scholarly journals Cholesterol Prevents Hypoxia-Induced Hypoglycemia by Regulation of a Metabolic Ketogenic Shift

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Naama Miron ◽  
Oren Tirosh
Keyword(s):  
Liver Fat ◽  
Blood Cholesterol ◽  
Whole Body ◽  
Adaptation To Hypoxia ◽  
Metabolic Shift ◽  
High Cholesterol ◽  
Liver Uptake ◽  
Metabolic Markers

Blood cholesterol levels have been connected to high-altitude adaptation. In the present study, we treated mice with high-cholesterol diets following exposure to acute hypoxic stress and evaluated the effects of the diets on whole-body, liver glucose, and liver fat metabolism. For rapid cholesterol liver uptake, 6-week-old male C57BL/J6 mice were fed with high-cholesterol/cholic acid (CH) diet for 6 weeks and then were exposed to gradual oxygen level reduction for 1 h and hypoxia at 7% oxygen for additional 1 hour using a hypoxic chamber. Animals were than sacrificed, and metabolic markers were evaluated. Hypoxic treatment had a strong hypoglycemic effect that was completely blunted by CH treatment. Decreases in gluconeogenesis and glycogenolysis as well as an increase in ketone body formation were observed. Such changes indicate a metabolic shift from glucose to fat utilization due to activation of the inducible nitric oxide synthase/AMPK axis in the CH-treated animals. Increased ketogenesis was also observed in vitro in hepatocytes after cholesterol treatment. In conclusion, our results show for the first time that cholesterol contributes to metabolic shift and adaptation to hypoxia in vivo and in vitro through induction of HIF-1α and iNOS expression.

Abstract 30: Apolipoprotein CIII Sialylation is a Critical Determinant of Liver Triglyceride Metabolism

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Hussein N Yassine ◽  
Ambika Ramrakhiani ◽  
Aarushi Parekh ◽  
Ryan Walker ◽  
Michael Goran ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Liver Cells ◽  
Liver Fat ◽  
Lipid Uptake ◽  
Liver Uptake ◽  
Critical Determinant ◽  
Triglyceride Metabolism ◽  
Apo E

Apolipoprotein (apo) CIII inhibits lipoprotein lipase (LPL) activity and remnant particle uptake in the liver by the lipolysis stimulated receptor (LSR); and therefore modulates liver and systemic lipid metabolism. Although post-translational modifications of apo CIII lead to asialylated, mono- or di-sialylated variants, the biological relevance of these sialylations is not known. Our objectives were to determine the association of apo C-III sialylation with plasma triglycerides and liver fat content in vivo, and to evaluate the effect of apo CIII sialylation on lipid uptake in liver cells or LPL activity in vitro. In 209 obese non-diabetic adolescent Hispanic participants, apo CIII variants in plasma were measured using mass spectrometric immunoassay. Increased plasma apo C-III sialylation (di- to mono-sialylated apo CIII ratio) was associated with lower triglyceride levels (r=-0.43, p<0.001) and liver fat (by MRI, r=-0.27, p<0.001) independent of total apo CIII concentrations. Higher plasma concentrations of the mono-, but not the di-sialylated variant, were associated with higher triglycerides concentrations (r=0.53, p<0.001). In HepG2 liver cells, immunoprecipitated apo CIII from VLDL of participants in the upper quartile of plasma apo CIII sialylation less effectively inhibited LSR-mediated VLDL uptake compared to apo CIII from those in the lower quartile of apo CIII sialylation (28% difference, p=0.02). This difference in inhibition was abolished by removal of sialic acid with neuraminidase. Apo CIII isolated from VLDL of participants with different level of apo CIII sialylation showed similar capacity to inhibit fatty acid release by LPL of control VLDL. VLDL particles with higher apo CIII sialylation also demonstrated a two-fold increase in ApoE. We conclude that a greater apo CIII sialylation together with particle enrichment in apo E allow for more efficient VLDL liver uptake and less liver fat accumulation. The measurement of plasma apo CIII sialylation may be a useful index of triglyceride metabolism and risk of fatty liver.

Use of Toxicokinetics in Risk Assessment Based on In Vitro Data

1993 ◽  
Vol 21 (2) ◽  
pp. 173-180
Author(s):  
Gunnar Johanson
Keyword(s):  
Risk Assessment ◽  
Whole Body ◽  
External Exposure ◽  
Target Dose ◽  
Toxic Response ◽  
Route Of Exposure ◽  
Vitro Data ◽  
In Vitro Data

This presentation addresses some aspects of the methodology, advantages and problems associated with toxicokinetic modelling based on in vitro data. By using toxicokinetic models, particularly physiologically-based ones, it is possible, in principle, to describe whole body toxicokinetics, target doses and toxic effects from in vitro data. Modelling can be divided into three major steps: 1) to relate external exposure (applied dose) of xenobiotic to target dose; 2) to establish the relationship between target dose and effect (in vitro data, e.g. metabolism in microsomes, partitioning in tissue homogenates, and toxicity in cell cultures, are useful in both steps); and 3) to relate external exposure to toxic effect by combining the first two steps. Extrapolations from in vitro to in vivo, between animal and man, and between high and low doses, can easily be carried out by toxicokinetic simulations. In addition, several factors that may affect the toxic response by changing the target dose, such as route of exposure and physical activity, can be studied. New insights concerning the processes involved in toxicity often emerge during the design, refinement and validation of the model. The modelling approach is illustrated by two examples: 1) the carcinogenicity of 1,3-butadiene; and 2) the haematotoxicity of 2-butoxyethanol. Toxicokinetic modelling is an important tool in toxicological risk assessment based on in vitro data. Many factors, some of which can, and should be, studied in vitro, are involved in the expression of toxicity. Successful modelling depends on the identification and quantification of these factors.

scholarly journals Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
KyeongJin Kim ◽  
Jin Ku Kang ◽  
Young Hoon Jung ◽  
Sang Bae Lee ◽  
Raffaela Rametta ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Whole Body ◽  
Acid Oxidation ◽  
Chow Diet ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Ph Domain ◽  
Peroxisome Proliferator Activated Receptor

AbstractIncreased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

scholarly journals IMMU-31. QUANTITATIVE EVALUATION OF ROUTES OF ADMINISTRATION OF IMMUNOTHERAPEUTIC T CELLS TO ORTHOTOPIC GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii111-ii111
Author(s):  
Lan Hoang-Minh ◽  
Angelie Rivera-Rodriguez ◽  
Fernanda Pohl-Guimarães ◽  
Seth Currlin ◽  
Christina Von Roemeling ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
Adoptive T Cell Therapy ◽  
Whole Body ◽  
T Cell Therapy ◽  
Clinical Responses

Abstract SIGNIFICANCE Adoptive T cell therapy (ACT) has emerged as the most effective treatment against advanced malignant melanoma, eliciting remarkable objective clinical responses in up to 75% of patients with refractory metastatic disease, including within the central nervous system. Immunologic surrogate endpoints correlating with treatment outcome have been identified in these patients, with clinical responses being dependent on the migration of transferred T cells to sites of tumor growth. OBJECTIVE We investigated the biodistribution of intravenously or intraventricularly administered T cells in a murine model of glioblastoma at whole body, organ, and cellular levels. METHODS gp100-specific T cells were isolated from the spleens of pmel DsRed transgenic C57BL/6 mice and injected intravenously or intraventricularly, after in vitro expansion and activation, in murine KR158B-Luc-gp100 glioma-bearing mice. To determine transferred T cell spatial distribution, the brain, lymph nodes, heart, lungs, spleen, liver, and kidneys of mice were processed for 3D imaging using light-sheet and multiphoton imaging. ACT T cell quantification in various organs was performed ex vivo using flow cytometry, 2D optical imaging (IVIS), and magnetic particle imaging (MPI) after ferucarbotran nanoparticle transfection of T cells. T cell biodistribution was also assessed in vivo using MPI. RESULTS Following T cell intravenous injection, the spleen, liver, and lungs accounted for more than 90% of transferred T cells; the proportion of DsRed T cells in the brains was found to be very low, hovering below 1%. In contrast, most ACT T cells persisted in the tumor-bearing brains following intraventricular injections. ACT T cells mostly concentrated at the periphery of tumor masses and in proximity to blood vessels. CONCLUSIONS The success of ACT immunotherapy for brain tumors requires optimization of delivery route, dosing regimen, and enhancement of tumor-specific lymphocyte trafficking and effector functions to achieve maximal penetration and persistence at sites of invasive tumor growth.

scholarly journals In Vivo Radioprotective Activity of Cell-Permeable Bifunctional Antioxidant Enzyme GST-TAT-SOD against Whole-Body Ionizing Irradiation in Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Jianru Pan ◽  
Huocong He ◽  
Ying Su ◽  
Guangjin Zheng ◽  
Junxin Wu ◽  
...  
Keyword(s):  
Growth Rate ◽  
Antioxidant Activity ◽  
Body Weight ◽  
Whole Body ◽  
White Pulp ◽  
Radioprotective Activity ◽  
Significant Difference ◽  
Wbc Count

GST-TAT-SOD was the fusion of superoxide dismutase (SOD), cell-permeable peptide TAT, and glutathione-S-transferase (GST). It was proved to be a potential selective radioprotector in vitro in our previous work. This study evaluated the in vivo radioprotective activity of GST-TAT-SOD against whole-body irradiation. We demonstrated that intraperitoneal injection of 0.5 ml GST-TAT-SOD (2 kU/ml) 2 h before the 6 Gy whole-body irradiation in mice almost completely prevented the splenic damage. It could significantly enhance the splenic antioxidant activity which kept the number of splenic white pulp and consequently resisted the shrinkage of the spleen. Moreover, the thymus index, hepatic antioxidant activity, and white blood cell (WBC) count of peripheral blood in irradiated mice pretreated with GST-TAT-SOD also remarkably increased. Although the treated and untreated irradiated mice showed no significant difference in the growth rate of animal body weight at 7 days postirradiation, the highest growth rate of body weight was observed in the GST-TAT-SOD-pretreated group. Furthermore, GST-TAT-SOD pretreatment increased resistance against 8 Gy whole-body irradiation and enhanced 30 d survival. The overall effect of GST-TAT-SOD seemed to be a bit more powerful than that of amifostine. In conclusion, GST-TAT-SOD would be a safe and potentially promising radioprotector.

scholarly journals The Potential of sGC Modulators for the Treatment of Age-Related Fibrosis: A Mini-Review

Gerontology ◽  
2016 ◽  
Vol 63 (3) ◽  
pp. 216-227 ◽  
Author(s):  
Peter Sandner ◽  
Peter Berger ◽  
Christoph Zenzmaier
Keyword(s):  
Transforming Growth Factor ◽  
Whole Body ◽  
In Vivo Models ◽  
Age Related ◽  
Cgmp Signaling ◽  
Fibrotic Diseases ◽  
Sgc Activators ◽  
Sgc Stimulators

Fibrotic diseases cause high rates of morbidity and mortality, and their incidence increases with age. Despite intense research and development efforts, effective and well-tolerated antifibrotic treatments are scarce. Transforming growth factor-β signaling, which is widely considered the most important profibrotic factor, causes a pro-oxidant shift in redox homeostasis and a concomitant decrease in nitric oxide (NO) signaling. The NO/cyclic guanosine monophosphate (cGMP) signaling cascade plays a pivotal role in the regulation of cell and organ function in whole-body hemostasis. Increases in NO/cGMP can lead to relaxation of smooth muscle cells triggering vasorelaxation. In addition, there is consistent evidence from preclinical in vitro and in vivo models that increased cGMP also exerts antifibrotic effects. However, most of these findings are descriptive and the molecular pathways are still being investigated. Furthermore, in a variety of fibrotic diseases and also during the natural course of aging, NO/cGMP production is low, and current treatment approaches to increase cGMP levels might not be sufficient. The introduction of compounds that specifically target and stimulate soluble guanylate cyclase (sGC), the so called sGC stimulators and sGC activators, might be able to overcome these limitations and could be ideal tools for investigating antifibrotic mechanisms in vitro and in vivo as they may provide effective treatment strategies for fibrotic diseases. These drugs increase cGMP independently from NO via direct modulation of sGC activity, and have synergistic and additive effects to endogenous NO. This review article describes the NO/cGMP signaling pathway and its involvement in fibrotic remodeling. The classes of sGC modulator drugs and their mode of action are described. Finally, the preclinical in vitro and in vivo findings and antifibrotic effects of cGMP elevation via sGC modulation are reviewed. sGC stimulators and activators significantly attenuate tissue fibrosis in a variety of internal organs and in the skin. Moreover, these compounds seem to have multiple intervention sites and may reduce extracellular matrix formation, fibroblast proliferation, and myofibroblast activation. Thus, sGC stimulators and sGC activators may offer an efficacious and tolerable therapy for fibrotic diseases, and clinical trials are currently underway to assess the potential benefit for patients with systemic sclerosis.

scholarly journals Is the resting rate of oxygen consumption of locomotor muscles in crustaceans limited by the low blood oxygenation strategy?

2001 ◽  
Vol 204 (5) ◽  
pp. 933-940 ◽  
Author(s):  
J. Forgue ◽  
A. Legeay ◽  
J.C. Massabuau
Keyword(s):  
Blood Oxygenation ◽  
Whole Body ◽  
Blood Gas ◽  
Astacus Leptodactylus ◽  
Night Time ◽  
Arterial Blood ◽  
Rate Of Oxygen Consumption ◽  
Locomotor Muscles

Numerous water-breathers exhibit a gas-exchange regulation strategy that maintains O(2) partial pressure, P(O2), in the arterial blood within the range 1–3 kPa at rest during the daytime. In a night-active crustacean, we examined whether this could limit the rate of O(2)consumption (M(O2)) of locomotor muscles and/or the whole body as part of a coordinated response to energy conservation. In the crayfish Astacus leptodactylus, we compared the in vitro relationship between the M(O2) of locomotor muscles as a function of the extracellular P(O2) and P(CO2) and in vivo circadian changes in blood gas tensions at various values of water P(O2). In vitro, the M(O2) of locomotor muscle, either at rest or when stimulated with CCCP, was O(2)-dependent up to an extracellular P(O2) of 8–10 kPa. In vivo, the existence of a night-time increase in arterial P(O2) of up to 4 kPa at water P(O2) values of 20 and 40 kPa was demonstrated, but an experimental increase in arterial P(O2) during the day did not lead to any rise in whole-body M(O2). This suggested that the low blood P(O2) in normoxia has no global limiting effect on daytime whole-body M(O2). The participation of blood O(2) status in shaping the circadian behaviour of crayfish is discussed.

Use of Medium Potency Statins Is Associated with Improved Outcomes after Frontline RCHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-45
Author(s):  
Sushanth Gouni ◽  
Paolo Strati ◽  
Jason Westin ◽  
Loretta J. Nastoupil ◽  
Raphael E Steiner ◽  
...  
Keyword(s):  
Cell Lines ◽  
Research Funding ◽  
Response Assessment ◽  
Cholesterol Content ◽  
In Vivo Studies ◽  
High Cholesterol ◽  
Improved Outcomes ◽  
Significant Difference

Background: Pre-clinical studies show that statins may improve the efficacy of chemoimmunotherapy in patients with DLBCL, through interference with cell membrane-initiated signaling pathways. Clinical retrospective studies, however, yield conflicting data, due to heterogeneous properties of statins, including potency and hydrophilicity. Methods: This is a retrospective analysis of patients with previously untreated, advanced stage DLBCL, non-double hit, treated with frontline R-CHOP between 01/01/2000 and 09/01/2019 (data cut-off 04/15/2020) at MD Anderson Cancer Center, and for whom data regarding statin use at time of initiation of treatment were available. Lugano 2014 response criteria were applied retrospectively for response assessment. Cellular cholesterol levels were analyzed in 6 DLBCL cell lines using an Amplex red fluorometric assay. A doxorubicin (DXR)-resistant cell line was generated exposing SUDHL4 cells to escalating doses of DXR; a DXR-resistant DLBCL patient-derived xenograft (PDX) model was established through serial transplantation and exposure to DXR. Results: 271 patients were included in the analysis, 182 (67%) were older than 60 years, 134 (49%) were male, 212 (72%) had stage IV disease, and 217 (80%) had an IPI score &gt; 3; upon pathological review, 38 (36%) cases were non-GCB type, and 18 (28%) were double-expressors; 214 (79%) were able to complete all planned 6 cycles of RCHOP. Seventy-nine (29%) patients received statins at time of initiation of chemoimmunotherapy: 15 patients received low potency statin, 51 medium and 13 high; 18 patients received hydrophilic statins and 61 lipophilic. Patients receiving statins were significantly older as compared to patients who did not (p&lt;0.001); no other significant difference in baseline characteristics was observed when comparing the 2 groups. Overall, 265 out of 271 patients were evaluable for response, as 6 stopped treatment because of toxicity before first response assessment. Among these, ORR was 95% (252/265) and CR rate was 62% (165/265). ORR rate was identical in patients who were treated with statin and those who did not (95% both, p=1). After a median follow-up of 77 months (95% CI, 70-84 months), 119 patients progressed/died, median PFS was not reached and 6-year PFS was 57%. 6-year PFS rate according to statin intensity was: 48% (low), 72% (medium), 57% (high). PFS. 6-year PFS rate was 64% for hydrophilic and 72% for lipophilic statins. Patients treated with statins had a trend for longer PFS (p=0.06), significantly longer for patients receiving medium potency statins (p=0.04). No significant difference in PFS was observed when comparing patients treated with lipophilic statins to all others (not reached vs 84 months, p=0.22). To confirm these clinical data, in-vitro and in-vivo studies were performed. Six cell lines were tested: 4 with high cholesterol content (SUDHL4, HBL1, HT, and U2932; 5.0-8.0 µg/mg protein), and 2 with low cholesterol content (DOHH2 and OCI-LY19; 1.5-2.0 µg/mg protein); the latter showed the highest sensitivity to DXR-mediated killing. The combination of lovastatin and DXR (10nM) was tested in all 4 cell lines with high cholesterol content, resulting in more cell death than either treatment alone. Lovastatin (at the nanomolar range) resensitized DXR-resistant SUDHL4 cells to DXR. Finally, in a DXR-resistant PDX model, the combination of lovastatin and DXR resulted in delayed tumor growth as compared to chemotherapy alone. Conclusions: Use of medium potency statins is associated with improved outcomes after frontline RCHOP in patients with DLBCL. This was further confirmed in functional in-vitro and in-vivo studies. Future interventional studies, aimed at improving outcomes in these patients using this novel combination, are warranted. Disclosures Westin: Amgen: Consultancy; 47: Research Funding; Kite: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding. Nastoupil:Gamida Cell: Honoraria; Merck: Research Funding; TG Therapeutics: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Novartis: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Gilead/KITE: Honoraria. Neelapu:Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Celgene: Other: personal fees, Research Funding; Novartis: Other: personal fees; Karus Therapeutics: Research Funding; N/A: Other; Takeda Pharmaceuticals: Patents & Royalties; Acerta: Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Precision Biosciences: Other: personal fees, Research Funding; Legend Biotech: Other; Adicet Bio: Other; Allogene Therapeutics: Other: personal fees, Research Funding; Cell Medica/Kuur: Other: personal fees; Calibr: Other; Incyte: Other: personal fees; Unum Therapeutics: Other, Research Funding. Landgraf:NCI/NIH: Research Funding. Vega:NCI: Research Funding.

scholarly journals Tetrandrine Attenuated Doxorubicin-Induced Acute Cardiac Injury in Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Gang Li ◽  
Wen-Rui Li ◽  
Ya-Ge Jin ◽  
Qi-Qiang Jie ◽  
Cheng-Yu Wang ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Cardiac Function ◽  
Cardiac Injury ◽  
Whole Body ◽  
Oxygen Species ◽  
Single Intraperitoneal Injection ◽  
Body Wasting ◽  
Nrf2 Expression

Oxidative damage is closely involved in the development of doxorubicin- (DOX-) induced cardiotoxicity. It has been reported that tetrandrine can prevent the development of cardiac hypertrophy by suppressing reactive oxygen species- (ROS-) dependent signaling pathways in mice. However, whether tetrandrine could attenuate DOX-related cardiotoxicity remains unclear. To explore the protective effect of tetrandrine, mice were orally given a dose of tetrandrine (50 mg/kg) for 4 days beginning one day before DOX injection. To induce acute cardiac injury, the mice were exposed to a single intraperitoneal injection of DOX (15 mg/kg). The data in our study showed that tetrandrine prevented DOX-related whole-body wasting and heart atrophy, decreased markers of cardiac injury, and improved cardiac function in mice. Moreover, tetrandrine supplementation protected the mice against oxidative damage and myocardial apoptotic death. Tetrandrine supplementation also reduced ROS production and improved cell viability after DOX exposure in vitro. We also found that tetrandrine supplementation increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression and activity in vivo and in vitro. The protection of tetrandrine supplementation was blocked by Nrf2 deficiency in mice. In conclusion, our study found that tetrandrine could improve cardiac function and prevent the development of DOX-related cardiac injury through activation of Nrf2.

scholarly journals New 55Co-labeled Albumin-Binding Folate Derivatives as Potential PET Agents for Folate Receptor Imaging

2019 ◽  
Vol 12 (4) ◽  
pp. 166 ◽  
Author(s):  
Lauren L. Radford ◽  
Solana Fernandez ◽  
Rebecca Beacham ◽  
Retta El Sayed ◽  
Renata Farkas ◽  
...  
Keyword(s):  
Folate Receptor ◽  
Small Animal ◽  
Small Animal Pet ◽  
Receptor Imaging ◽  
Albumin Binding ◽  
Liver Uptake ◽  
Biodistribution Studies ◽  
Positron Emission

Overexpression of folate receptors (FRs) on different tumor types (e.g., ovarian, lung) make FRs attractive in vivo targets for directed diagnostic/therapeutic agents. Currently, no diagnostic agent suitable for positron emission tomography (PET) has been adopted for clinical FR imaging. In this work, two 55Co-labeled albumin-binding folate derivatives-[55Co]Co-cm10 and [55Co]Co-rf42-with characteristics suitable for PET imaging have been developed and evaluated. High radiochemical yields (≥95%) and in vitro stabilities (≥93%) were achieved for both compounds, and cell assays demonstrated FR-mediated uptake. Both 55Co-labeled folate conjugates demonstrated high tumor uptake of 17% injected activity per gram of tissue (IA/g) at 4 h in biodistribution studies performed in KB tumor-bearing mice. Renal uptake was similar to other albumin-binding folate derivatives, and liver uptake was lower than that of previously reported [64Cu]Cu-rf42. Small animal PET/CT images confirmed the biodistribution results and showed the clear delineation of FR-expressing tumors.

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