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.

Download full-text


Available from: Tessa Buckle,
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Molecular imaging-and especially positron emission tomography (PET)-has gained increasing importance for diagnosis of various diseases and thus experiences an increasing dissemination. Therefore, there is also a growing demand for highly affine PET tracers specifically accumulating and visualizing target structures in the human body. Beyond the development of agents suitable for PET alone, recent tendencies aim at the synthesis of bimodal imaging probes applicable in PET as well as optical imaging (OI), as this combination of modalities can provide clinical advantages. PET, due to the high tissue penetration of the γ-radiation emitted by PET nuclides, allows a quantitative imaging able to identify and visualize tumors and metastases in the whole body. OI on the contrary visualizes photons exhibiting only a limited tissue penetration but enables the identification of tumor margins and infected lymph nodes during surgery without bearing a radiation burden for the surgeon. Thus, there is an emerging interest in bimodal agents for PET and OI in order to exploit the potential of both imaging techniques for the imaging and treatment of tumor diseases. This short review summarizes the available hybrid probes developed for dual PET and OI and discusses future directions for hybrid agent development.
    04/2014; 2014(16):153741. DOI:10.1155/2014/153741
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: CXCR4 was found to be expressed by many different types of human cancers and its expression has been correlated with tumor aggressiveness, poor prognosis and resistance to chemotherapy. CXCR4 was also shown to contribute to metastatic seeding of organs that express its ligand CXCL12 and support the survival of these cells. These findings suggest that CXCR4 is a potentially attractive therapeutic target, and several antagonists and antibodies for this receptor were developed and are under clinical evaluation. Quantifying CXCR4 expression non-invasively might aid in prognostication as a mean for personalized therapy and post treatment monitoring. Multiple attempts were done over the recent years to develop imaging agents for CXCR4 using different technologies including PET, SPECT, fluorescent and bioluminescence, and will be reviewed in this paper.
    Theranostics 01/2013; 3(1):76-84. DOI:10.7150/thno.4835 · 8.02 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Screening of biomarker expression levels in tumor biopsy samples not only provides an assessment of prognostic and predictive factors, but may also be used for selection of biomarker-specific imaging strategies. To assess the feasibility of using a biopsy specimen for a personalized selection of an imaging agent, the chemokine receptor 4 (CXCR4) was used as a reference biomarker. A hybrid CXCR4 targeting peptide (MSAP-Ac-TZ14011) containing a fluorescent dye and a chelate for radioactive labeling was used to directly compare initial flow cytometry-based target validation in fresh tumor tissue to in vivo single photon emission computed tomography (SPECT) imaging and in vivo and ex vivo fluorescence imaging. Flow cytometric analysis of mouse tumor derived cell suspensions enabled discrimination between 4T1 control tumor lesions (with low levels of CXCR4 expression) and CXCR4 positive early, intermediate and late stage MIN-O lesions based on their CXCR4 expression levels; CXCR4(basal), CXCR4(+) and CXCR4(++) cell populations could be accurately discriminated. Mean fluorescent intensity ratios between expression in MIN-O and 4T1 tissue found with flow cytometry were comparable to ratios obtained with in vivo SPECT/CT and fluorescence imaging, ex vivo fluorescence evaluation and standard immunohistochemistry. The hybrid nature of a targeting imaging agent like MSAP-Ac-TZ14011 enables integration of target selection, in vivo imaging and ex vivo validation using a single agent. The use of biopsy tissue for biomarker screening can readily be expanded to other targeting hybrid imaging agents and can possibly help increase the clinical applicability of tumor-specific imaging approaches.
    PLoS ONE 01/2013; 8(1):e48324. DOI:10.1371/journal.pone.0048324 · 3.23 Impact Factor
Show more