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Basic Science Investigations |
-MSH Analog: A Novel Cyclic-Peptide Analog with Improved Tumor-Targeting Properties
Departments of Biochemistry, Radiology, and Chemistry, University of Missouri–Columbia, Columbia; and Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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-melanocyte-stimulating hormone (-MSH) analog 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) coupled ReO-cyclized [Cys3,4,10,D-Phe7]-MSH3–13 (DOTA-ReCCMSH). Methods: DOTA-ReCCMSH was compared with its reduced nonmetalated linear homolog, DOTA-CCMSH, and an analog in which rhenium cyclization was replaced by disulfide bond cyclization, DOTA-[Cys4,10,D-Phe7]-MSH4–13 (CMSH). DOTA was also conjugated to the amino terminus of one of the highest-affinity -MSH receptor-binding peptides, [Nle4,D-Phe7]-MSH (NDP), as a linear peptide standard. The DOTA-conjugated -MSH analogs were radiolabeled with 111In and examined for their in vitro receptor-binding affinity with B16/F1 murine melanoma cells, and their in vivo biodistribution properties were evaluated and compared in melanoma tumor–bearing C57 mice. Results: The tumor uptake values of 111In-DOTA–ReCCMSH were significantly higher than those of the other closely related 111In-DOTA–-MSH conjugates. Even at 24 h after injection, a comparison of the tumor uptake values for 111In-DOTA-coupled ReCCMSH (4.86 ± 1.52 percentage injected dose [%ID]/g), CCMSH (1.91 ± 0.56 %ID/g), CMSH (3.09 ± 0.32 %ID/g), and NDP (2.47 ± 0.79 %ID/g) highlighted the high tumor retention property of ReCCMSH. Rhenium-coordinated cyclization resulted in less renal radioactivity accumulation of 111In-DOTA–ReCCMSH (8.98 ± 0.82 %ID/g) than of 111In-DOTA–CCMSH (63.2 ± 15.6 %ID/g), 111In-DOTA–CMSH (38.4 ± 3.6 %ID/g), and 111In-DOTA–NDP (12.0 ± 1.96 %ID/g) at 2 h after injection and significantly increased its clearance into the urine (92 %ID at 2 h after injection). A high radioactivity uptake ratio of tumor to normal tissue was obtained for 111In-DOTA–ReCCMSH (e.g., 489, 159, 100, and 49 for blood, muscle, lung, and liver, respectively, at 4 h after injection). Conclusion: The novel ReO-coordinated cyclic structure of DOTA-ReCCMSH contributes significantly to its enhanced tumor-targeting and renal clearance properties and makes DOTAReCCMSH an excellent candidate for melanoma radiodetection and radiotherapy.
Key Words: peptide • -melanocyte-stimulating hormone • 111In labeling • metal cyclization • melanoma targeting
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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-MSH) peptide analogs have been investigated for their abilities to target radionuclides (1), toxins, and chemotherapeutic agents (2) to melanoma tumor cells through specific binding with their cognate cell surface receptor. Wild-type -MSH (Ac-Ser1-Tyr2-Ser3-Met4-Glu5-His6-Phe7-Arg8-Trp9-Gly10-Lys11-Pro12-Val13-NH2) is a tridecapeptide that is primarily responsible for the regulation of skin pigmentation (3). -MSH receptors are present on human (4,5) and murine (6) melanoma cell lines. Moreover, reports show that >80% of human melanoma tumor samples obtained from patients with metastatic lesions display -MSH receptors (5). Several radiolabeled -MSH peptide analogs have been investigated for the possibility of specific melanoma targeting. For example, [Nle4,D-Phe7]-MSH (NDP) analogs radiohalogenated with succinimidyl 3- or 4 (125I or 18F)-benzoate or radiolabeled with 99mTc were stable and exhibited quick clearance from normal tissues in vivo (7,8). However, the radiolabeled NDP analogs did not display significant tumor uptake and retention in murine melanoma–bearing mice. 111In-labeled -MSH derivatives containing 2 NDP fragments linked through a single diethylenetriaminepentaacetic acid (DTPA) molecule have been examined for their abilities to image melanoma lesions in patients (1,9). Although the 111In-labeled DTPA–bis-NDP fragment conjugates could image melanoma tumors in vivo, routine clinical use appears limited because of high nonspecific radioactivity accumulation in the liver and kidneys. The use of 111In-DTPA–mono-NDP decreased background in liver and kidneys, but its tumor uptake value was significantly lower than that of 111In-DTPA–bis-NDP fragments (9,10).
The results of our previous studies showed significantly higher tumor radioactivity uptake values for 99mTc- or 188Re-labeled [Cys3,4,10,D-Phe7]-MSH3–13 (CCMSH) (11) than for other radiolabeled -MSH analogs in the B16/F1 murine melanoma–bearing mouse model (12–14). The high tumor uptake of 99mTc-CCMSH could be specifically blocked by coinjecting 2 µg nonradiolabeled peptide (14). 99mTc/188Re-CCMSH is an 11-amino acid -MSH peptide analog cyclized through metal coordination, with 3 Cys3,4,10 sulfhydryls and 1 Cys4 amide nitrogen positioned in the sequence of the peptide. 99mTc and 188Re cyclization of CCMSH resulted in increased uptake and retention of radioactivity by tumor and accelerated renal radioactivity clearance compared with 125I-NDP and 99mTc/188Re-NDP (12). Targeted radioactivity of 125I-NDP, 99mTc[Cys-Gly-Cys-Gly]-NDP, and 99mTc-mercaptoacetylglycylglycyl--aminobutyrate [MAG2]-NDP was found to be rapidly washed out of tumor tissue, and coupling of the tetrapeptide or MAG2 chelator increased the hydrophobicity of the peptide complex, causing radioactivity accumulation in the liver and gastrointestinal tract (12). Although most radiolabeled -MSH analogs were rapidly internalized after binding to tumor cells, only 99mTc/188Re-CCMSH was resistant to intracellular degradation and washout. Therefore, it has been postulated that the superior melanoma tumor-targeting properties and whole-body clearance kinetics of 99mTc/188Re-CCMSH were intimately related to the structure of the molecule (14).
In this study, the effect of metal-coordinated peptide cyclization on the tumor uptake and clearance kinetics of ReCCMSH were investigated in a B16/F1 murine melanoma animal model. The macrocyclic chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was conjugated to the amino terminus of ReCCMSH and 3 closely related -MSH analogs so that the molecules could be radiolabeled independent of their peptide sequences. The DOTA chelator was selected for the -MSH peptide because of its ability to chelate a wide variety of imaging and therapeutic radiometals. In addition to DOTA-ReCCMSH, a nonmetalated linear homolog (DOTA-CCMSH), a disulfide bond-cyclized analog (DOTA-[Cys4,10,D-Phe7]-MSH4–13 [CMSH]), and a linear -MSH standard (DOTA-NDP) were synthesized. The DOTA-conjugated -MSH analogs were radiolabeled with 111In and examined in vitro for their receptor-binding activities and in vivo for their tumor-targeting and biodistribution properties in melanoma-bearing mice. A comparison of the tumor uptake values and clearance kinetics of 111In-DOTA–ReCCMSH and the other closely related 111In-DOTA–-MSH analogs allowed us to address the relative contributions of peptide sequence and cyclization on its in vivo properties and its potential as a melanoma-targeting agent.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Peptide Cyclization
DOTA-ReCCMSH was cyclized by site-specific rhenium coordination. DOTA-CCMSH and ReOCl3(Me2S)(OPPh3) were dissolved in 60% MeOH aqueous solution with a molar ratio of 1:1.5. After the pH was adjusted to approximately 8, the reaction solution was incubated at 70°C for 1 h. The mixture was centrifuged to remove any precipitant, and the DOTA-ReCCMSH complex was purified by RP HPLC monitored at 420 nm with an inline detector. The product peak was collected, lyophilized, and confirmed by ESI MS. The structure of DOTA-ReCCMSH is shown in Figure 1.
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Radiolabeled Complex Preparation
The 111In-labeled DOTA-ReCCMSH, DOTA-CCMSH, DOTA-CMSH, and DOTA-NDP complexes were prepared under similar conditions. Briefly, 20 µL 111InCl3 (5 mCi/500 µL in 0.04 mol/L HCl) (Mallinckrodt, St. Louis, MO); 80 µL pH 5.5, 0.1 mol/L NH4OAc; and 10 µg peptide were mixed and incubated at 70°C for 45 min. The radiolabeled complex was purified by RP HPLC with a 20-min gradient of 18%–25% acetonitrile/0.1% TFA versus H2O/0.1% TFA. Purified preparations were flushed with nitrogen gas to remove the acetonitrile, and the pH was adjusted to neutral by adding 0.2 mol/L sodium phosphate (pH 8.0)/150 mmol/L NaCl. The 111In-DOTA–CCMSH complex was prepared from fresh DOTA-CCMSH to avoid oxidation of the cysteine thiols of the peptide.
125I-(Tyr2)-NDP was prepared by the chloramine-T method (15). Ten micrograms NDP; 1.5 µL Na125I (American Radiolabeled Chemicals, Inc., St. Louis, MO); 20 µL pH 7.4, 0.2 mol/L phosphate buffer; and 10 µL freshly prepared 1 mg/mL chloramine-T aqueous solution were mixed. After incubation at room temperature for 40 s, the reaction was quenched by adding 10 µL 1 mg/mL Na2S2O4. The radioiodinated complex was purified by RP HPLC, lyophilized, and stored at -20°C.
The stability of the radiolabeled complexes was determined in pH 7.4, 0.01 mol/L phosphate-buffered saline (PBS)/0.1% bovine serum albumin (BSA) or pH 7.4, 0.01 mol/L PBS/0.1 mmol/L ethylenediaminetetraacetic acid (EDTA). Biologic activity of the radiolabeled complexes was determined by in vitro receptor-binding assays with B16/F1 melanoma cells (14).
Cell Culture, Receptor Binding, and IC50 Determinations
The B16/F1 murine melanoma cell line was obtained from American Type Culture Collection (Manassas, VA). Cells were cultured in Roswell Park Memorial Institute 1640 medium containing NaHCO3 (2 g/L), which was supplemented with 10% heat-inactivated fetal calf serum, 2 mmol/L L-glutamine, and 48 mg gentamicin. The cells were expanded in 75-cm2 tissue culture flasks and kept in a humidified atmosphere of 5% CO2 at 37°C. The media were changed every other day. Confluent monolayers were detached with 0.02% EDTA in Ca2+- and Mg2+-free, pH 7.4, 0.01 mol/L PBS and dissociated into single-cell suspensions for further cell culture.
The receptor-binding properties of the 125I- or 111In-labeled complexes were assayed on a B16/F1 murine melanoma cell line. Cells were seeded at a density of 0.2 million per well in 24-well tissue culture plates and allowed to attach overnight. After 1 washing with binding medium (modified Eagle’s medium with 25 mmol/L N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid), 0.2% BSA, and 0.3 mmol/L 1,10-phenanthroline [Sigma, St. Louis, MO]), the cells were incubated at 25°C for 3 h with approximately 50,000 cpm radiolabeled complex in 0.5 mL binding medium. Nonspecific binding was determined by coincubation with nonradiolabeled NDP at a final concentration of 10 µmol/L. Cells were rinsed twice with pH 7.4, 0.01 mol/L PBS/0.2% BSA and lysed in 0.5 mL 1 mol/L NaOH for 5 min, and their radioactivity was measured. The cell-binding capacity was reported as the percentage of total added radioactivity that was bound to the cells.
The IC50, or concentration of competitor required to inhibit 50% of radioligand binding, was determined for the DOTA-coupled -MSH peptide analogs in competitive binding assays with 125I-(Tyr2)-NDP over a 10-14–10-6 mol/L concentration range. B16/F1 cells were prepared as described above in 24-well tissue culture plates and incubated at 25°C for 3 h with approximately 50,000 cpm 125I-(Tyr2)-NDP in 0.5 mL binding medium with different peptide concentrations. The radioactivity in the cells and in the medium was separately collected and measured. The data were processed, and the IC50 values of the DOTA-coupled peptide complexes were calculated with the Kell software package (Biosoft, Ferguson, MO).
In Vivo Studies
C57 BL/6 female mice, 7–8 wk old (Harlan, Indianapolis, IN), were inoculated subcutaneously in the right flank with 1 x 106 cultured B16/F1 murine melanoma cells. Ten days after the inoculation, when tumors reached a weight of approximately 500 mg, each mouse was injected with 2 µCi 111In-labeled peptide through the tail vein for in vivo studies. After radioactivity administration, the mice were housed separately and their urine and feces were collected. Groups of 5 mice were killed at different times (5 min to 72 h) after injection. Tumors and normal tissues of interest were dissected, and the blood on the samples was sponged off with gauze. The contents of the gastrointestinal tract were not removed. The whole body and tissue samples were weighed, and their radioactivity was measured in a 
-counter. The total-blood value was counted as 6.5% of the whole-body weight. Radioactivity uptake in the tumor and normal tissues of interest was expressed as a percentage of the injected radioactivity dose (%ID) per gram of tissue or as %ID. All animal studies were performed in compliance with federal and local institutional rules for the conduct of animal experimentation. Statistical analysis was performed using the Student t test for unpaired data.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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-MSH analogs were synthesized by solid-phase Fmoc synthesis and purified by RP HPLC, and their sequences were confirmed by ESI MS. The structure of DOTA-ReCCMSH is shown in Figure 1. The DOTA-ReCCMSH analogs included its linear nonmetalated homolog DOTA-CCMSH and a disulfide bond-cyclized analog, DOTA-CMSH. DOTA was also conjugated to the amino terminus of one of the highest-affinity -MSH receptor-binding peptides, NDP (16). Table 1 lists the sequences, IC50 values, and calculated and measured molecular weights of the DOTA–-MSH peptides used in this study. The 111In-labeled peptides were separated from their nonradiolabeled counterparts by RP HPLC. The radiochemical stabilities of the 111In-DOTA–-MSH analogs were assayed in pH 7.4, 0.01 mol/L PBS/0.1% BSA and pH 7.4, 0.01 mol/L PBS/0.1 mmol/L EDTA at 25°C. Over a 24-h incubation period, only radiolabeled peptide—not free radioactivity—was detected by RP HPLC. The receptor-binding activities of the individual radiolabeled complexes were determined before their use in vivo. Cell-binding capacities of 5%–10% were obtained for the 111In- and 125I-labeled -MSH analogs assayed with cultured B16/F1 murine melanoma cells.
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-MSH complexes were primarily cleared through the kidney into the urine, with low radioactivity accumulation in the gastrointestinal tract (Fig. 2). Approximately 92% of the total administrated 111In-DOTA–ReCCMSH radioactivity was eliminated into the urine at 2 h after injection, which was significantly faster than the other 3 111In-DOTA–peptides. Because of the muscle accumulation, the radioactivity clearance of 111In-DOTA–NDP was much slower, and approximately 52 %ID of the radioactivity still remained in the whole body at 2 h after radioactivity administration (Fig. 2).
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Figure 3 illustrates the radioactivity concentration (%ID/g) of 111In-DOTA–ReCCMSH in the tumor and normal tissues of interest over time. Because a high tumor uptake (8.6 %ID/g at as early as 5 min after injection) and high tumor retention (2.1 and 1.4 %ID/g at 48 and 72 h, respectively, after injection) were observed, the area under the curve (AUC) of tumor uptake for 111In-DOTA– ReCCMSH was 311.1. On the other hand, with fast radioactivity clearance from the blood and blood-rich organs, the half-life for whole-body radioactivity clearance of 111In-DOTA–ReCCMSH was 19.1 min. Figure 3 also lists the AUC and the ratio of tumor AUC to tissue AUC for blood, lung, liver, and carcass. The high tumor uptake and whole-body clearance of 111In-DOTA–ReCCMSH highlight the therapeutic potential of DOTA-ReCCMSH radiolabeled with ß-emitting radiolanthanides or -emitting radiobismuth for melanoma therapy.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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-MSH receptor-targeting peptides for melanoma diagnostic imaging and radiotherapy is attractive because receptor agonists are rapidly internalized on binding (14,17,18). Unfortunately, both directly labeled and chelator-labeled -MSH peptide analogs are degraded intracellularly, causing rapid release of the radioactivity from the target tissue (12,14). We have reported high melanoma tumor uptake and retention values for a 99mTc- or Recyclized -MSH analog, CCMSH (11,13,14). We hypothesized that the compact structure of 99mTc/ReCCMSH and the unique ReO-cysteine coordination chemistry resisted intracellular degradation while enhancing intracellular retention (14). To better understand the molecular basis for the favorable tumor-targeting and clearance properties of 99mTc/ReCCMSH, we compared 111In-DOTA-labeled ReCCMSH with 3 other closely related linear and cyclic 111In-DOTA-labeled -MSH peptide analogs. The linear, nonmetalated homolog of 111In-DOTA–ReCCMSH, 111In-DOTA–CCMSH, exhibited poor tumor uptake and retention, clearly showing the benefit of ReO-mediated cyclization or peptide cyclization itself. A comparison of 111In-DOTA–ReCCMSH with the disulfide bond-cyclized analog 111In-DOTA–CMSH showed that different methods of peptide cyclization yielded molecules with very different in vivo biodistribution properties. Together, these results provided strong evidence that ReO cyclization, not just peptide cyclization itself, was responsible for the high tumor uptake, retention, and whole-body clearance properties of ReCCMSH in vivo. The tumor uptake value of the linear 111In-DOTA–NDP was similar to that of DOTA-ReCCMSH at early times but was lower, with significance, at 24 h after injection. The similar tumor uptake values at earlier times likely result from the extremely high affinity NDP possesses for the -MSH receptor. Concurrently, high muscle uptake was observed for 111In-DOTA–NDP at 0.5–4 h after injection. It is not likely that the high muscle uptake values were caused by NDP-specific interactions because high muscle uptake was not observed for 99mTc[Cys-Gly-Cys-Gly]-NDP, 99mTc-MAG2–NDP, or 125I-(Try2)-NDP (12). The accompanying high muscle uptake of 111In-DOTA–NDP makes its therapeutic application unlikely. Nonspecific radioactivity accumulation in the kidneys is often associated with the in vivo application of radiolabeled peptides and antibody fragments (19–21). We postulated that the positive charge of the lysine residue was the main cause for the nonspecific radioactivity retention in the kidneys. In our previous studies, substitution of Lys11 with Nle11 or Gly11 in the 99mTc-CCMSH sequence yielded analogs with significantly reduced kidney uptake but sacrificed the high tumor-targeting property of the 99mTc-CCMSH (14). In this investigation, we found that high renal radioactivity uptake could also be caused by free sulfhydryls or the disulfide bond moiety. The kidney uptake of 111In-DOTA–ReCCMSH was 3–8 times lower than that of 111In-DOTA–CMSH and 111In-DOTA–CCMSH. Rhenium oxocoordination of the Cys-thiols appeared to shield them from interacting with the kidney, facilitating excretion of 111In-DOTA–ReCCMSH.
A comparison of clearance properties between 111In-DOTA–ReCCMSH and its related 99mTc-CCMSH analog revealed that 111In-DOTA–ReCCMSH exhibited superior clearance kinetics. Approximately 92 %ID of 111In-DOTA–ReCCMSH radioactivity was eliminated through the urine at 2 h after injection, compared with only 73 %ID for 99mTc-CCMSH at the same time point. Likewise, the blood clearance rate for 111In-DOTA–ReCCMSH was twice that for 99mTc-CCMSH (14). In addition, 111In-DOTA–ReCCMSH exhibited superior tumor retention values compared with 99mTc-CCMSH at 24 h after injection, although tumor uptake values for both complexes were not statistically different at early time points. The increased whole-body clearance kinetics and increased tumor retention properties of 111In-DOTA–ReCCMSH were likely to have resulted from greater hydrophilicity because of an increase in the number of charges. At a neutral pH, both 111In-DOTA–ReCCMSH and 99mTc-CCMSH have a net zero charge. However, 111In-DOTA–ReCCMSH has a larger number of ionizable groups because of the presence of the DOTA chelator. It is likely that a complex with a greater number of charges would have more difficulty diffusing across a cell membrane, thus resulting in an increase in tumor retention for 111In-DOTA–ReCCMSH. Moreover, an increase in hydrophilicity should promote rapid blood clearance and renal excretion, which are consistent with the biodistribution data.
Several benefits are associated with DOTA conjugation to ReCCMSH. The DOTA chelator is able to strongly chelate a variety of ß- or -particle–emitting radiometals, such as 111In, 90Y, 149Pm, 177Lu, 212Pb, and 212/213Bi, under physiologic conditions (22–26). The metal chelation flexibility of DOTA would allow DOTA–ReCCMSH to be labeled with radionuclides that deposit their energies over a range of approximately 10 µm to 1 cm. DOTA conjugation also appears to improve tumor cell retention. Redistribution of radioactive catabolites derived from internalized peptide complexes will dramatically influence tumor radioactivity uptake and retention (27). The radiometals used to complex with DOTA exhibit multiple charges. Free radiolabeled DOTA species produced on degradation of the radiolabeled peptide conjugates will remain largely intracellular because of the difficulty of moving a charged complex across cellular membranes (28). Hence, a reduction in the diffusion of charged radiolabeled DOTA species across the cell membrane will further reduce washout of tumor-targeted radioactivity, resulting in enhanced retention times. Compared with our previous results reported for 99mTc/ReCCMSH (11,13,14), the biodistribution data reported here for 111In-DOTA–ReCCMSH clearly show that the DOTA-conjugated complex has equally good tumor uptake kinetics, with increased tumor retention >24 h after injection and enhanced clearance kinetics. Because of both its higher tumor-targeting capacity and its low background, 111In-DOTA–ReCCMSH exhibited the highest uptake ratio of tumor to normal tissues of any reported radiolabeled -MSH complex, highlighting its ability to selectively deposit radionuclides in melanoma tumor cells.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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-emitter–radiolabeled DOTA–ReCCMSH an attractive potential therapeutic agent for melanoma.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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For correspondence or reprints contact: Thomas P. Quinn, PhD, Department of Biochemistry, 117 Schweitzer Hall, University of Missouri–Columbia, Columbia, MO 65211.
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S. R. Kumar and S. L. Deutscher 111In-Labeled Galectin-3-Targeting Peptide as a SPECT Agent for Imaging Breast Tumors J. Nucl. Med., May 1, 2008; 49(5): 796 - 803. [Abstract] [Full Text] [PDF]
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