Effects of phospholipid type and particle size on lipid nanoparticle distribution in vivo and in pancreatic islets.

Lipid nanoparticles (LNPs) have recently been used as nanocarriers in drug delivery systems for nucleic acid drugs. Their practical applications are currently primarily limited to the liver and specific organs. However, altering the type and composition ratio of phospholipids improves their distribution in organs other than the liver, such as the spleen and lungs. This study aimed to elucidate the effects of LNP components and particle size on in vivo distribution through systemic circulation to pancreatic islets to achieve better targeting of islets, which are a fundamental therapeutic target for diabetes. Fluorescence-labeled LNPs were prepared using three phospholipids: 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), with particle sizes of 30-160 nm (diameter) using a microfluidic device. Baffled-structured iLiNP devices with adjusted flow-rate ratios and total flow rates were used. After the intravenous administration of LNPs to C57BL/6 J mice, the distribution of each LNP type to the major organs, including the pancreas and pancreatic islets, was compared using ex vivo fluorescence imaging and observation of pancreatic tissue sections. DSPC-LNPs- and DOPE-LNPs showed the highest distribution in the spleen and liver, respectively. In contrast, the DOPC-LNPs showed the highest distribution in the pancreas and the lowest distribution in the liver and spleen. In addition, smaller particles showed better distribution throughout the pancreas. The most significant LNP distribution in the islets was observed for DOPC-LNPs with a particle size of 160 nm. Furthermore, larger LNPs tended to be distributed in the islets, whereas smaller LNPs tended to be distributed in the exocrine glands. DOPC-LNPs were distributed in the islets at all cholesterol concentrations, with a high distribution observed at >40% cholesterol and > 3% PEG and the distribution was higher at 24 h than at 4 h. Thus, LNP composition and particle size significantly affected islet distribution characteristics, indicating that DOPC-LNPs may be a drug delivery system for effectively targeting the pancreas and islets.

Quantitative analysis of inulin distribution in the brain focused on nose-to-brain route via olfactory epithelium by reverse esophageal cannulation.

This study aimed to determine the effect of intranasal dosing speed and administrating volume of nose-to-brain delivery on candidates for peptide drugs (molecular weight ca. 1-10 kDa). Using inulin as the model molecule of a peptide drug, intranasal administration by cannulation from the airway side through the esophagus was tested in mice. This was done to determine the quantitative distribution levels of the drug in the brain and cerebral spinal fluid (CSF). Distribution levels were increased with slower and constant speed (5 µL/min), with higher dosing volume equivalent to nasal volume per body weight in mice (25 µL), and were recorded 0.27% injected dose per gram of tissue (ID/g) in the brain, and 0.24% injected dose per milliliter (ID/mL) in the CSF at 60 min. Then, brain distribution resulting from reverse cannulation was two times more than that of the typical intranasal administration method using a micropipette. In addition, the percentage of inulin estimated to reach the brain via direct transport (%DTP) during reverse cannulation was estimated to be 93%, suggesting that ~95% of the total dose was transferred directly to the brain via the olfactory mucosa. These results show that distribution of the peptide drug in the brain was increased through constant administration at a slow and constant speed.