Improving susceptibility of neuroendocrine tumors to radionuclide therapies: personalized approaches towards complementary treatments.

Radionuclide therapies are an important tool for the management of patients with neuroendocrine neoplasms (NENs). Especially [131I]MIBG and [177Lu]Lu-DOTA-TATE are routinely used for the treatment of a subset of NENs, including pheochromocytomas, paragangliomas and gastroenteropancreatic tumors. Some patients suffering from other forms of NENs, such as medullary thyroid carcinoma or neuroblastoma, were shown to respond to radionuclide therapy; however, no general recommendations exist. Although [131I]MIBG and [177Lu]Lu-DOTA-TATE can delay disease progression and improve quality of life, complete remissions are achieved rarely. Hence, better individually tailored combination regimes are required. This review summarizes currently applied radionuclide therapies in the context of NENs and informs about recent advances in the development of theranostic agents that might enable targeting subgroups of NENs that previously did not respond to [131I]MIBG or [177Lu]Lu-DOTA-TATE. Moreover, molecular pathways involved in NEN tumorigenesis and progression that mediate features of radioresistance and are particularly related to the stemness of cancer cells are discussed. Pharmacological inhibition of such pathways might result in radiosensitization or general complementary antitumor effects in patients with certain genetic, transcriptomic, or metabolic characteristics. Finally, we provide an overview of approved targeted agents that might be beneficial in combination with radionuclide therapies in the context of a personalized molecular profiling approach.

Biomaterials in repairing rat femoral defects: In vivo insights from small animal positron emission tomography/computed tomography (PET/CT) studies.

Biomaterials coated with artificial extracellular matrices (aECM) are intended to support the healing of critical size bone defects. This pilot study investigated (i) the feasibility of dual-tracer PET/CT imaging for functional characterization of biomaterial-assisted bone healing in a rat femoral defect model and (ii) the bone healing ability of polycaprolactone-co-lactide (PCL) scaffolds, coated with various aECM consisting of collagen type I (Col) and glycosaminoglycans (GAGs) such as chondroitin sulfate (CS) or polysulfated hyaluronan (sHA3). [18F]FDG and [18F]fluoride PET 4 and 8 weeks after implantation of aECM-coated PCL scaffolds, which provide an in vivo measure of cellular activation and bone mineralization, respectively, combined with CT imaging (in vivo/ex vivo) and histological/immunohistochemical investigations (ex vivo) showed that coating with CS in particular is beneficial for bone healing. The possible involvement of COX-2 and TGase 2, key enzymes of inflammation and ECM remodeling, in these processes offers starting points for targeted adjuvant therapy in the course of various bone healing phases. Our investigations show the feasibility of the selected dual-tracer approach for PET/CT imaging. In principle, this approach can be extended by further PET tracers for the functional characterization of physiological processes such as hypoxia/reperfusion or selected molecular players.

Organotypical vascular model for characterization of radioprotective compounds: studies on antioxidant 2,3-diaryl-substituted indole-based cyclooxygenase-2 inhibitors.

Radiotherapy of various cancers is closely associated with increased cardiovascular morbidity and mortality. Arachidonic acid metabolites are supposed to play a key role in radiation-induced vascular dysfunction. This study was designed to evaluate the effects of novel, antioxidative 2,3-diaryl-substituted indole-based selective cyclooxygenase-2 (COX-2) inhibitors (2,3-diaryl-indole coxibs) on radiation-induced formation of arachidonic acid metabolites via COX-2 and oxidant stress pathways in an organotypical vascular model of rat aortic rings. Acute and subacute effects of X-ray radiation (4 and 10 Gy; 1 and 3 days post irradiation) with or without the presence of 1 µM of the 2,3-diaryl-indole coxib 2-[4-(aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-1H-indole (C1) or celecoxib as reference compared to sham-irradiated controls were assessed. The following parameters were measured: metabolic activity of the aortic rings; induction and regulation of COX-2 expression; release of prostaglandin E2 and F2α-isoprostane. Irradiation without presence of coxibs resulted in a dose-dependent augmentation of all parameters studied. When aortic rings were exposed to the 2,3-diaryl-indole coxib 1 h before irradiation, metabolic activity was restored and the release of both prostaglandin and isoprostane was inhibited. The latter indicates a direct interaction with oxidant stress pathways. By contrast, celecoxib exhibited only slight effects on the formation of isoprostane. The reduction of radiation-induced vascular dysfunction by antioxidative coxibs may widen the therapeutic window of COX-2 targeted treatment.

Synthesis and evaluation of 1,5-diaryl-substituted tetrazoles as novel selective cyclooxygenase-2 (COX-2) inhibitors.

A series of 1,5-diaryl-substituted tetrazole derivatives was synthesized via conversion of readily available diaryl amides into corresponding imidoylchlorides followed by reaction with sodium azide. All compounds were evaluated by cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibitory potency and selectivity. Tetrazoles 3a-e showed IC(50) values ranging from 0.42 to 8.1 mM for COX-1 and 2.0 to 200 µM for COX-2. Most potent compound 3c (IC(50) (COX-2)=2.0 µM) was further used in molecular modeling docking studies.

Reduction of arteriosclerotic nanoplaque formation and size by n-3 fatty acids in patients after valvular defect operation.

BACKGROUND/METHODS: Coating a silica surface with the isolated lipoprotein receptor heparan sulfate proteoglycan (HS-PG) from arterial endothelium and vascular matrices, we could observe the very earliest stages of arteriosclerotic plaque development by ellipsometric techniques in vitro (patent EP 0 946 876). This so-called nanoplaque formation is represented by the ternary aggregational complex of the HS-PG receptor, lipoprotein particles and calcium ions. The model was validated in several clinical studies on statins in cardiovascular high-risk patients applying their native blood lipoprotein fractions. RESULTS: In 7 patients who had undergone a valvular defect operation, the reduction of arteriosclerotic nanoplaque formation in normal Krebs solution amounted to 6.1 +/- 2.3% (p < 0.0156) and of nanoplaque size to 37.5 +/- 13.2% (p < 0.0312), respectively, after a 3-month therapy with n-3 fatty acids (3 ..3 g daily, Ameu 500 mg). Additionally, the quotient oxLDL/LDL was lowered by 6.8 +/- 2.1% (p < 0.0166), the MDA concentration remained unchanged and the lipoprotein(a) concentration decreased by 15.8 +/- 5.6% (p < 0.0469) in the patients' blood. The concentration of the nanoplaque promoting particles VLDL and total triglycerides was diminished by 34.1 +/- 11.6% (p < 0.0469) and 26.7 +/- 10.8% (p < 0.0156), respectively. Furthermore, the ratio of the strongly atherogenic small dense to the total LDL cholesterol (LDL5+LDL6)/LDLtot decreased by 9.9 +/- 3.0% (p < 0.0174). CONCLUSIONS: A combinatorial regression analysis revealed a basis for a mechanistic explanation of nanoplaque reduction under n-3 fatty acid treatment. This effect was possibly due to the beneficial changes in lipid concentrations and an attenuation of the risk factors oxLDL/LDL and (LDL5+LDL6)/LDLtot.