Distribution and Endocrine Morphology of Polypeptide YY (PYY) Containing Cells in the Human Gut

Using human materials, the distribution of PYY containing cells was determined by immunocytochemical methods and discussion was made on their morphological endocrinology. PYY cells were fairly numerous in the lower gastrointestinal tract of man, particularly in the colon and rectum. The cells were also present in the pancreas and duodenum but quite rarely. PYY cells were not observed at all in the lower part of the esophagus, stomach and gall bladder. Their peculiar and characteristic shapes as well as distribution suggest that PYY may have some action (probably specific) on the function of the distal gastrointestinal tract

Usefulness of competitive inhibitors of protein binding for improving the pharmacokinetics of 186Re-MAG3-conjugated bisphosphonate (186Re-MAG3-HBP), an agent for treatment of painful bone metastases

金沢大学学際科学実験センターアイソトープ総合研究施設Purpose: We have developed a 186Re-mercaptoacetylglycylglycylglycine complex-conjugated bisphosphonate (186Re-MAG3-HBP) for the treatment of painful bone metastases. We assumed competitive inhibitors of protein binding to be useful for procuring a favorable biodistribution of 186Re-MAG3-HBP for the palliation of bone pain because it has been reported that the concurrent administration of 99mTc-MAG3 and drugs with high affinity for serum protein produced competitive displacement at specific binding sites and enhanced total clearance and tissue distribution. Methods: The displacement effects of several protein-binding inhibitors on the protein binding of 186Re-MAG3-HBP were investigated. Biodistribution experiments were performed by intravenously administering 186Re-MAG3-HBP into rats with ceftriaxone as a competitive protein-binding inhibitor or saline. Results: The protein binding of 186Re-MAG3-HBP in rat serum, human serum, and a human serum albumin solution was significantly decreased by the addition of ceftriaxone, which has high affinity for binding site I on serum albumin. In the biodistribution experiments, pretreatment with ceftriaxone enhanced the clearance of the radioactivity of 186Re-MAG3-HBP in blood and nontarget tissues but had no effect on accumulation in bone. Conclusions: The findings suggested that the use of protein-binding competitive inhibitors would be effective in improving the pharmacokinetics of radiopharmaceuticals with high affinity for serum protein. © 2008 Springer-Verlag

Therapeutic effects of a 186re-complex-conjugated bisphosphonate for the palliation of metastatic bone pain in an animal model

金沢大学疾患モデル総合研究センターPreviously, based on the concept of bifunctional radiopharmaceuticals, we developed a highly stable 186Re-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy-4,4-diphosphonobutyl) carbamoylmethyl]carbamoylmethyl] carbamoylmethyl]carbamoylmethanethiolate] oxorhenium(V) (186Re-MAG3-HBP), for the treatment of painful bone metastases. This agent showed a superior biodistribution as a bone-seeking agent in normal mice when compared with 186Re-1-hydroxyethylidene-1,1- diphosphonate (186Re-HEDP). In this study, we evaluated the therapeutic effects of 186Re-MAG3-HBP using an animal model of bone metastasis. Methods: The model was prepared by injecting syngeneic MRMT-1 mammary tumor cells into the left tibia of female Sprague-Dawley rats. 186Re-MAG3-HBP (55.5, 111, or 222 MBq/kg) or 186Re-HEDP (55.5 MBq/kg) was then administered intravenously 21 d later. To evaluate the therapeutic effects and side effects, tumor size and peripheral blood cell counts were determined. Palliation of bone pain was evaluated by a von Frey filament test. Results: In the rats treated with 186Re-HEDP, tumor growth was comparable with that in untreated rats. In contrast, when 186Re-MAG3-HBP was administered, tumor growth was significantly inhibited. Allodynia induced by bone metastasis was attenuated by treatment with 186Re-MAG3-HBP or 186Re-HEDP, but 186Re-MAG3- HBP tended to be more effective. Conclusion: These results indicate that 186Re-MAG3-HBP could be useful as a therapeutic agent for the palliation of metastatic bone pain. Copyright © 2006 by the Society of Nuclear Medicine, Inc

実験胃炎・胃粘膜の GEP ホルモン細胞動態

The aim of this study was to ascertain the morphological changes in the endocrine cell profile in the atrophic mucosa of mice with autoimmune gastritis induced by neonatal thymectomy and administration of carcinogenic chemical, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Proliferation of argyrophil cells, gastrin (G17, G34) cells in areas of pseudopyloric metaplasia, enteric hormone (GIP, secretin, substance P, enteroglucagon) containing cells and enterochromaffin cells in areas of intestinal metaplasia of the atrophic mucosa was observed in mice with autoimmune gastritis together with proliferation of enterochromaffin-like cells and undifferentiated endocrine cells in their atrophic mucosa. These findings suggest that atrophic mucosae, especially epithelia of pseudopyloric and intestinal metaplasia as well, have the potential of producing endocrine cells which are normally present in the gastric antrum and intestine

Stability Study of mRNA-Lipid Nanoparticles Exposed to Various Conditions Based on the Evaluation between Physicochemical Properties and Their Relation with Protein Expression Ability

Lipid nanoparticles (LNPs) are currently in the spotlight as delivery systems for mRNA therapeutics and have been used in the Pfizer/BioNTech and Moderna COVID-19 vaccines. mRNA-LNP formulations have been indicated to require strict control, including maintenance at fairly low temperatures during their transport and storage. Since it is a new pharmaceutical modality, there is a lack of information on the systematic investigation of how storage and handling conditions affect the physicochemical properties of mRNA-LNPs and their protein expression ability. In this study, using the mRNA-LNPs with standard composition, we evaluated the effects of temperature, cryoprotectants, vibration, light exposure, and syringe aspiration from the vials on the physicochemical properties of nanoparticles in relation to their in vitro/in vivo protein expression ability. Among these factors, storage at −80 °C without a cryoprotectant caused a decrease in protein expression, which may be attributed to particle aggregation. Exposure to vibration and light also caused similar changes under certain conditions. Exposure to these factors can occur during laboratory and hospital handling. It is essential to have sufficient knowledge of the stability of mRNA-LNPs in terms of their physical properties and protein expression ability at an early stage to ensure reproducible research and development and medical care

A Novel Bispecific Antibody against Human CD3 and Ephrin Receptor A10 for Breast Cancer Therapy.

Ephrin receptor A10 (EphA10), a transmembrane receptor that binds to ephrin, is a newly identified breast cancer marker protein that has also been detected in HER2-negative tissue. In this study, we report creation of a novel bispecific antibody (BsAb) binding both EphA10 and CD3, thereby forming a bridge between antigens expressed on both tumor and immune cells and promoting recognition of tumor cells by immune cells and redirection of cytotoxic T cells (CTL). This BsAb (EphA10/CD3) was expressed in supernatants of BsAb gene-transfected cells as monomeric and dimeric molecules. Redirected T-cell lysis was observed when monomeric and dimeric BsAb were added to EphA10-overexpressing tumor cells in vitro. Furthermore, dimeric BsAb (EphA10/CD3) was more cytotoxic than monomeric BsAb, with efficient tumor cell lysis elicited by lower concentrations (≤10(-1) μg/mL) and a lower effector to target (E/T) cell ratio (E/T = 2.5). Dimeric BsAb (EphA10/CD3) also showed significant anti-tumor effects in human xenograft mouse models. Together, these results revealed opportunities to redirect the activity of CTL towards tumor cells that express EphA10 using the BsAb (EphA10/CD3), which could be tested in future clinical trials as a novel and potent therapeutic for breast cancer tumors

Stability Study of mRNA-Lipid Nanoparticles Exposed to Various Conditions Based on the Evaluation between Physicochemical Properties and Their Relation with Protein Expression Ability

Lipid nanoparticles (LNPs) are currently in the spotlight as delivery systems for mRNA therapeutics and have been used in the Pfizer/BioNTech and Moderna COVID-19 vaccines. mRNA-LNP formulations have been indicated to require strict control, including maintenance at fairly low temperatures during their transport and storage. Since it is a new pharmaceutical modality, there is a lack of information on the systematic investigation of how storage and handling conditions affect the physicochemical properties of mRNA-LNPs and their protein expression ability. In this study, using the mRNA-LNPs with standard composition, we evaluated the effects of temperature, cryoprotectants, vibration, light exposure, and syringe aspiration from the vials on the physicochemical properties of nanoparticles in relation to their in vitro/in vivo protein expression ability. Among these factors, storage at −80 °C without a cryoprotectant caused a decrease in protein expression, which may be attributed to particle aggregation. Exposure to vibration and light also caused similar changes under certain conditions. Exposure to these factors can occur during laboratory and hospital handling. It is essential to have sufficient knowledge of the stability of mRNA-LNPs in terms of their physical properties and protein expression ability at an early stage to ensure reproducible research and development and medical care.Pharmaceutics, 14(11), art. no. 2357; 202