Macrocyclic chelator assembled RGD multimers for tumor targeting

Molecular Imaging Program at Stanford, Department of Radiology, Stanford University Medical Center, California 94305, USA.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 06/2011; 21(11):3423-6. DOI: 10.1016/j.bmcl.2011.03.110
Source: PubMed


Macrocyclic chelators have been extensively used for complexation of metal ions. A widely used chelator, DOTA, has been explored as a molecular platform to assemble multiple bioactive peptides in this paper. The multivalent DOTA-peptide bioconjugates demonstrate promising tumor targeting ability.

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    • "These probes demonstrated the high tumor to background ratios. For example, the tumor to muscle ratio reached 20.46 ± 4.47 at 4 h post injection of 64Cu-Mal2Sar-RGD2, which is consistent with high contrast shown in Fig. 3. 64Cu-Mal2Sar-RGD2 also had significantly increased tumor uptake compared with 64Cu-BaMalSar-RGD, which could be caused by a multivalency effect as has been observed before 8, 26-28. Similar to previous reports, increased tumor uptake was accompanied with an elevated kidney uptake 27-28. "
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    ABSTRACT: Purpose We and others have reported that Sarcophagine-based bifunctional chelators could be effectively used in the syntheses of 64Cu radiopharmaceuticals. The resulted 64Cu-Sarcophagine complexes demonstrated great in vivo stability. The goal of this study was to further derivatize Sarcophagine cage with amino and maleimide functional groups for conjugation with bioligands. Methods Starting from DiAmSar, three novel chelators (AnAnSar, BaMalSar, and Mal2Sar) with two functional groups have been synthesized. Among those, BaMalSar and Mal2Sar have been conjugated with cyclic peptide c(RGDyC) (denoted as RGD) and the resulted conjugates, BaMalSar-RGD and Mal2Sar-RGD2 have been labeled with 64Cu. The tumor targeting efficacy of 64Cu-labeled RGD peptides were evaluated in a subcutaneous U87MG glioblastoma xenograft model. Results The conjugates, BaMalSar-RGD and Mal2Sar-RGD2 could be labeled with 64CuCl2 in 10 min with high purity (>98%) and high radiochemical yield (>90%). Both 64Cu-BaMalSar-RGD and 64Cu-Mal2Sar-RGD2 exhibited high tumor uptake and tumor-to-normal tissue ratios. Conclusion Three novel chelators with two functional groups have been developed based on Sarcophagine cage. The platform developed in this study could have broad applications in the design and synthesis of 64Cu-radiopharmaceuticals.
    Theranostics 06/2012; 2(6):589-96. DOI:10.7150/thno.4295 · 8.02 Impact Factor
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    ABSTRACT: The role of the multivalent effect has been well recognized in the design of molecular imaging probes toward the desired imaging signal amplification. Recently, we reported a bifunctional chelator (BFC) scaffold design, which provides a simple and versatile approach to impart multivalency to radiometal based nuclear imaging probes. In this work, we report a series of BFC scaffolds ((t)Bu(3)-1-COOH, (t)Bu(3)-2-(COOH)(2), and (t)Bu(3)-3-(COOH)(3)) constructed on the framework of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) for (68)Ga-based PET probe design and signal amplification via the multivalent effect. For proof of principle, a known integrin α(v)β(3) specific ligand (c(RGDyK)) was used to build the corresponding NOTA conjugates (H(3)1, H(3)2, and H(3)3), which present 1-3 copies of c(RGDyK) peptide, respectively, in a systematic manner. Using the integrin α(v)β(3) binding affinities (IC(50) values), enhanced specific binding was observed for multivalent conjugates (H(3)2: 43.9 ± 16.1 nM; H(3)3: 14.7 ± 5.0 nM) as compared to their monovalent counterpart (H(3)1: 171 ± 60 nM) and the intact c(RGDyK) peptide (204 ± 76 nM). The obtained conjugates were efficiently labeled with (68)Ga(3+) within 30 min at room temperature in high radiochemical yields (>95%). The in vivo evaluation of the labeled conjugates, (68)Ga-1, (68)Ga-2, and (68)Ga-3, was performed using male severe combined immunodeficiency (SCID) mice bearing integrin α(v)β(3) positive PC-3 tumor xenografts (n = 3). All (68)Ga-labeled conjugates showed high in vivo stability with no detectable metabolites found by radio-HPLC within 2 h postinjection (p.i.). The PET signal amplification in PC-3 tumor by the multivalent effect was clearly displayed by the tumor uptake of the (68)Ga-labeled conjugates ((68)Ga-3: 2.55 ± 0.50%ID/g; (68)Ga-2: 1.90 ± 0.10%ID/g; (68)Ga-1: 1.66 ± 0.15%ID/g) at 2 h p.i. In summary, we have designed and synthesized a series of NOTA-based BFC scaffolds with signal amplification properties, which may find potential applications as diagnostic gallium radiopharmaceuticals.
    Bioconjugate Chemistry 08/2011; 22(8):1650-62. DOI:10.1021/bc200227d · 4.51 Impact Factor
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    ABSTRACT: Two bicyclic compounds containing Arg-Gly-Asp (RGD) motifs (RGDf and RGD) were synthesized by cyclizing the peptide sequence across the macrocyclic ring of DOTA via two non-adjacent carboxylate pendent arms. The Lu(3+) or Cu(2+) complexes of these compounds, c(DOTA-RGDf) and c(DOTA-RGD), showed a metal dependent affinity towards integrin α(v)β(3)in vitro and the (177)Lu(3+) or (64)Cu(2+) labelled derivatives showed specific tumour uptake in MCF7 and U87MG tumour bearing mice.
    Dalton Transactions 10/2012; 41(46). DOI:10.1039/c2dt31493b · 4.20 Impact Factor
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