BackgroundGa-[1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE) positron emission tomography (PET) is commonly used for the visualization of somatostatin receptor (SSTR)-positive neuroendocrine tumors. SSTR is also known to be expressed on macrophages, which play a major role in inflammatory processes in the walls of coronary arteries and large vessels. Therefore, imaging SSTR expression has the potential to visualize vulnerable plaques. We assessed 68Ga-DOTATATE accumulation in large vessels in comparison to 18F-2-fluorodeoxyglucose (FDG) uptake, calcified plaques (CPs), and cardiovascular risk factors.MethodsSixteen consecutive patients with neuroendocrine tumors or thyroid cancer underwent both 68Ga-DOTATATE and 18F-FDG PET/CT for staging or restaging purposes. Detailed clinical data, including common cardiovascular risk factors, were recorded. For a separate assessment, they were divided into a high-risk and a low-risk group. In each patient, we calculated the maximum target-to-background ratio (TBR) of eight arterial segments. The correlation of the TBRmean of both tracers with risk factors including plaque burden was assessed.ResultsThe mean TBR of 68Ga-DOTATATE in all large arteries correlated significantly with the presence of CPs (r = 0.52; p < 0.05), hypertension (r = 0.60; p < 0.05), age (r = 0.56; p < 0.05), and uptake of 18F-FDG (r = 0.64; p < 0.01). There was one significant correlation between 18F-FDG uptake and hypertension (0.58; p < 0.05). Out of the 37 sites with the highest focal 68Ga-DOTATATE uptake, 16 (43.2%) also had focal 18F-FDG uptake. Of 39 sites with the highest 18F-FDG uptake, only 11 (28.2%) had a colocalized 68Ga-DOTATATE accumulation.ConclusionsIn this series of cancer patients, we found a stronger association of increased 68Ga-DOTATATE uptake with known risk factors of cardiovascular disease as compared to 18F-FDG, suggesting a potential role for plaque imaging in large arteries. Strikingly, we found that focal uptake of 68Ga-DOTATATE and 18F-FDG does not colocalize in a significant number of lesions.
Objective-Nuclear imaging of active plaques still remains challenging. Advanced atherosclerotic plaques have a strong expression of P-selectin by the endothelium overlying active atherosclerotic plaques, but not on the endothelium overlying inactive fibrous plaques. We proposed a new approach for noninvasive in vivo characterization of P-selectin on active plaques based on 68 Ga-Fucoidan, which is a polysaccharidic ligand of P-selectin with a nanomolar affinity. Approach and Results-68 Ga-Fucoidan was tested for its potential to discriminate vulnerable plaques on apolipoprotein E-deficient mice receiving a high cholesterol diet by positron emission tomography and in correlation with 17.6T MRI. Furthermore, 68 Ga-Fucoidan was evaluated on endothelial cells in vitro and ex vivo on active plaques using autoradiography. The cellular uptake rate was increased ≈2-fold by lipopolysaccharide induction. Interestingly, on autoradiography, more intensive tracer accumulation at active plaques with thin fibrous caps and high-density foam cells were observed in comparison with a weaker focal uptake in inactive fibrous plaque segments (R=1.7±0.3; P<0.05) and fatty streaks (R=2.4±0.4; P<0.01). Strong uptake of radiotracer colocalized with increased P-selectin expression and high-density macrophage. Focal vascular uptake (mean of target to background ratio=5.1±0.8) of 68 Ga-Fucoidan was detected in all apolipoprotein E-deficient mice. Anatomic structures of plaque were confirmed by 17.6T MRI. The autoradiography showed a good agreement of 68 Ga-Fucoidan uptake with positron emission tomography. Conclusions-Our data suggest that 68 Ga-Fucoidan represents a versatile imaging biomarker for P-selectin with the potential to specifically detect P-selectin expression using positron emission tomography and to discriminate vulnerable plaques in vivo. pivotal role in recruiting leukocytes to the sites of injury. 14-16This interaction is mediated by P-selectin glycoprotein ligand 1, expressed by monocytes, neutrophils, and platelets. 17,18 Most active atherosclerotic lesions remain undetected until plaque rupture and thrombosis occur. A previous study found that inflamed atherosclerotic plaques have a strong expression of P-selectin on the overlying endothelium, but much less in normal arterial endothelium or in endothelium overlying inactive fibrous plaques.19 Consequently, P-selectin is thought to be an effective biomarker for assessing the bioactivity of active plaques.Fucoidan is a synthetic sialyl-lewis X mimic, which is the natural ligand of P-selectin and is found on leukocytes. 20,21 It is mainly derived from brown seaweed with an efficient binding of P-selectin as well. 22 In previous studies, a high specific affinity of fucoidan for P-selectin was confirmed. 22We developed a novel PET tracer by an efficient introduction of the positron emitter 68 Ga into the Fucoidan moiety. The 68 Ga-Fucoidan obtained this way was used to validate the P-selectin expression in vivo on an established apolipoprotein E-deficient (apoE −/− ) m...
BackgroundTraumatic brain injury (TBI) is a major cause of death and disability. Neuroinflammation contributes to acute damage after TBI and modulates long-term evolution of degenerative and regenerative responses to injury. The aim of the present study was to evaluate the relationship of microglia activation to trauma severity, brain energy metabolism, and cellular reactions to injury in a mouse closed head injury model using combined in vivo PET imaging, ex vivo autoradiography, and immunohistochemistry.MethodsA weight-drop closed head injury model was used to produce a mixed diffuse and focal TBI or a purely diffuse mild TBI (mTBI) in C57BL6 mice. Lesion severity was determined by evaluating histological damage and functional outcome using a standardized neuroscore (NSS), gliosis, and axonal injury by immunohistochemistry. Repeated intra-individual in vivo μPET imaging with the specific 18-kDa translocator protein (TSPO) radioligand [18F]DPA-714 was performed on day 1, 7, and 16 and [18F]FDG-μPET imaging for energy metabolism on days 2–5 after trauma using freshly synthesized radiotracers. Immediately after [18F]DPA-714-μPET imaging on days 7 and 16, cellular identity of the [18F]DPA-714 uptake was confirmed by exposing freshly cut cryosections to film autoradiography and successive immunostaining with antibodies against the microglia/macrophage marker IBA-1.ResultsFunctional outcome correlated with focal brain lesions, gliosis, and axonal injury. [18F]DPA-714-μPET showed increased radiotracer uptake in focal brain lesions on days 7 and 16 after TBI and correlated with reduced cerebral [18F]FDG uptake on days 2–5, with functional outcome and number of IBA-1 positive cells on day 7. In autoradiography, [18F]DPA-714 uptake co-localized with areas of IBA1-positive staining and correlated strongly with both NSS and the number of IBA1-positive cells, gliosis, and axonal injury. After mTBI, numbers of IBA-1 positive cells with microglial morphology increased in both brain hemispheres; however, uptake of [18F]DPA-714 was not increased in autoradiography or in μPET imaging.Conclusions[18F]DPA-714 uptake in μPET/autoradiography correlates with trauma severity, brain metabolic deficits, and microglia activation after closed head TBI.
A new concept for modular biosurface engineering of titanium implants based on the self-assembly of complementary oligonucleotides was biochemically investigated and optimized. This study describes the synthesis and characterization (RP-HPLC and Sakaguchi assay) of oligodeoxyribonucleotide (ODN) conjugates of the hexapeptide GRGDSP containing the RGD sequence as the recognition motif for cellular adhesion receptors (integrins). The peptide was chosen exemplarily as a model molecule, because it is a simple but potent bioactive molecule and relatively well investigated. The conjugation products must fulfill two main requirements: (I) the ability to hybridize and (II) the preservation of biological activity of the RGD peptide for the enhancement of osteoblast adhesion. In the following text, the term "hybridization" is generally used for Watson-Crick base pairing. The ability of the conjugates to hybridize to surface-immobilized complementary ODN was verified by competitive hybridization with radiolabeled ((32)P) complementary strands and by hybridization experiments using a quartz crystal microbalance (QCM). Surface hybridization was further characterized using different adsorption isotherms (e.g., Freundlich and Frumkin types), since the type of isotherm and the derived thermodynamic parameters may reveal characteristic differences between ODN and conjugates thereof. Biological activity of the conjugates was examined in vitro with osteoblasts. The cells were either cultured directly on the ODN-GRGDSP modified titanium implants or used for competition adhesion studies with dissolved ODN-GRGDSP conjugates. All results support the successful establishment of the new surface modification system. Hybridization of RGD peptide-modified nucleic acids to ODN-modified titanium implant materials is thus a promising method for osteoblast attachment in a modular and self-organizing system on implant surfaces.
p-131 I-iodo-L-phenylalanine ( 131 I-IPA) is a tumor-specific amino acid derivative that demonstrated antiproliferative and tumoricidal effects on experimental gliomas. This study tested the efficacy of 131 I-IPA combined with external beam photon radiotherapy as a new therapeutic approach against gliomas. Methods: Glioma cells derived from the rat F98 glioma or human Tx3868 or A1207 glioblastoma cell lines were stereotactically inoculated into the brains of Fischer 344 rats or RNU rats. Tumor formation was verified radiologically. On day 8, groups of glioma-bearing rats of each tumor model underwent whole-brain radiotherapy with 8 Gy, an intravenous administration of 131 I-IPA (30 MBq), or combined treatment, aiming for a total of 12 rats per group. Another 12 animals were treated with physiologic saline and served as control. Results: Control rats had a combined median survival (6SD) of 21 6 6 d. All revealed metabolically and histologically large tumor masses. Efficacy of radiotherapy alone or a monotherapy with 30 MBq of 131 I-IPA was statistically insignificant on the syngeneic Fischer-F98 model (P $ 0.45 and P 5 0.10, respectively). In contrast, a subset of long-term survivors (.120 d) was observed in RNU rats bearing Tx3868 and A1207 glioblastoma xenografts (18%225% and 35%245% for radiotherapy and 131 I-IPA, respectively). Combined 131 I-IPA and radiotherapy treatment significantly prolonged median survival for the syngeneic Fischer-F98 glioma model (P , 0.01) and human glioblastoma-bearing RNU rats alike (P , 0.05). On day 120 after monotherapy with 131 I-IPA, 45% of the RNU rats were still alive, but after 8 Gy of photon radiotherapy only 18%225% of the RNU and none of the Fischer rats survived. In comparison, 55%275% survival rates were registered after combined treatment on day 120 for all animal models. Conclusion: These data convincingly demonstrated that systemic radionuclide therapy with 131 I-IPA combined with external photon radiotherapy is a safe and highly effective treatment for experimental gliomas, which may merit a clinical trial to ascertain its potential in patients with gliomas. Because only a low 131 I-IPA activity and low radiotherapy doses were applied, further optimizations including higher radiation doses and conventional fractionated radiotherapy are warranted.
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