Somatostatin analogues labeled with copper radioisotopes: current status.
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ABSTRACT:
SUBMITTER: Marciniak A
PROVIDER: S-EPMC5533839 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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Project description:The decay of terbium-161 results in the emission of β¯-particles as well as conversion and Auger electrons, which makes terbium-161 interesting for therapeutic purposes. The aim of this study was to use dual-isotope SPECT imaging in order to demonstrate visually that terbium-161 and lutetium-177 are interchangeable without compromising the pharmacokinetic profile of the radiopharmaceutical. The 161Tb- and 177Lu-labeled somatostatin (SST) analogues DOTATOC (agonist) and DOTA-LM3 (antagonist) were tested in vitro to demonstrate equal properties regarding distribution coefficients and cell uptake into SST receptor-positive AR42J tumor cells. The radiopeptides were further investigated in AR42J tumor-bearing nude mice using the method of dual-isotope (terbium-161/lutetium-177) SPECT/CT imaging to enable the visualization of their distribution profiles in the same animal. Equal pharmacokinetic profiles were demonstrated for either of the two peptides, irrespective of whether it was labeled with terbium-161 or lutetium-177. Moreover, the visualization of the sub-organ distribution confirmed similar behavior of 161Tb- and 177Lu-labeled SST analogues. The data were verified in quantitative biodistribution studies using either type of peptide labeled with terbium-161 or lutetium-177. While the radionuclide did not have an impact on the organ distribution, this study confirmed previous data of a considerably higher tumor uptake of radiolabeled DOTA-LM3 as compared to the radiolabeled DOTATOC.
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Project description:BackgroundThe use of somatostatin analogues (SSAs) has not been formally approved in pulmonary neuroendocrine tumours (NETs) in the absence of positive controlled trials, even though it is recommended as a potential therapeutic option in recent guidelines.Patients and methodsWe have assessed the use of SSA in the general practice in Austria by retrospectively analysing patients with pulmonary NETs referred to our European Neuroendocrine Tumor Society centre in Vienna for second opinion or further therapy. In addition, we have analysed the somatostatin receptor (SSTR) expression of those patients by immunohistochemistry (IHC) and SSTR imaging, e.g. 68Ga-DOTANOC-positron emission tomography/computed tomography, and whether such analyses had been carried out before referral at our centre.ResultsOut of 34 patients (19 atypical and 15 typical carcinoids) with metastatic or advanced disease, 10/34 (29%) had been prescribed SSA before referral. No IHC for SSTR had been carried out, and only 9/34 (27%) had undergone SSTR imaging by nuclear medicine. Sufficient material for IHC was available in 29/34 (85%) patients and SSTR-IHC was rated negative in 13/29 (45%), weakly positive in 4/29 (14%), moderately positive in 5/29 (17%) and strongly positive in 7/29 (24%) patients. On SSTR imaging, 8/34 patients (24%) were positive, 13/34 (38%) negative and 13/34 patients (38%) showed a mix of positive and negative NET lesions. In 11/29 (38%) patients with both IHC and imaging available, discordance of SSTR expression on imaging and histological assessment was detected.ConclusionsThese data show that uncritical use of SSA should be discouraged, and assessment of SSTR, preferably by imaging, is mandatory before prescription of SSA in pulmonary NETs.
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Project description:Neuroendocrine tumors (NETs) are associated with variable prognosis, with grade 1 and 2 NETs having more favorable outcomes than grade 3. Patients with gastroenteropancreatic (GEP)-NET need individualized interdisciplinary evaluations and treatment. New treatment options have become available with significant improvements in progression-free survival. Peptide receptor radionuclide therapy (PRRT) using (90)Y or (177)Lu-labeled somatostatin analogues (SSTa) has also shown promise in the treatment of advanced progressive NETs. (68)Ga-1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA)-SSTa can be used as companion imaging agents to assist in radionuclide therapy selection. (68)Ga-DOTA-SSTa PET/computed tomography might also provide information for prognosis, tumor response assessment to PRRT, and internal dosimetry.
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Project description:Photodynamic therapy (PDT) is an established treatment modality, used mainly for anticancer therapy that relies on the interaction of photosensitizer, light and oxygen. For the treatment of pathologies in certain anatomical sites, improved targeting of the photosensitizer is necessary to prevent damage to healthy tissue. We report on a novel dual approach of targeted PDT (vascular and cellular targeting) utilizing the expression of neuropeptide somatostatin receptor (sst2) on tumor and neovascular-endothelial cells. We synthesized two conjugates containing the somatostatin analogue [Tyr3]-octreotate and Chlorin e6 (Ce6): Ce6-K3-[Tyr3]-octreotate (1) and Ce6-[Tyr3]-octreotate-K3-[Tyr3]-octreotate (2). Investigation of the uptake and photodynamic activity of conjugates in-vitro in human erythroleukemic K562 cells showed that conjugation of [Tyr3]-octreotate with Ce6 in conjugate 1 enhances uptake (by a factor 2) in cells over-expressing sst2 compared to wild-type cells. Co-treatment with excess free Octreotide abrogated the phototoxicity of conjugate 1 indicative of a specific sst2-mediated effect. In contrast conjugate 2 showed no receptor-mediated effect due to its high hydrophobicity. When compared with un-conjugated Ce6, the PDT activity of conjugate 1 was lower. However, it showed higher photostability which may compensate for its lower phototoxicity. Intra-vital fluorescence pharmacokinetic studies of conjugate 1 in rat skin-fold observation chambers transplanted with sst2+ AR42J acinar pancreas tumors showed significantly different uptake profiles compared to free Ce6. Co-treatment with free Octreotide significantly reduced conjugate uptake in tumor tissue (by a factor 4) as well as in the chamber neo-vasculature. These results show that conjugate 1 might have potential as an in-vivo sst2 targeting photosensitizer conjugate.
| S-EPMC4128677 | biostudies-literature
Project description:Neuroendocrine tumours are a heterogeneous group of neoplasms with a variety of treatment options, but studies suggest they should in most cases, if they are not curable surgically, be treated initially with monthly long-acting somatostatin analogues. New data recently published suggest that if patients show progression on the current analogues at the recommended doses, increasing the dose or frequency of these analogues may provide a further therapeutic effect, although proper randomised trials will be necessary to confirm this effect.
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Project description:The current state of thin film heterojunction solar cells based on cuprous oxide (Cu?O), cupric oxide (CuO) and copper (III) oxide (Cu?O?) is reviewed. These p-type semiconducting oxides prepared by Cu oxidation, sputtering or electrochemical deposition are non-toxic, sustainable photovoltaic materials with application potential for solar electricity. However, defects at the copper oxide heterojunction and film quality are still major constraining factors for achieving high power conversion efficiency, ?. Amongst the Cu?O heterojunction devices, a maximum ? of 6.1% has been obtained by using pulsed laser deposition (PLD) of AlxGa1-xO onto thermal Cu?O doped with Na. The performance of CuO/n-Si heterojunction solar cells formed by magnetron sputtering of CuO is presently limited by both native oxide and Cu rich copper oxide layers at the heterointerface. These interfacial layers can be reduced by using a two-step sputtering process. A high ? of 2.88% for CuO heterojunction solar cells has been achieved by incorporation of mixed phase CuO/Cu?O nanopowder. CuO/Cu?O heterojunction solar cells fabricated by electrodeposition and electrochemical doping has a maximum efficiency of 0.64% after surface defect passivation and annealing. Finally, early stage study of Cu?O?/GaN deposited on sapphire substrate has shown a photovoltaic effect and an ? of ~10-2%.
| S-EPMC5502964 | biostudies-literature
Project description:IntroductionFamilial amyloid polyneuropathy (FAP) is a genetic disease leading to the production of a variant transthyretin (TTR) or a beta variant β2-microglobulin. FAP may be associated with refractory diarrhoea. In this study, we assessed the efficacy and tolerance of somatostatin analogues in refractory diarrhoea associated with FAP.MethodsFAP patients from the French national referral center who received somatostatin analogues for a refractory diarrhoea were retrospectively studied. We assessed remission of diarrhoea, as defined by a stool consistence of five or less on the Bristol stool scale, assessed after three to six months of follow-up. Stool frequency and continence before and after three to six months of treatment were also compared by the means of Wilcoxon and McNemar's exact tests, respectively.ResultsFourteen patients treated with somatostatin analogues were evaluable. After three to six months of follow-up, 9/14 patients (64% 95%CI = [35%; 87%]) had remission of diarrhoea. This was significantly higher than a theoretical remission rate of 20% (p = 0.0004). There was a significant decrease of daily bowel movement from 6 to 2.5 per day (p = 0.002). Twelve/14 (85%) patients had incontinence at baseline vs 8/14 (57%) after three to six months of follow-up (p = 0.134). Three out of 14 patients (21%) had a severe adverse event; two patients had hypoglycaemia, and one had endocarditis due to an injection-site bacterial infection.ConclusionThis study suggests that somatostatin analogues may benefit to patients with FAP and refractory diarrhoea. Approximately 20% of patients had severe adverse events, including hypoglycaemia.
| S-EPMC6116977 | biostudies-literature
Project description:The expression of somatostatin receptor subtypes (SSTRs) in pituitary growth hormone- (GH-) secreting adenomas may predict the response to somatostatin analogues (SSA). Our aim was to evaluate the value of the immunohistochemical (IHC) scores of 2 subtypes, SSTR2 and SSTR5, in predicting the short-term efficacy of SSA therapy in patients with active acromegaly. Ninety-three newly diagnosed acromegalic patients were included in our study. These patients were categorized into either a SSA-pretreated group (SA, n = 63) or a direct-surgery group (DS, n = 30), depending on whether or not presurgical SSA treatment was received. IHC analysis, using a 12-grade scoring system, with rabbit monoclonal antibodies against SSTR2 and SSTR5, was performed on all adenoma tissues. The reduction of GH, IGF-1, and tumor size after treatment with SSA for 3 months was measured. Compared with that in the DS group, SSTR2 expression was lower in the SA group. Additionally, in the SA group, SSTR2 expression was positively correlated with the reduction of IGF-1 and tumor volume. However, there was no correlation between the SSTR5 score and the efficacy of SSA. In conclusion, the protein expression of SSTR2, but not of SSTR5, is a valuable indicator in predicting biochemical and tumor size response to short-term SSA treatment in acromegalic patients.
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Project description:Somatostatin receptor subtype 2 (sstr2) is a G-protein-coupled receptor (GPCR) that is overexpressed in neuroendocrine tumors. The homology model of sstr2 was built and was used to aid the design of new somatostatin analogues modified with phosphonate-containing cross-bridged chelators for evaluation of using them as PET imaging radiopharmaceuticals. The new generation chelators were conjugated to Tyr3-octreotate (Y3-TATE) through bioorthogonal, strain-promoted alkyne azide cycloaddition (SPAAC) to form CB-TE1A1P-DBCO-Y3-TATE (AP) and CB-TE1K1P-PEG4-DBCO-Y3-TATE (KP) in improved yields compared to standard direct conjugation methods of amide bond formation. Consistent with docking studies, the clicked bioconjugates showed high binding affinities to sstr2, with Kd values ranging from 0.6 to 2.3 nM. Selected isomers of the clicked products were used in biodistribution and PET/CT imaging. Introduction of the bulky dibenzocyclooctyne group in AP decreased clearance rates from circulation. However, the additional carboxylate group and PEG linker from the KP conjugate significantly improved labeling conditions and in vivo stability of the copper complex and ameliorated the slower pharmacokinetics of the clicked somatostatin analogues.
| S-EPMC4261236 | biostudies-literature
Project description:BackgroundGrowth hormone-secreting pituitary adenomas (somatotroph adenoma) predominantly express somatostatin receptors (SSTRs) subtypes 2 and 5. Higher SSTR2 expression on somatotroph adenomas results in a better response to somatostatin analogues (SSAs), which preferentially bind, but also downregulate, SSTR2. The effect of the combined treatment with SSAs and the GH receptor antagonist pegvisomant (PEGV) on SSTR expression in somatotroph adenomas is currently unknown.Aim of the studyTo assess SSTR2 and SSTR5 expression in three groups of somatotroph adenomas: drug-naive, treated with long-acting (LA) SSA monotherapy, or LA-SSA/PEGV combination therapy before surgery. Additionally, we evaluated the required PEGV dose to achieve insulin-like growth factor I (IGF-I) normalization in relation to the SSTR expression.Materials and methodsAt our Pituitary Center Rotterdam, we selected acromegalic patients who underwent transsphenoidal neurosurgery. All patients were eventually treated with LA-SSA/PEGV combination therapy during their medical history. SSTR2 and SSTR5 expression in somatotroph adenoma tissues was determined using immunohistochemistry.ResultsOut of 39 somatotroph adenoma tissue samples, 23 were drug-naive, 9 received pretreatment with LA-SSA and 7 LA-SSA/PEGV combined treatment. SSTR2 expression was significantly higher in treatment-naive compared to combined treatment somatotroph adenomas (p = 0.048), while SSTR5 expression did not differ. Noteworthy, SSTR2 expression in naive somatotroph adenoma tissues was inversely correlated with the required PEGV dose to achieve IGF-I normalization during postsurgical medical treatment (? = -0.538, p = 0.024).ConclusionIn our specific cohort, the SSTR2 expression was lower in patients pretreated with LA-SSA/PEGV compared to the drug-naive acromegalic patients. Additionally, the SSTR2 expression in treatment-naive somatotroph adenoma tissues was inversely correlated with the required PEGV dose to achieve IGF-I normalization.
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