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Oxytocin (OXT) is a cyclic nonapeptide, two amino acids of which are cysteine, forming an intramolecular disulfide bond. OXT is produced in the hypothalamus and is secreted into the bloodstream from the posterior pituitary. As recent studies have suggested that OXT is a neurotransmitter exhibiting central effects important for social deficits, it has drawn much attention as a drug candidate for the treatment of autism. Although human-stage clinical trials of the nasal spray of OXT for the treatment of autism have already begun, few studies have examined the pharmacokinetics and brain distribution of OXT after nasal application. The aim of this study is to evaluate the disposition, nasal absorption, and therapeutic potential of OXT after nasal administration. The pharmacokinetics of OXT after intravenous bolus injection to rats followed a two-compartment model, with a rapid initial half-life of 3 min. The nasal bioavailability of OXT was approximately 2%. The brain concentration of OXT after nasal application was much higher than that after intravenous application, despite much lower concentrations in the plasma. More than 95% of OXT in the brain was directly transported from the nasal cavity. The in vivo stress-relief effect by OXT was observed only after intranasal administration. These results indicate that pharmacologically active OXT was effectively delivered to the brain after intranasal administration. In conclusion, the nasal cavity is a promising route for the efficient delivery of OXT to the brain.

P-Glycoprotein (P-gp) is a plasma membrane glycoprotein of about 170 kDa that belongs to the superfamily of ATPbinding cassette (ABC) transporters. P-gp is extensively expressed in tumor cells, liver, intestinal brush border membranes, kidney, brain, and adrenal glands.1) It can actively pump drugs out of cells, thus reducing the oral bioavailability of a wide range of drugs such as digoxin, vinca alkaloids, and b-adrenergic agonists.It has been reported that some P-glycoprotein inhibitors such as verapamil and cyclosporin A could enhance the bioavailability of P-gp substrate drugs.2-4) But it is well known that these drugs themselves have pharmacological activities. Therefore, it is important to find a P-gp inhibitor which does not have pharmacological activities. It has been demonstrated that a number of excipients could inhibit the function of P-gp, thereby increasing the absorption of P-gp substrate drugs. 5) These excipients include polyethylene glycols (PEGs), nonionic surfactants, fatty acids and bile salts. [6][7][8][9][10][11][12][13][14][15][16] It has been reported that several excipients such as Cremophor EL, Tween 80, n-lauryl-b-D-maltopyranoside (LM), Pluronic P85, vitamin E-TPGS, PEGs, sodium caprate and dimethyl-b-cyclodextrin could inhibit the function of Pgp by in vitro and in vivo methods. [6][7][8][9][10][11][12][13][14][15][16] Among these pharmaceutical excipients, Labrasol is one which has been widely used for the solubilization of hydrophobic drugs.17) Labrasol is obtained from coconut oil and has very low toxicity with an LD 50 of 22 g/kg for rats. Recently, it was reported that Labrasol had a strong absorption enhancing effect and that intestinal absorption of various poorly absorbable drugs including gentamicin, insulin and vancomycin was enhanced in its presence. [18][19][20] However, few studies examined the effect of Labrasol on the function of P-gp in the intestine and the intestinal absorption of P-gp substrates. Cornaire et al. (2004) examined the effect of Labrasol on the transport of digoxin by an in vitro everted sac experiment, and reported that 0.5% Labrasol increased the transport of digoxin in this experiment.21) However, they demonstrated that 0.5% Labrasol could increase the lactate dehydrogenase (LDH), and so the increase in digoxin transport might be due to the intestinal membrane damage, and not to the inhibition of P-gp function in the intestine. Furthermore, they did not study the different regional effects of Labrasol on the transport of P-gp substrate and in situ or in vivo intestinal absorption of P-gp substrate with or without Labrasol.In this study, therefore, we studied the effect of Labrasol on the function of P-gp using two different intestinal absorption experiments. We first adopted an in vitro diffusion chamber system using the isolated rat intestinal membrane to evaluate the effects of Labrasol and other pharmaceutical excipients, Gelucire44/14 and Transcutol P on the intestinal transport of rhodamine123, a P-gp substrate. In addition, the intestinal mem...

Purpose: Lipid nanoparticle (LNP) formulations facilitate tumor uptake and intracellular processing through an enhanced permeation and retention effect (EPR), and currently multiple products are undergoing clinical evaluation. Clusterin (CLU) is a cytoprotective chaperone induced by androgen receptor (AR) pathway inhibition to facilitate adaptive survival pathway signaling and treatment resistance. In our study, we investigated the efficacy of siRNA tumor delivery using LNP systems in an enzalutamide-resistant (ENZ-R) castration-resistant prostate cancer (CRPC) model.Experimental Design: Gene silencing of a luciferase reporter gene in the PC-3M-luc stable cell line was first assessed in subcutaneous and metastatic PC-3 xenograft tumors. Upon validation, the effect of LNP siRNA targeting CLU in combination with AR antisense oligonucleotides (ASO) was assessed in ENZ-R CRPC LNCaP in vitro and in vivo models.Results: LNP LUC-siRNA silenced luciferase expression in PC-3M-luc subcutaneous xenograft and metastatic models. LNP CLUsiRNA potently suppressed CLU and AR ASO-induced CLU and AKT and ERK phosphorylation in ENZ-R LNCaP cells in vitro, more potently inhibiting ENZ-R cell growth rates and increased apoptosis when compared with AR-ASO monotherapy. In subcutaneous ENZ-R LNCaP xenografts, combinatory treatment of LNP CLU-siRNA plus AR-ASO significantly suppressed tumor growth and serum PSA levels compared with LNP LUC-siRNA (control) and AR-ASO.Conclusions: LNP siRNA can silence target genes in vivo and enable inhibition of traditionally non-druggable genes like CLU and other promising cotargeting approaches in ENZ-R CRPC therapeutics.

Brain tumors are one of the most lethal and difficult to treat. Their treatment is limited by the inadequate delivery of antitumor drugs to the tumor. In order to overcome this limitation, the possibility of the nose-brain direct transport pathway was evaluated using methotrexate (MTX) as a model antitumor agent. The direct transport of nasal MTX to the cerebrospinal fluid (CSF) was examined by comparing the concentration of MTX in the plasma and the CSF after intraperitoneal (IP) and intranasal (IN) administrations. The brain uptake of MTX was evaluated based on a multiple-time/graphical analysis by measuring the concentration of MTX in the plasma and in the brain. The feasibility of nasal chemotherapy was examined by three nasal dosings of MTX to tumor-bearing rats in vivo at two day intervals with peritoneal application as a positive control. MTX showed a significant inhibitory effect on the in vitro growth of 9L glioma cells with 50% growth inhibitory concentration at 7.99 ng/mL. The pharmacokinetic studies clarified the significant direct transport of MTX from nasal cavity both to the CSF and to the brain. Nasal chemotherapy with MTX significantly reduced the tumor weight as compared to nontreatment control and IP group. The strategy to utilize the nose-brain direct transport can be applicable to a new therapeutic system not only for brain tumors but also for other central nervous system disorders such as neurodegenerative diseases.

Effective delivery of drug carriers selectively to the kidney is challenging because of their uptake by the reticuloendothelial system in the liver and spleen, which limits effective treatment of kidney diseases and results in side effects. To address this issue, we synthesized L-serine (Ser)-modified polyamidoamine dendrimer (PAMAM) as a potent renal targeting drug carrier. Approximately 82% of the dose was accumulated in the kidney at 3 h after i.v. injection of 111 In-labeled Ser-PAMAM in mice, while i.v. injection of 111 In-labeled unmodified PAMAM, L-threonine modified PAMAM, and L-tyrosine modified PAMAM resulted in kidney accumulations of 28%, 35%, and 31%, respectively. Single-photon emission computed tomography/computed tomography (SPECT/ CT) images also indicated that 111 In-labeled Ser-PAMAM specifically accumulated in the kidneys. An intrakidney distribution study showed that fluorescein isothiocyanate-labeled Ser-PAMAM accumulated predominantly in renal proximal tubules. Results of a cellular uptake study of Ser-PAMAM in LLC-PK1 cells in the presence of inhibitors [genistein, 5-(N-ethyl-N-isopropyl)amiloride, and lysozyme] revealed that caveolae-mediated endocytosis, micropinocytosis, and megalin were associated with the renal accumulation of Ser-PAMAM. The efficient renal distribution and angiotensinconverting enzyme (ACE) inhibition effect of captopril (CAP), an ACE inhibitor, was observed after i.v. injection of the Ser-PAMAM-CAP conjugate. These findings indicate that Ser-PAMAM is a promising renal targeting drug carrier for the treatment of kidney diseases. Thus, the results of this study demonstrate efficient renal targeting of a drug carrier via Ser modification.drug delivery | renal targeting | L-serine | dendrimer

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