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Abstract
Overexpression of the chemokine-4 receptor (CXCR4) in brain tumors is associated with high cancer cell invasiveness. Recently, we reported the preclinical evaluation of 99mTc-CXCR4-L (cyclo-D-Tyr-D-[NMe]Orn[EDDA-99mTc-6-hydrazinylnicotinyl]-Arg-NaI-Gly) as a SPECT radioligand capable of specifically detecting the CXCR4 protein. This research aimed to estimate the biokinetic behavior and radiation dosimetry of 99mTc-CXCR4-L in healthy subjects, as well as to correlate the radiotracer uptake by brain tumors in patients, with the histological grade of differentiation and CXCR4 expression evaluated by immunohistochemistry. 99mTc-CXCR4-L was obtained from freeze-dried kits prepared under GMP conditions (radiochemical purities >97%). Whole-body scans from six healthy volunteers were acquired at 0.3, 1, 2, 4, 6, and 24 h after 99mTc-CXCR4-L administration (0.37 GBq). Time-activity curves of different source organs were obtained from the image sequence to adjust the biokinetic models. The OLINDA/EXM code was employed to calculate the equivalent and effective radiation doses. Nine patients with evidence of brain tumor injury (6 primaries and 3 recurrent), determined by MRI, underwent cerebral SPECT at 3 h after administration of 99mTc-CXCR4-L (0.74 GBq). Data were expressed as a T/B (tumor uptake/background) ratio. Biopsy examinations included histological grading and anti-CXCR4 immunohistochemistry. Results showed a fast blood activity clearance (T1/2α = 0.81 min and T1/2β = 12.19 min) with renal and hepatobiliary elimination. The average equivalent doses were 6.10E − 04, 1.41E − 04, and 3.13E − 05 mSv/MBq for the intestine, liver, and kidney, respectively. The effective dose was 3.92E − 03 mSv/MBq. SPECT was positive in 7/9 patients diagnosed as grade II oligodendroglioma (two patients), grade IV glioblastoma (two patients), grade IV gliosarcoma (one patient), metastasis, and diffuse astrocytoma with T/B ratios of 1.3, 2.3, 13, 7, 19, 5.5, and 3.9, respectively, all of them with positive immunohistochemistry. A direct relationship between the grade of differentiation and the expression of CXCR4 was found. The two negative SPECT studies showed negative immunohistochemistry with a diagnosis of reactive gliosis. This “proof-of-concept” research warrants further clinical studies to establish the usefulness of 99mTc-CXCR4-L in the diagnosis and prognosis of brain tumors.
Highlights
Glioblastomas produce many malignant tissue satellites that frequently migrate to substantial distance from the primary tumors, the reason for which they are challenging to eradicate by surgical techniques and chemo- and radiotherapeutic regimens [2, 3]
Is research aimed to estimate the biokinetic behavior and radiation dosimetry of 99mTc-CXCR4-L in healthy subjects, as well as to correlate the radiotracer uptake by brain tumors in patients, with the histological grade of differentiation and CXCR4 expression evaluated by immunohistochemistry
Visual and semiquantitative analyses were performed by two physicians with an experience of >9 years in the use of the Siemens Syngo Acquisition Workplace equipment workstation with processing software for volumetric analysis. e tumor/background (T/Bmax) uptake ratio was calculated by quantifying the number of maximum counts obtained by delimiting volumetric regions (3D) of interest (VOI) with the isocontour around the entire tumor area (T) and in the contralateral brain region (B)
Summary
Informed consent was given by the patients, and the protocol was approved by the institutional ethics committee, considering the following aspects: (a) Helsinki Declaration (1975; revised version, 2008) and the ethical standards of the institutional committee related to human experimentation, (b) the GMP certificate granted to ININ by COFEPRIS (“Comision Federal para la Proteccion contra Riesgos Sanitarios”: regulatory authority in Mexico), (c) the complete preclinical studies of 99mTc-CXCR4-L, and (d) the basis of “proof-of-concept” and microdosing studies. 99mTc-CXCR4-L images in volunteers were obtained with a Symbia TruePoint dual-head gamma camera (SPECT/CT, Siemens), with high-resolution and low-energy collimators. Cam Signature double detector) images were acquired at 3 h after 99mTc-CXCR4-L (0.74 GBq) administration using a 128 × 128 matrix, window centered on 140 keV, with scattering correction, 360-degree
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