving the preparation and characterization imaging and biodistribution of Pb-203 and Pb-212-labeled peptides under the Project Partner Agreement.AlphaMed, Inc. develops supplies of alpha-emitter isotopes for medical applications such as new cancertreatment agents. AlphaMed performs work under contract with the Department of Energy and the National Cancer Institute. Much of this work is performed for AlphaMed at PNNL. On this project, AlphaMed provided scientific guidance and implementing background technology, oversaw all aspects of materials development and applications research, and directed the commercialization and business planning efforts.Pacific Northwest National Laboratory supports the mission objectives of the Department of Energy, which include methods for improving the supply of isotopes for applications in science, medicine, 2 industry, and national security using the capabilities of its professional staff and the infrastructure associated with the Radiochemical Processing Laboratory. On this project, PNNL provided the lead-212/bismuth-212 generators for use on this project in Russia, and also provided internal radiation dosimetry calculations.

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Melanoma Therapy via Peptide-Targeted α-Radiation

Cited by 121 publications

References 25 publications

⁶⁴Cu-Labeled Alpha-Melanocyte-Stimulating Hormone Analog for MicroPET Imaging of Melanocortin 1 Receptor Expression

⁶⁴Cu-Labeled Alpha-Melanocyte-Stimulating Hormone Analog for MicroPET Imaging of Melanocortin 1 Receptor Expression

²⁰³Pb-Labeled α-Melanocyte–Stimulating Hormone Peptide as an Imaging Probe for Melanoma Detection

Development and Testing of a 212Pb/212Bi Peptide for Targeting Metastatic Melanoma

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Melanoma Therapy via Peptide-Targeted α-Radiation

Cited by 121 publications

References 25 publications

64Cu-Labeled Alpha-Melanocyte-Stimulating Hormone Analog for MicroPET Imaging of Melanocortin 1 Receptor Expression

64Cu-Labeled Alpha-Melanocyte-Stimulating Hormone Analog for MicroPET Imaging of Melanocortin 1 Receptor Expression

203Pb-Labeled α-Melanocyte–Stimulating Hormone Peptide as an Imaging Probe for Melanoma Detection

Development and Testing of a 212Pb/212Bi Peptide for Targeting Metastatic Melanoma

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⁶⁴Cu-Labeled Alpha-Melanocyte-Stimulating Hormone Analog for MicroPET Imaging of Melanocortin 1 Receptor Expression

⁶⁴Cu-Labeled Alpha-Melanocyte-Stimulating Hormone Analog for MicroPET Imaging of Melanocortin 1 Receptor Expression

²⁰³Pb-Labeled α-Melanocyte–Stimulating Hormone Peptide as an Imaging Probe for Melanoma Detection