Hybrid Peptide Dendrimers for Imaging of Chemokine Receptor 4 (CXCR4) Expression

Division of Diagnostic Oncology, The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands.
Molecular Pharmaceutics (Impact Factor: 4.38). 11/2011; 8(6):2444-53. DOI: 10.1021/mp200401p
Source: PubMed


The chemokine receptor 4 (CXCR4), which is overexpressed in many types of cancer, is an emerging target in the field of molecular imaging and therapeutics. The CXCR4 binding of several peptides, including the cyclic Ac-TZ14011, has already been validated. In this study mono-, di- and tetrameric Ac-TZ14011-containing dendrimers were prepared and functionalized with a multimodal (hybrid) label, consisting of a Cy5.5-like fluorophore and a DTPA chelate. Confocal microscopy revealed that all three dendrimers were membrane bound at 4 °C, consistent with CXCR4 binding in vitro. The unlabeled dimer and tetramer had a somewhat lower affinity for CXCR4 than the unlabeled monomer. However, when labeled with the multimodal label the CXCR4 affinity of the dimer and tetramer was considerably higher compared to that of the labeled monomer. On top of that, biodistribution studies revealed that the additional peptides in the dimer and tetramer reduced nonspecific muscle uptake. Thus, multimerization of the cyclic Ac-TZ14011 peptide reduces the negative influence of the multimodal label on the receptor affinity and the biodistribution.

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    • "Besides hybrid agents for combined PET/OI, also markers for dual SPECT/OI have been developed over the last years, comprising dually labeled antibodies [28, 29], peptides [30–35], a nontargeted small molecule [36], and nanoparticles [37–40]. However, as PET is—in contrast to SPECT—fully quantifiable and exhibits a much higher sensitivity than the latter, the main focus in this young field of bimodal probe development for use in nuclear medicine and optical imaging lies on the development of PET/OI agents, having a greater potential for a possible clinical application. "
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    • "Kuil et al. developed a multimodality probe based on T140 derivative, Ac-Tz14011, by conjugating the D-lys of the peptide to multifunctional single attachment point reagent that contains a DTPA chelate and a CyAL-5.5b fluorochrome 54. The researchers chelated Inidium-111 into the DTPA and performed SPECT/CT and fluorescent imaging of tumor bearing mice. "
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    • "Similar to the in vitro evaluation of fluorescently labeled imaging agents [21], [22], flow cytometriy could be used to analyze the level of CXCR4 expression in the tumor cell suspensions. In this application incubation with MSAP-Ac-TZ14011 allowed effective discrimination between MIN-O (stages) and 4T1 tumor lesions using the fluorescent label of the targeting hybrid imaging agent (Fig. 4 and Table 2). "
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