SPECT and PET Imaging of Meningiomas

Meningiomas arise from the meningothelial cells of the arachnoid membranes. They are the most common primary intracranial neoplasms and represent about 20% of all intracranial tumors. They are usually diagnosed after the third decade of life and they are more frequent in women than in men. According to the World Health Organization (WHO) criteria, meningiomas can be classified into grade I meningiomas, which are benign, grade II (atypical) and grade III (anaplastic) meningiomas, which have a much more aggressive clinical behaviour. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are routinely used in the diagnostic workup of patients with meningiomas. Molecular Nuclear Medicine Imaging with Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) could provide complementary information to CT and MRI. Various SPECT and PET tracers may provide information about cellular processes and biological characteristics of meningiomas. Therefore, SPECT and PET imaging could be used for the preoperative noninvasive diagnosis and differential diagnosis of meningiomas, prediction of tumor grade and tumor recurrence, response to treatment, target volume delineation for radiation therapy planning, and distinction between residual or recurrent tumour from scar tissue

The cientificWorldJOURNAL Review Article SPECT and PET Imaging of Meningiomas

Meningiomas arise from the meningothelial cells of the arachnoid membranes. They are the most common primary intracranial neoplasms and represent about 20% of all intracranial tumors. They are usually diagnosed after the third decade of life and they are more frequent in women than in men. According to the World Health Organization (WHO) criteria, meningiomas can be classified into grade I meningiomas, which are benign, grade II (atypical) and grade III (anaplastic) meningiomas, which have a much more aggressive clinical behaviour. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are routinely used in the diagnostic workup of patients with meningiomas. Molecular Nuclear Medicine Imaging with Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) could provide complementary information to CT and MRI. Various SPECT and PET tracers may provide information about cellular processes and biological characteristics of meningiomas. Therefore, SPECT and PET imaging could be used for the preoperative noninvasive diagnosis and differential diagnosis of meningiomas, prediction of tumor grade and tumor recurrence, response to treatment, target volume delineation for radiation therapy planning, and distinction between residual or recurrent tumour from scar tissue

In vivo anticancer evaluation of the hyperthermic efficacy of anti-human epidermal growth factor receptor-targeted PEG-based nanocarrier containing magnetic nanoparticles

Polymeric nanoparticles with targeting moieties containing magnetic nanoparticles as theranostic agents have considerable potential for the treatment of cancer. Here we report the chemical synthesis and characterization of a poly(D,L-lactide-co-glycolide)-b-poly(ethylene glycol)-based nanocarrier containing iron oxide nanoparticles and human epithelial growth factor receptor on the outer shell. The nanocarrier was also radiolabeled with (99m)Tc and tested as a theranostic nanomedicine, ie, it was investigated for both its diagnostic ability in vivo and its therapeutic hyperthermic effects in a standard A431 human tumor cell line. Following radiolabeling with (99m)Tc, the biodistribution and therapeutic hyperthermic effects of the nanosystem were studied noninvasively in vivo in tumor-bearing mice. A substantial decrease in tumor size correlated with an increase in both nanoparticle concentration and local temperature was achieved, confirming the possibility of using this multifunctional nanosystem as a therapeutic tool for epidermoid carcinoma

A Novel Metal-Based Imaging Probe for Targeted Dual-Modality SPECT/MR Imaging of Angiogenesis

Superparamagnetic iron oxide nanoparticles with well-integrated multimodality imaging properties have generated increasing research interest in the past decade, especially when it comes to the targeted imaging of tumors. Bevacizumab (BCZM) on the other hand is a well-known and widely applied monoclonal antibody recognizing VEGF-A, which is overexpressed in angiogenesis. The aim of this proof-of-concept study was to develop a dual-modality nanoplatform for in vivo targeted single photon computed emission tomography (SPECT) and magnetic resonance imaging (MRI) of tumor vascularization. Iron oxide nanoparticles (IONPs) have been coated with dimercaptosuccinic acid (DMSA), for consequent functionalization with the monoclonal antibody BCZM radiolabeled with 99mTc, via well-developed surface engineering. The IONPs were characterized based on their size distribution, hydrodynamic diameter and magnetic properties. In vitro cytotoxicity studies showed that our nanoconstruct does not cause toxic effects in normal and cancer cells. Fe3O4-DMSA-SMCC-BCZM-99mTc were successfully prepared at high radiochemical purity (>92%) and their stability in human serum and in PBS were demonstrated. In vitro cell binding studies showed the ability of the Fe3O4-DMSA-SMCC-BCZM-99mTc to bind to the VEGF-165 isoform overexpressed on M-165 tumor cells. The ex vivo biodistribution studies in M165 tumor-bearing SCID mice showed high uptake in liver, spleen, kidney and lungs. The Fe3O4-DMSA-SMCC-BCZM-99mTc demonstrated quick tumor accumulation starting at 8.9 ± 1.88%ID/g at 2 h p.i., slightly increasing at 4 h p.i. (16.21 ± 2.56%ID/g) and then decreasing at 24 h p.i. (6.01 ± 1.69%ID/g). The tumor-to-blood ratio reached a maximum at 24 h p.i. (~7), which is also the case for the tumor-to-muscle ratio (~18). Initial pilot imaging studies on an experimental gamma-camera and a clinical MR camera prove our hypothesis and demonstrate the potential of Fe3O4-DMSA-SMCC-BCZM-99mTc for targeted dual-modality imaging. Our findings indicate that Fe3O4-DMSA-SMCC-BCZM-99mTc IONPs could serve as an important diagnostic tool for biomedical imaging as well as a promising candidate for future theranostic applications in cancer

Labeling and evaluation of rgd peptide derivatives for angiogenesis imaging

The aim of the present project is the study of the labeling of two novel derivatives of the cyclic peptide cRGDfK (Arg-Gly-Asp-D-Phe-Lys) with 99mTc(I). The derivatives which were synthesized and studied were cRGDfK-His and cRGDfK-CPA. The pentapeptide cRGDfK was synthesized by employing the SPPS method on an o-chloro-amidomethylpolystyrene resin, according to the F-moc strategy. The two bifunctional chelating agents, His and CPA, were linked to the peptide moiety via the Nε­-amino group of Lys. The labeling of both derivatives was performed via the technetium precursor [99mTc(H2O)3(CO)3]+ and led to the formation of one labeled product each time, with a yield of more than 98%. The effect of heating time and peptide concentration on the labeling of the peptides was next studied. It was found that for >20 min heating, the formation of cRGDfK-His-99mTc(H2O)(CO)3 and cRGDfK-CPA-99mTc(CO)3 occurs in high percentages (>98%). From the study it was found that both peptide derivatives can be labeled in high yields, even at very low concentrations; cRGDfK-His: 10-5Μ (>87%) and cRGDfK-CPA: 5 / 10-5Μ (>93%). The in vitro stability of the labeled peptide derivatives was studied: a) at different time-points, b) in the presence of an excess of His and Cys, c) in human plasma, d) in human serum and e) in liver and kidney homogenates. Both products remain quite stable under these conditions, since no decomposition/exchange is noticed, while cRGDfK-CPA-99mTc(CO)3 is a bit more stable than cRGDfK-His-99mTc(H2O)(CO)3 in human serum. A good percentage of both labeled compounds internalizes quickly in vitro in cancer cells and no capture of radioactivity is observed. The study and comparative evaluation of the in vivo behavior and the pharmacokinetic properties of the radiolabeled products were assessed after their biodistribution in normal mice and pathological scid mice with breast cancer. From the comparative biodistribution study of the two radiolabeled peptide derivatives, it was found that both have fast blood clearance, with cRGDfK-His-99mTc(H2O)(CO)3 remaining for a longer time than cRGDfK-CPA-99mTc(CO)3 in all organs examined. Both are eliminated via the hepatobiliary and urinary systems. The percentage of tumor uptake at 30min p.i. was higher for cRGDfK-His-99mTc(H2O)(CO)3 (2,79 ± 1,48% ID/G) than for cRGDfK-CPA-99mTc(CO)3 (4.14 ± 1,52% ID/g). Scintigraphic studies showed that the tumor could be better visualized between 20 and 40min p.i. for both radiolabeled compounds. The fact that imaging is not very clear can be attributed to the high radioactive concentration in the abdominal area. It was finally concluded that the smaller the size of the tumor, the higher the concentration of the radiolabeled peptide derivative in the tumor areaΑντικείμενο της παρούσας διδακτορικής διατριβής αποτελεί η μελέτη της επισήμανσης δύο νέων παραγώγων του κυκλικού πεπτιδίου cRGDfK (Arg-Gly-Asp-D-Phe-Lys) με 99mTc(Ι). Τα παράγωγα που συντέθηκαν και μελετήθηκαν ήταν το cRGDfK-His και το cRGDfK-CPA. Το πενταπεπτίδιο cRGDfK συντέθηκε με τη μέθοδο της SPPS πάνω σε μια ο-χλωρο-αμιδομεθυλοπολυστυρενική ρητίνη ακολουθώντας την Fmoc στρατηγική. Στο μόριο του πεπτιδίου συζεύχθηκαν μέσω της Nε-αμινομάδας της Lys οι δύο περιφερειακοί υποκαταστάτες His και CPA. Η επισήμανση των παραγώγων έγινε μέσω του προσυμπλόκου [99mTc(H2O)3(CO)3]+ και οδήγησε στο σχηματισμό ενός επισημασμένου προϊόντος κάθε φορά με απόδοση >98%. Ακολούθως μελετήθηκαν η επίδραση του χρόνου θέρμανσης και της συγκέντρωσης του πεπτιδίου στην επισήμανση. Βρέθηκε ότι για χρόνους θέρμανσης ?20min ο σχηματισμός των cRGDfK-His-99mTc(H2O)(CO)3 και cRGDfK-CPA-99mTc(CO)3 λαμβάνει χώρα σε υψηλό ποσοστό (>98%). Από τη μελέτη προέκυψε ότι και τα δύο πεπτιδικά παράγωγα μπορούν να επισημανθούν σε μεγάλο ποσοστό, ακόμα και σε πολύ μικρές συγκεντρώσεις. cRGDfK-His: 10-5Μ (>87%) και cRGDfK-CPA: 5 / 10-5Μ (>93%). Η in vitro σταθερότητα των επισημασμένων πεπτιδικών παραγώγων μελετήθηκε: α) με την πάροδο του χρόνου, β) παρουσία περίσσειας His/Cys, γ) παρουσία ανθρώπινου πλάσματος, δ) παρουσία ανθρώπινου ορού και ε) σε ομογενοποιήματα νεφρών και ήπατος. Και τα δύο επισημασμένα πεπτιδικά παράγωγα παρουσιάζουν ικανοποιητική σταθερότητα στις παραπάνω συνθήκες, αφού δεν παρατηρείται σε καμία περίπτωση κανενός είδους διαμοριακή ανταλλαγή/αντικατάσταση, ενώ το cRGDfK-CPA-99mTc(CO)3 είναι λίγο σταθερότερο από το cRGDfK-His-99mTc(H2O)(CO)3 μετά από επώαση σε ανθρώπινο ορό. Και τα δύο παράγωγα εσωτερικοποιούνται γρήγορα και σε αρκετά μεγάλο ποσοστό σε καρκινικά κύτταρα, ενώ δεν παρατηρείται εγκλωβισμός της ραδιενέργειας σε αυτά. Η μελέτη και συγκριτική αξιολόγηση της in vivo συμπεριφοράς των προϊόντων έγινε μετά από βιοκατανομή τους σε φυσιολογικούς μυς άλλα και σε παθολογικά πρότυπα καρκίνου. Από τη συγκριτική μελέτη της βιοκατανομής τους βρέθηκε ότι και τα δύο παρουσιάζουν παρόμοια, ταχεία αιματική κάθαρση, με το cRGDfK-His-99mTc(H2O)(CO)3 να παραμένει για μεγαλύτερο χρονικό διάστημα στον οργανισμό συγκριτικά με το cRGDfK-CPA-99mTc(CO)3. Η αποβολή και των δύο επισημασμένων RGD πεπτιδικών παραγώγων γίνεται κατά πρώτο λόγο μέσω του ηπατοχολικού και κατά δεύτερο μέσω του ουροποιητικού συστήματος. Το ποσοστό πρόσληψης στον όγκο 30min p.i. ήταν υψηλότερο για το cRGDfK-CPA-99mTc(CO)3 (4.14 ± 1,52% ID/g) από ότι για το cRGDfK-His-99mTc(H2O)(CO)3 (2,79 ± 1,48% ID/G). Οι σπινθηρογραφικές μελέτες έδειξαν ότι ο όγκος ήταν πιο διακριτός στο χρονικό διάστημα από 20 μέχρι 40min p.i. και για τα δύο. Το ότι δεν λαμβάνεται ευκρινής σπινθηρογραφική απεικόνιση οφείλεται στη μεγάλη ραδιενεργή συγκέντρωση στην κοιλιακή περιοχή. Τέλος διαπιστώθηκε ότι όσο μικρότερος σε μέγεθος είναι ο όγκος τόσο μεγαλύτερος είναι ο εντοπισμός του επισημασμένου πεπτιδικού παραγώγου σε αυτόν

Polymeric micelles and vesicles: biological behavior evaluation using radiolabeling techniques

The application of combined diagnosis and therapy through nanotechnology applications is attracting increasing attention worldwide. Polymeric self-assembled nanoparticles (NPs) have been studied for this purpose. Micelles and vesicles with or without a magnetic core can efficiently carry diagnostic and/or therapeutic agents to a desired target. The biological behavior of these NPs has been evaluated in this study, after radiolabeling with Tc-99m. In vitro stability, in media that mimic the environment of the living body, was better for vesicles than for micelles at 1 h and decreased for both as time passed. After administration to healthy animals, all NPs presented major uptake at liver and spleen as expected. Biodistribution and imaging studies confirmed the higher uptake in these organs for the hybrid NPs and at higher extent for the ones with larger size, indicating that the magnetic load and size play an important role on in vivo distribution

Targeted delivery of silver nanoparticles and alisertib:in vitroandin vivosynergistic effect against glioblastoma

Targeted biocompatible nanoplatforms presenting multiple therapeutic functions have great potential for the treatment of cancer. Materials & methods: Multifunctional nanocomposites formed by polymeric nanoparticles (PNPs) containing two cytotoxic agents \u2013 the drug alisertib and silver nanoparticles \u2013 were synthesized. These PNPs have been conjugated with a chlorotoxin, an active targeting 36-amino acid-long peptide that specifically binds to MMP\u20112, a receptor overexpressed by brain cancer cells. Results: The individual and synergistic activity of these two cytotoxic agents against glioblastoma multiforme was tested both in vitro and in vivo. The induced cytotoxicity in a human glioblastoma\u2013astrocytoma epithelial\u2011like cell line (U87MG) was studied in vitro through a trypan blue exclusion test after 48 and 72 h of exposure. Subsequently, the PNPs\u2019 biodistribution in healthy animals and their effect on tumor reduction in tumor\u2011bearing mice were studied using PNPs radiolabeled with 99mTc. Conclusion: Tumor reduction was achieved in vivo when using silver/alisertib@PNPs\u2013chlorotoxin

Targeted delivery of silver nanoparticles and alisertib: in vitro and in vivo synergistic effect against glioblastoma

Aim: Targeted biocompatible nanoplatforms presenting multiple therapeutic functions have great potential for the treatment of cancer. Materials & methods: Multifunctional nanocomposites formed by polymeric nanoparticles (PNPs) containing two cytotoxic agents – the drug alisertib and silver nanoparticles – were synthesized. These PNPs have been conjugated with a chlorotoxin, an active targeting 36-amino acid-long peptide that specifically binds to MMP‑2, a receptor overexpressed by brain cancer cells. Results: The individual and synergistic activity of these two cytotoxic agents against glioblastoma multiforme was tested both in vitro and in vivo. The induced cytotoxicity in a human glioblastoma–astrocytoma epithelial‑like cell line (U87MG) was studied in vitro through a trypan blue exclusion test after 48 and 72 h of exposure. Subsequently, the PNPs’ biodistribution in healthy animals and their effect on tumor reduction in tumor‑bearing mice were studied using PNPs radiolabeled with 99mTc. Conclusion: Tumor reduction was achieved in vivo when using silver/alisertib@PNPs–chlorotoxin.JRC.I.4-Nanobioscience

In vivo anticancer evaluation of the hyperthermic efficacy of anti-human epidermal growth factor receptor-targeted PEG-based nanocarrier containing magnetic nanoparticles

Polymeric nanoparticles with targeting moieties containing magnetic nanoparticles as theranostic agents have considerable potential for the treatment of cancer. Here we report the chemical synthesis and characterization of a poly(D,L-lactide-co-glycolide)-b-poly(ethylene glycol)-based nanocarrier containing iron oxide nanoparticles and human epithelial growth factor receptor on the outer shell. The nanocarrier was also radiolabeled with 99mTc and tested as a theranostic nanomedicine, ie, it was investigated for both its diagnostic ability in vivo and its therapeutic hyperthermic effects in a standard A431 human tumor cell line. Following radiolabeling with 99mTc, the biodistribution and therapeutic hyperthermic effects of the nanosystem were studied noninvasively in vivo in tumor-bearing mice. A substantial decrease in tumor size correlated with an increase in both nanoparticle concentration and local temperature was achieved, confirming the possibility of using this multifunctional nanosystem as a therapeutic tool for epidermoid carcinoma