Evaluation of prognostic integrin α2β1 PET tracer and concurrent targeting delivery using focused ultrasound for brain glioma detection
Journal
Molecular Pharmaceutics
Journal Volume
11
Journal Issue
11
Pages
3904-3914
Date Issued
2014
Author(s)
Abstract
The ability to early detect and assess the treatment response of recurrent and/or disseminated metastatic glioblastoma is critical for the effective management of this group of patients. Accumulating experimental evidence indicates that integrin α2β1 might be a prognostic biomarker for advanced phenotype of cancers. In this study, a novel 68Ga-labeled integrin α2β1-targeted PET tracer 68Ga-NOTA-PEG4-cyclo (GDGEAyK) (68Ga-A2B1) was designed and evaluated for the potential prognostic imaging of glioblastoma tumor in preclinical model. To prospectively verify the prognostic value of integrin α2β1, the in vitro Western blot and flow cytometry studies were performed to validate the integrin expression level of human glioblastoma (U87MG) cells. Extremely high expression level of integrin α2β1 justifies its role as a potential targeting marker. Thus, 68Ga-A2B1 positron emission tomography was performed in subcutaneous U87MG tumor bearing athymic mice at 15 min postinjection after injection of 7-8MBq tracers. The receptor targeting specificity was confirmed in a competition blocking experiment. The tumor uptake of 68Ga-A2B1 in the control and blockage groups was 1.57 ± 0.13 %ID/g (n = 3) and 0.96 ± 0.23 %ID/g?? (n = 3), respectively. However, because of the quick renal washout rate and labile nature of peptide tracers in circulation conditions, the focus ultrasound (FUS) mediated delivery method was adopted to enhance tumor uptake and retention of tracers. To test the FUS delivery efficacy in vivo, three experimental arms were designed as follows: tumor bearing mice were administrated with 68Ga-A2B1 only or microbubbles (MBs) with FUS treatment (68Ga-A2B1 + FUS + MBs) or embedded 68Ga-A2B1-microbubbles (68Ga-A2B1-MBs + FUS) followed with FUS sonication. The average radioactivity accumulation within a tumor was quantified from the multiple region of interest volumes using the %ID/g value and was analyzed in accordance with the ex vivo autoradiographic and pathologic data. The significant tumor uptake in 68Ga-A2B1 + FUS +MBs group (n = 6) and 68Ga-A2B1-MBs + FUS group (n = 4) following FUS treatment were calculated as 2.25 ± 0.50 %ID/g? and 2.6 ± 0.49 %ID/g??, comparing with 68Ga-A2B1 only group 1.48 ± 0.42 %ID/g (n = 10). These results suggest that there is significant difference in 68Ga-A2B1 tumor uptake by FUS treatment either with or without tracer integration with microbubbles, which demonstrate a promising delivery strategy and critical multimodal setting for phenotyping imaging of aggressive glioma tumor. In conclusion, 68Ga labeled 68Ga-A2B1 allows noninvasive imaging of tumor-associated α2β1 expression and can be embedded in MB lipid shell for enhanced delivery and controlled release by sonoporation. ? 2014 American Chemical Society.
Subjects
Focus ultrasound; Glioblastoma; Integrin α2β1; PET imaging
SDGs
Other Subjects
gallium 68; tracer; unclassified drug; very late activation antigen 2; very late activation antigen 2 ga 68; peptide; radiopharmaceutical agent; very late activation antigen 2; animal experiment; animal model; Article; cancer diagnosis; cancer prognosis; controlled study; drug delivery system; flow cytometry; glioblastoma; human; human cell; microbubble; mouse; neuroimaging; nonhuman; positron emission tomography; priority journal; radioactivity; Western blotting; animal; binding competition; brain; brain tumor; cancer transplantation; chemistry; diagnostic use; disease course; echography; electroencephalography; glioma; HEK293 cell line; high performance liquid chromatography; male; pathology; phenotype; positron emission tomography; scintiscanning; tissue distribution; tumor cell line; Animals; Binding, Competitive; Brain; Brain Neoplasms; Cell Line, Tumor; Chromatography, High Pressure Liquid; Disease Progression; Electroencephalography; Glioma; HEK293 Cells; Humans; Integrin alpha2beta1; Male; Mice; Neoplasm Transplantation; Peptides; Phenotype; Positron-Emission Tomography; Radiopharmaceuticals; Tissue Distribution
Publisher
American Chemical Society
Type
journal article