Dosimetry and pharmacokinetics of [177Lu]Lu-satoreotide tetraxetan in patients with progressive neuroendocrine tumours.

PURPOSE: To evaluate the dosimetry and pharmacokinetics of the novel radiolabelled somatostatin receptor antagonist [177Lu]Lu-satoreotide tetraxetan in patients with advanced neuroendocrine tumours (NETs). METHODS: This study was part of a phase I/II trial of [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three planned cycles (median activity/cycle: 4.5 GBq), in 40 patients with progressive NETs. Organ absorbed doses were monitored at each cycle using patient-specific dosimetry; the cumulative absorbed-dose limits were set at 23.0 Gy for the kidneys and 1.5 Gy for bone marrow. Absorbed dose coefficients (ADCs) were calculated using both patient-specific and model-based dosimetry for some patients. RESULTS: In all evaluated organs, maximum [177Lu]Lu-satoreotide tetraxetan uptake was observed at the first imaging timepoint (4 h after injection), followed by an exponential decrease. Kidneys were the main route of elimination, with a cumulative excretion of 57-66% within 48 h following the first treatment cycle. At the first treatment cycle, [177Lu]Lu-satoreotide tetraxetan showed a median terminal blood half-life of 127 h and median ADCs of [177Lu]Lu-satoreotide tetraxetan were 5.0 Gy/GBq in tumours, 0.1 Gy/GBq in the bone marrow, 0.9 Gy/GBq in kidneys, 0.2 Gy/GBq in the liver and 0.8 Gy/GBq in the spleen. Using image-based dosimetry, the bone marrow and kidneys received median cumulative absorbed doses of 1.1 and 10.8 Gy, respectively, after three cycles. CONCLUSION: [177Lu]Lu-satoreotide tetraxetan showed a favourable dosimetry profile, with high and prolonged tumour uptake, supporting its acceptable safety profile and promising efficacy. TRIAL REGISTRATION: NCT02592707. Registered October 30, 2015.

A PBPK model for PRRT with [177Lu]Lu-DOTA-TATE: Comparison of model implementations in SAAM II and MATLAB/SimBiology.

Physiologically based pharmacokinetic (PBPK) models offer the ability to simulate and predict the biodistribution of radiopharmaceuticals and have the potential to enable individualised treatment planning in molecular radiotherapy. The objective of this study was to develop and implement a whole-body compartmental PBPK model for peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-TATE in SimBiology to allow for more complex analyses. The correctness of the model implementation was ensured by comparing its outputs, such as the time-integrated activity (TIA), with those of a PBPK model implemented in SAAM II software. METHODS: A combined PBPK model for [68Ga]Ga-DOTA-TATE and [177Lu]Lu-DOTA-TATE was developed and implemented in both SAAM II and SimBiology. A retrospective analysis of 12 patients with metastatic neuroendocrine tumours (NETs) was conducted. First, time-activity curves (TACs) and TIAs from the two software were calculated and compared for identical parameter values. Second, pharmacokinetic parameters were fitted to activity concentrations, analysed and compared. RESULTS: The PBPK model implemented in SimBiology produced TIA results comparable to those generated by the model implemented in SAAM II, with a relative deviation of less than 0.5% when using the same input parameters. The relative deviation of the fitted TIAs was less than 5% when model parameter values were fitted to the measured activity concentrations. CONCLUSION: The proposed PBPK model implemented in SimBiology can be used for dosimetry in radioligand therapy and TIA prediction. Its outputs are similar to those generated by the PBPK model implemented in SAAM II, confirming the correctness of the model implementation in SimBiology.

Altered biodistribution of [68Ga]Ga-DOTA-TOC during somatostatin analogue treatment.

PURPOSE: The need for an interval between the administration of long-acting Somatostatin Receptor Analogues (SSA) and the [68Ga]Ga-DOTA-TATE PET has been questioned based on recent literature in the new EANM guidelines. Here an earlier studies showed that SSA injection immediately before SSTR PET had minimal effect on normal organ and tumor uptake (1). However, data are scarce and there are (small) differences between [68Ga]Ga-DOTA-TATE and [68Ga]Ga-DOTA-TOC binding affinity, and it remains unknown whether these findings can be directly translated to scans with [68Ga]Ga-DOTA-TOC as well. The purpose of this study was to assess the effect of SSA use on the biodistribution in a subsequent [68Ga]Ga-DOTA-TOC PET/CT and compare this intra-individually across several cycles of SSA treatments. METHODS: Retrospectively, 35 patients with NENs were included. [68Ga]Ga-DOTA-TOC PET at staging and after the 1st and 2nd cycle of SSA were included. SUVmean and SUVmax of blood, visceral organs, primary tumor and two metastases were determined. Also, the interval between SSA therapy and the PET scan was registered. RESULTS: Treatment with SSA resulted in a significantly higher bloodpool activity and lower visceral tracer uptake. This effect was maintained after a 2nd cycle of SSA therapy. Furthermore, there was an inverse relationship between bloodpool tracer availability and visceral tracer binding and a positive correlation between bloodpool tracer availability and primary tumor tracer uptake. With an interval of up to 5 days, there was a significantly higher bloodpool activity than at longer intervals. CONCLUSION: Absolute comparison of the SUV on [68Ga]Ga-DOTA-TOC PET should be done with caution as the altered biodistribution of the tracer after SSA treatment should be taken into account. We recommend not to perform a scan within the first 5 days after the injection of lanreotide.

Minimizing the initial burst of octreotide acetate from glucose star PLGA microspheres prepared by the solvent evaporation method.

Sandostatin long-acting release (SLAR) depot for 1-month controlled release of octreotide is a somatostatin analogue product that has been used extensively in the pharmacological treatment of acromegaly. The complexities in the SLAR coacervation manufacturing processes and the use of a unique glucose-starpoly(lactic-co-glycolic acid) (PLGA-glu) may have contributed to the lack of US FDA-approved generic products referencing SLAR in the USA. To address this challenge, we encapsulated octreotide acetate by the commonly used solvent evaporation method in microspheres of a similar composition to SLAR, including the use of a comparable PLGA-glu. Based on our previous study that identified key formulation variables to prepare octreotide acetate/PLGA-glu microspheres, including lowering initial peptide pH and introducing an annealing step post loading, here we added NaCl to the external water phase to further improve the formulation. The resulting microspheres exhibited highly similar release and stability performance in vitro to SLAR, including an exceptionally low initial burst. The very low initial burst was also confirmed by pharmacokinetics in rats. Full erosion behavior analysis (polymer MW, water uptake and mass loss) revealed a slightly faster degradation of SLAR than the solvent evaporation formulations. Analysis of kinetics of dry Tg of the formulations reflected (a) the elevated residual solvent in SLAR and was not duplicated in the solvent evaporation formulations, and (b) the slightly higher Tg of peptide loaded formulations relative to than blank microspheres, consistent with the interaction of the acetate salt of octreotide with linear PLGA chains in the PLGA-glu. These data indicate that it is possible to prepare peptide loaded microspheres by the solvent evaporation method with extraordinarily similar performance to microspheres, such as those in SLAR, that are prepared by the low-burst release coacervation method.

Dosimetry of 177Lu-DOTATOC first circle treatment in patients with advanced metastatic neuroendocrine tumors: A pilot study in China.

First cycle dosimetry calculation of 177Lu-DOTATOC (single activity:1.59-3.49 GBq) was carried out in eight patients with advanced neuroendocrine tumors (NETs) who underwent whole-body planar (0.5, 24, 48, 72 h) and SPECT/CT scans (24 h). Focal uptake of 177Lu-DOTATOC was found in primary and metastatic tumors. Organs with the highest absorbed doses per injected activity were tumors (1.293 ± 0.862 mGy/MBq) and spleen (0.461 ± 0.408 mGy/MBq), while low absorbed doses were observed in kidneys (0.384 ± 0.112 mGy/MBq) and bone marrow (0.0297 ± 0.0123 mGy/MBq). 177Lu-DOTATOC is safe, well-tolerated and appropriate in Chinese NETs patients for PRRT.

Dosimetric analyses of intra-arterial versus standard intravenous administration of 177Lu-DOTATATE in patients of well differentiated neuroendocrine tumor with liver-dominant metastatic disease.

OBJECTIVE: The aim of the present study was to perform calculation of the absorbed doses to organs at risk and to neuroendocrine tumors and to determine whether hepatic intra-arterial (IA) injection of 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy (PRRT) would achieve higher intratumoral concentrations than standard intravenous administration of 177Lu-DOTATATE. METHODS: 29 patients with Grade I-II, inoperable, metastatic gastro-entero-pancreatic neuroendocrine tumor (GEPNET) were prospectively identified and enrolled for the study. 15 patients of GEPNETs with liver-dominant metastatic disease and less than 3 sites of extrahepatic metastatic disease were administered a single dose of 177Lu-DOTATATE therapy through the selective catheterization of the hepatic artery (IA group). The other 14 patients received a single dose of 177 Lu- DOTATATE through standard intravenous route (IV group). For dosimetry, whole-body γ (anterior and posterior planar acquisitions) and SPECT/CT scans of the abdomen at 2, 24 and 96 h post 177Lu-DOTATATE administration were acquired. Dosimetric calculations were done using the HERMES software. RESULTS: The mean dose per unit activity (DpA) in the liver and tumor lesions in the IA group differed significantly (p < 0.05) but differed insignificantly in spleen and kidneys (p > 05) with the IV group. The mean tumor/non-tumor concentration at 96 h was 76.83 ± 7.9 (range 10.2-251.3) in the IA group whereas it was 25.6 ± 5.9 (Range: 12-55) in the IV group. There was an average threefold increase in tumoral concentration over the standard intravenous group. CONCLUSION: IA administration of 177Lu-DOTATATE results in higher concentration and absorbed dose in hepatic metastases in patients of GEPNETs as compared to a single dose of PRRT administered through standard IV route, and thus seems to be a powerful tool to improve the efficacy of PRRT. ADVANCES IN KNOWLEDGE: Measurement of the dose received by the tumor lesions and the critical organs is of paramount importance for the prognostication of a radionuclide therapy. Scant data exist on the dosimetric impact of IA administration of the therapy with 177Lu-DOTATATE on the tumors and other organs, and this study would add an impact towards the better treatment outcome in patients of neuroendocrine tumor with liver-dominant metastatic disease.

Do Macrocyclic Peptide Drugs Interact with Bile Salts under Simulated Gastrointestinal Conditions?

Peptide drugs face several barriers to oral delivery, including enzymatic degradation in the gastrointestinal tract and low membrane permeability. Importantly, the direct interaction between various biorelevant colloids (i.e., bile salt micelles and bile salt-phospholipid mixed micelles) present in the aqueous gastrointestinal environment and peptide drug molecules has not been studied. In this work, we systematically characterized interactions between a water-soluble model peptide drug, octreotide, and a range of physiologically relevant bile salts in solution. Octreotide membrane flux in pure bile salt solutions and commercially available biorelevant media, i.e., fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF), was evaluated using a side-by-side diffusion cell equipped with a cellulose dialysis membrane. All seven micellar bile salt solutions as well as FaSSIF and FeSSIF decreased octreotide membrane flux, and dihydroxy bile salts were found to have a much larger effect than trihydroxy bile salts. An inverse relationship between octreotide membrane flux and pancreatic enzymatic stability was also observed; bile salt micelles and bile salt-phospholipid mixed micelles provided a protective effect toward enzymatic degradation and prolonged octreotide half-life in vitro. Diffusion ordered nuclear magnetic resonance (DOSY NMR) spectroscopy and dynamic light scattering (DLS) were used as complementary experimental techniques to confirm peptide-micelle interactions in solution. Experiments were also performed using desmopressin as a second model peptide drug; desmopressin interacted with bile salts in solution, albeit to a lower extent relative to octreotide. The findings described herein demonstrate that amphiphilic, water-soluble peptide drugs do interact with bile salts and phospholipids in solution, with an effect on peptide membrane flux and enzymatic stability. Correspondingly, oral peptide drug absorption and bioavailability may be impacted.

Lipophilic Salts and Lipid-Based Formulations: Enhancing the Oral Delivery of Octreotide.

PURPOSE: Successful oral peptide delivery faces two major hurdles: low enzymatic stability in the gastro-intestinal lumen and poor intestinal membrane permeability. While lipid-based formulations (LBF) have the potential to overcome these barriers, effective formulation of peptides remains challenging. Lipophilic salt (LS) technology can increase the apparent lipophilicity of peptides, making them more suitable for LBF. METHODS: As a model therapeutic peptide, octreotide (OCT) was converted to the docusate LS (OCT.DoS2), and compared to the commercial acetate salt (OCT.OAc2) in oral absorption studies and related in vitro studies, including parallel artificial membrane permeability assay (PAMPA), Caco-2, in situ intestine perfusion, and simulated digestion in vitro models. The in vivo oral absorption of OCT.DoS2 and OCT.OAc2 formulated in self-emulsifying drug delivery systems (SEDDS) was studied in rats. RESULTS: LS formulation improved the solubility and loading of OCT in LBF excipients and OCT.DoS2 in combination with SEDDS showed higher OCT absorption than the acetate comparator in the in vivo studies in rats. The Caco-2 and in situ intestine perfusion models indicated no increases in permeability for OCT.DoS2. However, the in vitro digestion studies showed reduced enzymatic degradation of OCT.DoS2 when formulated in the SEDDS formulations. Further in vitro dissociation and release studies suggest that the enhanced bioavailability of OCT from SEDDS-incorporating OCT.DoS2 is likely a result of higher partitioning into and prolonged retention within lipid colloid structures. CONCLUSION: The combination of LS and LBF enhanced the in vivo oral absorption of OCT primarily via the protective effect of LBF sheltering the peptide from gastrointestinal degradation.

Prospective Within-Patient Assessment of the Impact of an Unlabeled Octreotide Pre-dose on the Biodistribution and Tumor Uptake of 68Ga DOTATOC as Assessed by Dynamic Whole-body PET in Patients with Neuroendocrine Tumors: Implications for Diagnosis and Therapy.

PURPOSE: Gastroenteropancreatic neuroendocrine tumors (GEP NETs) are often associated with high expression of somatostatin receptors (SSTRs) which allows for PET/CT imaging with radiolabeled somatostatin analogs such as 68Ga-DOTATOC. The interplay between 68Ga-DOTATOC and the synthetic somatostatin analogs commonly used to manage patient symptoms may lead to competition between the labelled and unlabeled peptides for receptor binding sites and current product labelling recommends patients be taken off somatostatin analogs before imaging. In this study, we prospectively investigated in human patients the effect of a pre-dose of octreotide, a short-acting somatostatin analog, on the distribution of 68Ga-DOTATOC in GEP NETs and normal organs. PROCEDURE: Research participants with GEP NETs were studied on two occasions using dynamic whole-body 68Ga-DOTATOC PET/CT. The two imaging studies were performed within 21 days of each other, using an identical acquisition protocol except for the administration of 50 µg of short-acting octreotide (pre-dose) immediately before the second PET/CT. Paired t-tests were used to compare tracer uptake with and without octreotide, for tumor and various normal organs. RESULTS: Seven participants with a mean age of 53 ± 10 years were studied. Octreotide pre-dosing decreased radiotracer uptake in the normal liver and spleen by 25 % (p = 0.04) and 47 % (p = 0.05) respectively but did not significantly change uptake in tumor (p = 0.53), red marrow (p = 0.12), kidneys (p =0.57), or pituitary gland (p = 0.27). CONCLUSIONS: Our data indicate SSTR imaging can be improved with a pre-dose of unlabeled octreotide given just prior to injection of the radiotracer. These data suggest there may be no need to discontinue somatostatin analog therapy prior to PET/CT with 68Ga-DOTATOC, allowing for a simpler, less disruptive patient protocol. This approach warrants further study in a variety of settings.

Preparation of long-acting microspheres loaded with octreotide for the treatment of portal hypertensive.

The purpose of this study was to optimize the preparation method of injectable Octreotide microspheres. To explore the correlation between the solvent system and the general properties of microspheres to reduce burst release and enable them to be used for portal hypertension. Octreotide microspheres were prepared by modified double emulsion solution evaporation method after optimizing preparation conditions. The results showed that Octreotide microspheres had a particle size of 57.48 ± 15.24 µm, and the initial release was significantly reduced. In vitro release and in vivo pharmacokinetic data indicated that Octreotide was released stably within 1200 h. The effects on portal vein pressure, liver tissue morphology and other related indexes were observed after administration. As obvious results, injection of Octreotide microspheres could significantly reduce portal vein pressure and reduce the portal vein lumen area in experimental cirrhotic portal hypertensive rats. The optimized Octreotide PLGA microsphere preparation has been proved to have a good effect on PHT in vivo after detecting aminotransferase (AST) and alanine aminotransferase (ALT) activity, liver tissue hydroxyproline (Hyp) content, serum and liver tissue malondialdehyde (MDA) levels, plasma prostacyclin (PGI2) levels, and liver tissue tumor necrosis factor (TNFα) content. In addition, serum and liver tissue superoxide dismutase (SOD) activity and liver tissue glutathione (GSH) content, plasma thromboxane (TXA2), serum nitric oxide (NO), liver tissue nitric oxide synthase (NOS), and plasma and liver tissue endothelin (ET) were significantly increased.

Inter and intra-tumor somatostatin receptor 2 heterogeneity influences peptide receptor radionuclide therapy response.

Patients with neuroendocrine tumors (NETs) can be treated with peptide receptor radionuclide therapy (PRRT). Here, the somatostatin analogue octreotate radiolabeled with lutetium-177 is targeted to NET cells by binding to the somatostatin receptor subtype 2 (SST2). During radioactive decay, DNA damage is induced, leading to NET cell death. Although the therapy proves to be effective, mortality rates remain high. To appropriately select more optimal treatment strategies, it is essential to first better understand the radiobiological responses of tumor cells to PRRT. Methods: We analyzed PRRT induced radiobiological responses in SST2 expressing cells and xenografted mice using SPECT/MRI scanning and histological and molecular analyses. We measured [177Lu]Lu-DOTA-TATE uptake and performed analyses to visualize induction of DNA damage, cell death and other cellular characteristics. Results: The highest accumulation of radioactivity was measured in the tumor and kidneys. PRRT induced DNA damage signaling and repair in a time-dependent manner. We observed intra-tumor heterogeneity of DNA damage and apoptosis, which was not attributed to proliferation or bioavailability. We found a strong correlation between high DNA damage levels and high SST2 expression. PRRT elicited a different therapeutic response between models with different SST2 expression levels. Heterogeneous SST2 expression levels were also confirmed in patient NETs. Conclusion: Heterogeneous SST2 expression levels within NETs cause differentially induced DNA damage levels, influence recurrent tumor phenotypes and impact the therapeutic response in different models and potentially in patients. Our results contribute to a better understanding of PRRT effects, which might impact future therapeutic outcome of NET patients.

Capecitabine-Temozolomide in Advanced Grade 2 and Grade 3 Neuroendocrine Neoplasms: Benefits of Chemotherapy in Neuroendocrine Neoplasms with Significant 18FDG Uptake.

INTRODUCTION: Capecitabine-temozolomide (CAPTEM) chemotherapy, alone or with concurrent peptide receptor radionuclide therapy (PRRT), has activity in advanced WHO grade 2 and grade 3 neuroendocrine neoplasms (NENs). The objective of this study was to evaluate the activity of the CAPTEM in patients with grade 2 and grade 3 NENs and identify prognostic factors. MATERIALS AND METHODS: A retrospective analysis of patients with metastatic grade 2 and grade 3 NENs, who were having baseline significant dual uptake on 68Ga-DOTATATE/18F-fluorodeoxyglucose (FDG)-PET-CT scan and treated with CAPTEM chemotherapy between January 2014 and December 2019 at Tata Memorial Hospital, was conducted. The clinical variables and survival data were collected. Progression-free survival (PFS) was estimated using the Kaplan-Meier method. RESULTS: A total of 68 patients received the CAPTEM regimen, of whom 29 patients (43%) received CAPTEM alone and 39 patients (57%) received concurrent PRRT. The primary sites were pancreas in 32 (47%) and small intestine in 12 (18%) patients. Mean Ki-67 index was 12.6% (range: 3-50). Forty-five patients (65%) were treatment naïve. There were no significant differences in baseline clinical variables between patients treated with CAPTEM alone or with CAPTEM-PRRT. Both regimens were well tolerated. With a median follow-up of 22.1 months, the median PFS for the entire cohort was 27.5 months. There was no statistical difference in the median PFS between patients receiving CAPTEM alone or CAPTEM-PRRT (33.7 vs. 22 months; p = 0.199). A Ki-67 index of >5% predicted for inferior PFS on multivariate analysis (24 versus 73.8 months; p = 0.04; hazard ratio -3.77; 95% confidence interval: 1.07-13.26). CONCLUSION: CAPTEM, alone or concurrent with PRRT, has a significant activity in grade 2 and grade 3 NENs with dual SSTR and 18FDG expression. A Ki-67 index >5% predicts strongly for inferior outcomes and should be further explored as a prognostic cutoff in grade 2 NENs. Early initiation of CAPTEM should be considered in this group of tumors with significant baseline 18FDG expression.

Dissecting the target leukocyte subpopulations of clinically relevant inflammation radiopharmaceuticals.

BACKGROUND: Leukocyte subtypes bear distinct pro-inflammatory, reparative, and regulatory functions. Imaging inflammation provides information on disease prognosis and may guide therapy, but the cellular basis of the signal remains equivocal. We evaluated leukocyte subtype specificity of characterized clinically relevant inflammation-targeted radiotracers. METHODS AND RESULTS: Leukocyte populations were purified from blood- and THP-1-derived macrophages were polarized into M1-, reparative M2a-, or M2c-macrophages. In vitro uptake assays were conducted using tracers of enhanced glucose or amino acid metabolism and molecular markers of inflammatory cells. Both 18F-deoxyglucose (18F-FDG) and the labeled amino acid 11C-methionine (11C-MET) displayed higher uptake in neutrophils and monocytes compared to other leukocytes (P = 0.005), and markedly higher accumulation in pro-inflammatory M1-macrophages compared to reparative M2a-macrophages (P < 0.001). Molecular tracers 68Ga-DOTATATE targeting the somatostatin receptor type 2 and 68Ga-pentixafor targeting the chemokine receptor type 4 (CXCR4) exhibited broad uptake by leukocyte subpopulations and polarized macrophages with highest uptake in T-cells/natural killer cells and B-cells compared to neutrophils. Mitochondrial translocator protein (TSPO)-targeted 18F-flutriciclamide selectively accumulated in monocytes and pro-inflammatory M1 macrophages (P < 0.001). Uptake by myocytes and fibroblasts tended to be higher for metabolic radiotracers. CONCLUSIONS: The different in vitro cellular uptake profiles may allow isolation of distinct phases of the inflammatory pathway with specific inflammation-targeted radiotracers. The pathogenetic cell population in specific inflammatory diseases should be considered in the selection of an appropriate imaging agent.

Altered Biodistribution of 68Ga-DOTATOC.

ABSTRACT: 68Ga-DOTATOC PET/CT of a patient with metastatic neuroendocrine tumor reveals an abnormal biodistribution of the tracer with a vascular binding and a very low fixation on the known lesions despite the temporary discontinuation of "cold" somatostatin analogs. A possible interaction with a high intake of turmeric may be suspected by inhibition of hepatic uptake process.

Salcaprozate sodium (SNAC) enhances permeability of octreotide across isolated rat and human intestinal epithelial mucosae in Ussing chambers.

Octreotide is approved as a one-month injectable for treatment of acromegaly and neuroendocrine tumours. Oral delivery of the octapeptide is a challenge due mainly to low intestinal epithelial permeability. The intestinal permeation enhancer (PE) salcaprozate sodium (SNAC) has Generally Regarded As Safe (GRAS) status and is a component of an approved oral peptide formulation. The purpose of the study was to examine the capacity of salcaprozate sodium (SNAC), to increase its permeability across isolated rat intestinal mucosae from five regions and across human colonic mucosae mounted in Ussing chambers. Apical-side buffers were Kreb's-Henseleit (KH), fasted simulated intestinal fluid (FaSSIF-V2), rat simulated intestinal fluid (rSIF), and colonic simulated intestinal fluid (FaSSCoF). The basal apparent permeability coefficient (Papp) of [3H]-octreotide was equally low across rat intestinal regional mucosae in KH, rSIF, and FaSSIF-V2. Apical addition of 20 mM SNAC increased the Papp across rat tissue in KH: colon (by 3.2-fold) > ileum (3.4-fold) > upper jejunum (2.3-fold) > duodenum (1.4-fold) > stomach (1.4-fold). 20 mM and 40 mM SNAC also increased the Papp by 1.5-fold and 2.1-fold respectively across human colonic mucosae in KH. Transepithelial electrical resistance (TEER) values were reduced in the presence in SNAC especially in colonic regions. LC-MS/MS analysis of permeated unlabelled octreotide across human colonic mucosae in the presence of SNAC indicated that [3H]-octreotide remained intact. No gross damage was caused to rat or human mucosae by SNAC. Attenuation of the effects of SNAC was seen in rat jejunal mucosae incubated with FaSSIF-V2 and rSIF, and also to some extent in human colonic mucosae using FaSSCoF, suggesting interaction between SNAC with buffer components. In conclusion, SNAC showed potential as an intestinal permeation enhancer for octreotide, but in vivo efficacy may be attenuated by interactions with GI luminal fluid contents.

Nasal absorption enhancement of protein drugs independent to their chemical properties in the presence of hyaluronic acid modified with tetraglycine-L-octaarginine.

Our previous mouse studies demonstrated that mean bioavailability of exendin-4, which is an injectable glucagon-like peptide-1 (GLP-1) analogue whose molecular weight (Mw) and isoelectric point (pI) are ca. 4.2 kDa and 4.5, respectively, administered nasally with poly(N-vinylacetamide-co-acrylic acid) (PNVA-co-AA) bearing D-octaarginine, which is a typical cell-penetrating peptide, was 20% relative to subcutaneous administration even though it was less than 1% when exendin-4 alone was given nasally. The studies also revealed that the absorption-enhancing ability of D-octaarginine-linked PNVA-co-AA for exendin-4 was statistically equivalent to that of sodium salcaprozate (SNAC), which is an absorption enhancer formulated in tablets of semaglutide approved recently as an orally available GLP-1 analogue. From a perspective of clinical application of our technology, we have separately developed hyaluronic acid modified with L-octaarginine via a tetraglycine spacer which would be degraded in biological conditions. The present study revealed that tetraglycine-L-octaarginine-linked hyaluronic acid enhanced nasal absorption of exendin-4 in mice, as did D-octaarginine-linked PNVA-co-AA. There was no significant difference in absorption-enhancing abilities between the hyaluronic acid derivative and SNAC when octreotide (Mw: ca. 1.0 kDa, pI: 8.3) and lixisenatide (Mw: ca. 4.9 kDa, pI: 9.5) were used as a model protein drug. On the other hand, SNAC did not significantly enhance nasal absorption of somatropin (Mw: ca. 22.1 kDa, pI: 5.3) when compared with absorption enhancer-free conditions. Substitution of SNAC with tetraglycine-L-octaarginine-linked hyaluronic acid resulted in a 5-fold increase in absolute bioavailability of somatropin with statistical significance. It appeared that pI hardly ever influenced absorption-enhancing abilities of both enhancers. Results indicated that our polysaccharide derivative would be a promising absorption enhancer which delivers biologics applied on the nasal mucosa into systemic circulation and was of greater advantage than SNAC for enhancing nasal absorption of protein drugs with a larger Mw.

Three-dimensional Monte Carlo-based voxel-wise tumor dosimetry in patients with neuroendocrine tumors who underwent 177Lu-DOTATOC therapy.

BACKGROUND: Patients with advanced neuroendocrine tumors (NETs) of the midgut are suitable candidates for 177Lu-DOTATOC therapy. Integrated SPECT/CT systems have the potential to help improve the accuracy of patient-specific tumor dosimetry. Dose estimations to target organs are generally performed using the Medical Internal Radiation Dose scheme. We present a novel Monte Carlo-based voxel-wise dosimetry approach to determine organ- and tumor-specific total tumor doses (TTD). METHODS: A cohort of 14 patients with histologically confirmed metastasized NETs of the midgut (11 men, 3 women, 62.3 ± 11.0 years of age) underwent a total of 39 cycles of 177Lu-DOTATOC therapy (mean 2.8 cycles, SD ± 1 cycle). After the first cycle of therapy, regions of interest were defined manually on the SPECT/CT images for the kidneys, the spleen, and all 198 tracer-positive tumor lesions in the field of view. Four SPECT images, taken at 4 h, 24 h, 48 h and 72 h after injection of the radiopharmaceutical, were used to determine their effective half-lives in the structures of interest. The absorbed doses were calculated by a three-dimensional dosimetry method based on Monte Carlo simulations. TTD was calculated as the sum of all products of single tumor doses with single tumor volumes divided by the sum of all tumor volumes. RESULTS: The average dose values per cycle were 3.41 ± 1.28 Gy (1.91-6.22 Gy) for the kidneys, 4.40 ± 2.90 Gy (1.14-11.22 Gy) for the spleen, and 9.70 ± 8.96 Gy (1.47-39.49 Gy) for all 177Lu-DOTATOC-positive tumor lesions. Low- and intermediate-grade tumors (G 1-2) absorbed a higher TTD compared to high-grade tumors (G 3) (signed-rank test, p = < 0.05). The pre-therapeutic chromogranin A (CgA) value and the TTD correlated significantly (Pearson correlation: = 0.67, p = 0.01). Higher TTD resulted in a significant decrease of CgA after therapy. CONCLUSION: These results suggest that Monte Carlo-based voxel-wise dosimetry is a very promising tool for predicting the absorbed TTD based on histological and clinical parameters.

Improving Contrast and Detectability: Imaging with [55Co]Co-DOTATATE in Comparison with [64Cu]Cu-DOTATATE and [68Ga]Ga-DOTATATE.

PET imaging at late time points after injection may allow tracer clearance from normal tissue and hence improve image contrast and detectability. 55Co is a promising isotope with high positron yield and a long half-life suitable for imaging at delayed time points. Here, we compared the 3 radioconjugates [68Ga]Ga-DOTATATE, [64Cu]Cu-DOTATATE, and [55Co]Co-DOTATATE by PET/CT imaging in NOD-SCID mice bearing subcutaneous somatostatin receptor-expressing AR42J tumors. Methods:55Co and 64Cu were produced by the 54Fe(d,n)55Co and 64Ni(p,n)64Cu nuclear reactions, whereas 68Ga was obtained from a 68Ge/68Ga generator. 55Co and 64Cu were labeled with DOTATATE by heating in a sodium acetate buffer and 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer, respectively. AR42J tumor-bearing mice were dynamically scanned 0-1 h after injection. For 64Cu and 55Co, additional imaging was also performed at late time points after 4 and 24 h. Dose calculations were based on a known biodistribution. The cumulated disintegrations in each organ were calculated by integration of a fitted exponential function to the biodistribution of each respective organ. Equivalent doses were calculated by OLINDA/EXM using the MIRD formalism. Results: Tumor uptake was rapid from 0 to 1 h after injection for all 3 radioconjugates. Normal-tissue ratios as represented by tumor-to-liver, tumor-to-kidney, and tumor-to-muscle ratios increased significantly over time, with [55Co]Co-DOTATATE reaching the highest ratio of all radioconjugates. For [55Co]Co-DOTATATE, the tumor-to-liver ratio increased to 65 ± 16 at 4 h and 50 ± 6 at 24 h, which were 15 (P < 0.001) and 30 (P < 0.001) times higher, respectively, than the corresponding ratios for [64Cu]Cu-DOTATATE and 5 (P < 0.001) times higher than that of [68Ga]Ga-DOTATATE at 1 h. Correspondingly, tumor-to-kidney and tumor-to-muscle ratios for [55Co]Co-DOTATATE were 4 (P < 0.001) and 11 (P < 0.001) times higher than that of [64Cu]Cu-DOTATATE at 24 h. An equivalent dose was calculated as 9.6E-02 mSv/MBq for [55Co]Co-DOTATATE. Conclusion: [55Co]Co-DOTATATE demonstrated superior image contrast compared with [64Cu]Cu-DOTATATE and [68Ga]Ga-DOTATATE for PET imaging of somatostatin receptor-expressing tumors, warranting translation into clinical trials. Dosimetry calculations found that effective doses for [55Co]Co-DOTATATE were comparable to those for both [64Cu]Cu-DOTATATE and [68Ga]Ga-DOTATATE.

Lower 68 Ga-DOTATOC uptake in nonfunctioning pituitary neuroendocrine tumours compared to normal pituitary gland-A proof-of-concept study.

OBJECTIVES: 68  Ga-DOTATOC PET targets somatostatin receptors (SSTRs) and is well established for the detection of SSTR-expressing tumors, such as gastrointestinal neuroendocrine tumors. Pituitary adenomas, recently designated as pituitary neuroendocrine tumors (PitNETs), also express SSTRs, but there has been no previous evaluations of 68  Ga-DOTATOC PET in PitNET patients. The aim of this pilot study was to evaluate the diagnostic properties of 68  Ga-DOTATOC PET in the most common PitNET, ie non-functioning (NF)-PitNET. DESIGN/PATIENTS: NF-PitNET patients (n = 9) and controls (n = 13) were examined preoperatively with 68  Ga-DOTATOC PET for 45 min after tracer injection in dynamic list mode. Tumor specimens were collected during surgery in patients. MRI and PET images were co-registered using PMOD software. The maximum standard uptake value (SUVmax ) was analyzed in manually outlined regions of interest (ROI) around the tumor in patients and around the pituitary gland in controls. Immunohistochemical analyses were conducted on tumor specimens for assessment of tumor cell type and SSTR expression. RESULTS: Median SUVmax (IQR) was lower in patients than in controls (3.9 [3.4-8.5] vs 14.1 [12.5-15.9]; P < .01]. In ROC analysis, the area under the curve was 0.87 (P < .01) for SUVmax , with 78% sensitivity and 92% specificity. Immunohistochemical analysis showed NF-PitNETs were of gonadotroph (n = 7) and corticotroph (n = 2) origin. SSTR expression was high for SSTR3, low-to-moderate for SSTR2, and low for SSTR1 and SSTR5. CONCLUSIONS: This proof-of-concept study shows that 68 Ga-DOTATOC PET can be used to differentiate between normal pituitary tissue and NF-PitNET.

177Lu-DOTATATE Peptide Receptor Radionuclide Therapy: Dose Response in Small Intestinal Neuroendocrine Tumors.

INTRODUCTION: Peptide receptor radionuclide therapy (PRRT) has during the last few years been frequently used in patients with progressive, disseminating, well-differentiated neuroendocrine tumors (NETs). OBJECTIVE: To study whether the absorbed dose in small intestinal NET (SI-NET) metastases from PRRT with 177Lu-DOTATATE is related to tumor shrinkage. MATERIALS AND METHODS: Dosimetry for 1 tumor was performed in each of 25 SI-NET patients based on sequential SPECT/CT 1, 4, and 7 days after 177Lu-DOTATATE infusion. The SPECT data were corrected for the partial volume effect based on previous phantom measurements, and the unit density sphere model from OLINDA was used for absorbed dose calculations. Morphological therapy response was assessed by CT/MRI regarding tumor diameter, tumor volume, total liver tumor volume, liver volume, and overall tumor response according to RECIST 1.1. Plasma chromogranin A and urinary 5-hydroxy-indole-acetic-acid were measured during PRRT and follow-up to assess biochemical response. RESULTS: At the time of best response with respect to tumor diameter and volume shrinkage, the median absorbed dose was 128.6 Gy (range 28.4-326.9) and 140 Gy (range 50.9-487.4), respectively. All metrics regarding tumor shrinkage and biochemical response were unrelated to the absorbed dose. A correlation was, however, found between the administered radioactivity and the tumor volume shrinkage (p = 0.01) and between the administered radioactivity and RECIST 1.1 response (p = 0.01). CONCLUSIONS: It was not possible to demonstrate a tumor dose-response relationship in SI-NET metastases with the applied dosimetry method, contrary to what was previously shown for pancreatic NETs.