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Extrahepatic delivery of small interfering RNAs (siRNAs) may have applications in the development of novel therapeutic approaches. However, reports on such approaches are limited, and the scarcity of reports concerning the systemically targeted delivery of siRNAs with effective gene silencing activity presents a challenge. We herein report for the first time the targeted delivery of CD206-targetable chemically modified mannose–siRNA (CMM–siRNA) conjugates to macrophages and dendritic cells (DCs). CMM–siRNA exhibited a strong binding ability to CD206 and selectively delivered contents to CD206-expressing macrophages and DCs. Furthermore, the conjugates demonstrated strong gene silencing ability with long-lasting effects and protein downregulation in CD206-expressing cells in vivo. These findings could broaden the use of siRNA technology, provide additional therapeutic opportunities, and establish a basis for further innovative approaches for the targeted delivery of siRNAs to not only macrophages and DCs but also other cell types.

Supplemental doses of antithrombin (AT) are widely used to treat sepsis-induced disseminated intravascular coagulation (DIC) in Japan. However, evidence on the benefits of AT supplementation for DIC is insufficient. This multicenter retrospective observational study aimed to clarify the effect of AT supplementation on sepsis-induced DIC using propensity score analyses. Data from 3,195 consecutive adult patients admitted to 42 intensive care units for severe sepsis treatment were retrospectively analyzed; 1,784 patients were diagnosed with DIC (n = 715, AT group; n = 1,069, control group). Inverse probability of treatment-weighted propensity score analysis indicated a statistically significant association between AT supplementation and lower in-hospital all-cause mortality (n = 1,784, odds ratio [95% confidence intervals]: 0.748 [0.572-0.978], P = 0.034). However, quintile-stratified propensity score analysis (n = 1,784, odds ratio: 0.823 [0.646-1.050], P = 0.117) and propensity score matching analysis (461 matching pairs, odds ratio: 0.855 [0.649-1.125], P = 0.263) did not show this association. In the early days after intensive care unit admission, the survival rate was statistically higher in the propensity score-matched AT group than in the propensity score-matched control group (P = 0.007). In DIC patients without concomitant heparin administration, similar results were observed. In conclusion, AT supplementation may be associated with reduced in-hospital all-cause mortality in patients with sepsis-induced DIC. However, the statistical robustness of this connection was not strong. In addition, although the number of transfusions needed in patients with AT supplementation increased, severe bleeding complications did not.

IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age and body composition (ratio of total body weight to ideal body weight [TBW/IBW]) were greater than the median age and TBW/IBW of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 area under the concentration versus time curve (AUC) to sum total CPT-11 AUC. Patients aged

Background The administration of low-dose intravenous immunoglobulin G (IVIgG) (5 g/day for 3 days; approximate total 0.3 g/kg) is widely used as an adjunctive treatment for patients with sepsis in Japan, but its efficacy in the reduction of mortality has not been evaluated. We investigated whether the administration of low-dose IVIgG is associated with clinically important outcomes including intensive care unit (ICU) and in-hospital mortality. Methods This is a post-hoc subgroup analysis of data from a retrospective cohort study, the Japan Septic Disseminated Intravascular Coagulation (JSEPTIC DIC) study. The JSEPTIC DIC study was conducted in 42 ICUs in 40 institutions throughout Japan, and it investigated associations between sepsis-related coagulopathy, anticoagulation therapies, and clinical outcomes of 3195 adult patients with sepsis and septic shock admitted to ICUs from January 2011 through December 2013. To investigate associations between low-dose IVIgG administration and mortalities, propensity score-based matching analysis was used. Results IVIgG was administered to 960 patients (30.8%). Patients who received IVIgG were more severely ill than those who did not (Acute Physiology and Chronic Health Evaluation (APACHE) II score 24.2 ± 8.8 vs 22.6 ± 8.7, p

A pharmacokinetic model was constructed to explain the difference in brain- and cerebrospinal fluid (CSF)-to-plasma and brain-to-CSF unbound drug concentration ratios (Kp,uu,brain, Kp,uu,CSF, and Kp,uu,CSF/brain, respectively) of drugs under steady-state conditions in rats. The passive permeability across the blood-brain barrier (BBB), PS1, was predicted by two methods using log(D/molecular weight(0.5)) for PS1(1) or the partition coefficient in octanol/water at pH 7.4 (LogD), topologic van der Waals polar surface area, and van der Waals surface area of the basic atoms for PS1(2). The coefficients of each parameter were determined using previously reported in situ rat BBB permeability. Active transport of drugs by P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) measured in P-gp- and Bcrp-overexpressing cells was extrapolated to in vivo by introducing scaling factors. Brain- and CSF-to-plasma unbound concentration ratios (Kp,uu,brain and Kp,uu,CSF, respectively) of 19 compounds, including P-gp and Bcrp substrates (daidzein, dantrolene, flavopiridol, genistein, loperamide, quinidine, and verapamil), were simultaneously fitted to the equations in a three-compartment model comprising blood, brain, and CSF compartments. The calculated Kp,uu,brain and Kp,uu,CSF of 17 compounds were within a factor of three of experimental values. Kp,uu,CSF values of genistein and loperamide were outliers of the prediction, and Kp,uu,brain of dantrolene also became an outlier when PS1(2) was used. Kp,uu,CSF/brain of the 19 compounds was within a factor of three of experimental values. In conclusion, the Kp,uu,CSF/brain of drugs, including P-gp and Bcrp substrates, could be successfully explained by a kinetic model using scaling factors combined with in vitro evaluation of P-gp and Bcrp activities.

We previously identified dibenzooxepine derivative 1 as a potent PPARγ ligand with a unique binding mode owing to its non-thiazolidinedione scaffold. However, while 1 showed remarkably potent MKN-45 gastric cancer cell aggregation activity, an indicator of cancer differentiation-inducing activity induced by PPARγ activation, we recognized that 1 was metabolically unstable. In the present study, we identified a metabolically soft spot, and successfully discovered 3-fluoro dibenzooxepine derivative 9 with better metabolic stability. Further optimization provided imidazo[1,2-a]pyridine derivative 17, which showed potent MKN-45 gastric cancer cell aggregation activity and excellent PK profiles compared with 9. Compound 17 exerted a growth inhibitory effect on AsPC-1/AG1 pancreatic tumor in mice. Furthermore, the decrease in the hematocrit (an indicator of localized edema, a serious adverse effect of PPARγ ligands) was tolerable even with oral administration at 200 mg/kg in healthy mice.

To investigate pharmacokinetics (PK) of encapsulated CPT-11, released CPT-11 and the active metabolite SN-38 following administration of IHL-305 and to identify factors that may influence IHL-305 PK.Plasma samples from 39 patients with solid tumors were collected in a phase I study. IHL-305 was administered as a 1 h IV infusion with doses ranging from 3.5 to 210 mg/m(2). Plasma concentrations of encapsulated CPT-11, released CPT-11 and SN-38 were used to develop a population PK model using NONMEM®.PK of encapsulated CPT-11 was described by 1-compartment model with nonlinear clearance and PK of released CPT-11 was described by a 1-compartment model with linear clearance for all patients. PK of the active metabolite SN-38 was described by a 2-compartment model with linear clearance for all patients. Covariate analysis revealed that gender was a significant covariate for volume of distribution of encapsulated CPT-11. Vencap in male patients is 1.5-fold higher compared with female patients.The developed population PK modeling approach is useful to predict PK exposures of encapsulated and released drug and can be applied to the more than 300 other nanoparticle formulations of anticancer agents that are currently in development. The effect of gender on PK of IHL-305 needs to be further evaluated.

Severe sepsis is a major concern in the intensive care unit (ICU), although there is very little epidemiological information regarding severe sepsis in Japan. This study evaluated 3195 patients with severe sepsis in 42 ICUs throughout Japan. The patients with severe sepsis had a mean age of 70 ± 15 years and a mean Acute Physiology and Chronic Health Evaluation II score of 23 ± 9. The estimated survival rates at 28 and 90 days after ICU admission were 73.6 and 56.3 %, respectively. Electronic supplementary material The online version of this article (doi:10.1186/s40560-016-0169-9) contains supplementary material, which is available to authorized users.

IHL-305 is a novel PEGylated liposome containing irinotecan. This study examined the safety profile and pharmacokinetics of IHL-305 and established the maximum tolerated dose and recommended phase II dose (RP2D). In a standard 3 + 3 design, IHL-305 was administered IV on day 1 of a 28-day treatment schedule. Subsequently, a 14-day treatment schedule was also explored. Two patient populations were evaluated separately: Patients with at least one wild-type (wt) allele of UGT1A1 (UDP glucoronosyltransferase 1A1) wt/wt or wt/*28 as one group (referred to as UGT1A1 wt group) and patients with UGT1A1*28 homozygous variant (*28/*28) as another group. Sixty patients were treated: 42 on the 28-day schedule and 18 on the 14-day schedule. Seven patients were homozygous variant (*28/*28). In the UGT1A1 wt group, the MTD and RP2D of IHL-305 was 160 mg/m2 every 28 days and 80 mg/m2 every 14 days. DLTs included nausea, vomiting, diarrhea, and neutropenia. The most common adverse events were nausea (75 %), vomiting (52 %), diarrhea (62 %), anorexia (57 %), and fatigue (57 %). At the MTD for both schedules, IHL-305 administration resulted in a high and prolonged exposure of sum total irinotecan, released irinotecan, and SN-38 in plasma. One partial response was observed in a patient with breast cancer and eight patients had stable disease for >6 months. IHL-305, a novel preparation of irinotecan encapsulated in liposomes, can be safely given to patients in a repeated fashion on a 4- or 2-week dosing schedule.

We have developed a novel and potent chemical series of 5,5-diphenylpentadienamides for targeting TRPV1 in vitro and in vivo. In this investigation, we examined a variety of replacements for the 5-position of dienamides with the goal of addressing issues related to pharmacokinetics. Our data suggest that substitution with alkoxy groups on the phenyl ring at the 5-position increases their ability to penetrate the blood-brain barrier. This investigation culminated in the discovery of compound (R)-36b, which showed a good pharmacokinetic profile. In vivo, compound (R)-36b was found to be effective at reversing mechanical allodynia in rats in a dose-dependent manner, and it reversed thermal hyperalgesia in a model of neuropathic pain induced by sciatic nerve injury.

Species differences in the pharmacokinetics of KW-7158 [(2S)-(+)-3,3,3-Trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide] were studied in in vivo and in vitro experiments. The exposure ratio of hydrolyzed metabolite (M2, primary metabolite in human plasma)/KW-7158 was higher than the ratio of thiophen-to-furan converted metabolite (M1)/KW-7158 in human subjects after oral administration, but the mouse, rat and dog studies gave opposite results. M2 was produced in the highest amount by the 9000g supernatant of small intestine, followed by that of liver and kidney in human subjects. After correction for protein contents, the results obtained suggested that the small intestine plays a major role in the metabolism to M2 for the first pass effect after oral administration of KW-7158. The formation of M2 was independent of the presence of NADPH and was inhibited by various esterase inhibitors. These observations suggested that the predominant enzymes or isozymes involved in the formation of M2 are esterases, which differ between humans and animals. Such differences may be one of the reasons for the species differences in the pharmacokinetics of KW-7158 between humans and animals.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure. To develop effective treatments for this devastating disease, an appropriate strategy for targeting the molecule responsible for the pathogenesis of ALS is needed. We previously reported that mutant SOD1 protein causes motor neuron death through activation of ASK1, a mitogen-activated protein kinase kinase kinase. Additionally, we recently developed K811 and K812, which are selective inhibitors for ASK1. Here, we report the effect of K811 and K812 in a mouse model of ALS (SOD1(G93A) transgenic mice). Oral administration of K811 or K812 significantly extended the life span of SOD1(G93A) transgenic mice (1.06 and 1.08% improvement in survival). Moreover, ASK1 activation observed in the lumbar spinal cord of mice at the disease progression stage was markedly decreased in the K811- and K812-treated groups. In parallel, immunohistochemical analysis revealed that K811 and K812 treatment inhibited glial activation in the lumbar spinal cord of SOD1(G93A) transgenic mice. These results reinforce the importance of ASK1 as a therapeutic target for ALS treatment.

Huali Wu,1 Jeffrey R Infante,2 Vicki L Keedy,3 Suzanne F Jones,2 Emily Chan,3 Johanna C Bendell,2 Wooin Lee,4 Whitney P Kirschbrown,1 Beth A Zamboni,5 Satoshi Ikeda,6 Hiroshi Kodaira,6 Mace L Rothenberg,3 Howard A Burris III,2 William C Zamboni1,7–9 1UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 2Sarah Cannon Research Institute/Tennessee Oncology, PLLC, 3Vanderbilt University, Nashville, TN, 4Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington,KY, 5Department of Mathematics, Carlow University, Pittsburgh, PA,USA; 6Yakult Honsha Co., Ltd., Medical Development Department, Tokyo, Japan; 7UNC Lineberger Comprehensive Cancer Center, 8UNCInstitute for Pharmacogenomics and Individualized Therapy, 9Carolina Center for Cancer Nanotechology Excellence, University of North Carolina, Chapel Hill, NC, USA Abstract: IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age and body composition (ratio of total body weight to ideal body weight [TBW/IBW]) were greater than the median age and TBW/IBW of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 area under the concentration versus time curve (AUC) to sum total CPT-11 AUC. Patients aged

Purpose: In this study, to optimize the polymeric drug delivery system for cancer chemotherapy, we developed a new pH-sensitive polymeric carrier, poly(vinylpyrrolidone-co-dimethylmaleic anhydride) [PVD], that could gradually release native form of drugs with full activity, from the conjugates in response to changes in pH. We examined the usefulness of PVD as a polymeric drug carrier. Experimental Design: PVD was radically synthesized with vinylpyrrolidone and 2,3-dimethylmaleic anhydride, which is known to be a pH-reversible amino-protecting reagent. Conjugates between PVD and other drugs, such as Adriamycin (ADR), were prepared under the slightly basic conditions (pH 8.5). The drug-release pattern and the antitumor activity of PVD were examined. Results: At pH 8.5, the release of the drugs from the conjugate was not observed. In contrast, PVD could release fully active drugs in the native form in response to the change in pH near neutrality, and gradually released drugs at neutral pH (7.0) and slightly acidic pH (6.0). The drug-release pattern in serum was almost similar to that observed during these physiological conditions. The PVD-conjugated ADR showed superior antitumor activity against sarcoma-180 solid tumor in mice, and it had less toxic side effects than free ADR. This enhancement in the antitumor therapeutic window may be due to not only the improvement of plasma half-lives and tumor accumulation of ADR, but also its controlled and sustained release from the conjugates in vivo. Conclusions: These results indicate that PVD is an effective polymeric carrier for optimizing cancer therapy.

For use in various applications in research on herpes simplex virus type 1, we attempted to generate recombinant HSV-1 expressing green fluorescent protein (GFP) without any loss of viral genes. Our results were as follows. (i) A recombinant HSV-1 (YK333), in which a GFP expression cassette driven by the Egr-1 promoter was inserted into the intergenic region between UL3 and UL4, was constructed. (ii) YK333 replicated as well as wild-type HSV-1 F strain in Vero cells. (iii) As one application of the recombinant YK333 for research on HSV-1, we developed a system to detect anti-herpetic activity, termed a fluorescence-based anti-viral assay. The 50% inhibitory concentration of ganciclovir for YK333 determined using our newly developed assay was comparable to that determined using a plaque reduction assay. YK333 will be a convenient tool for herpes simplex virus research, including such applications as monitoring of viral replication in vitro and in vivo, and rapid screening of potential anti-herpetic agents.

We report a rare case of phyllodes tumor of the breast in a juvenile patient with bloody nipple discharge. An 11 -year-old girl had a chief complaint of a palpable 5 cm well-circumscribed tumor with nipple discharge in the left breast. The histopathological diagnosis of the resected specimen was benign phyllodes tumor showing extensive areas of hemorrhagic necrosis. The bloody nipple discharge was caused by spontaneous infarction of the tumor. Preoperative ultrasonography and galactography were helpful in evaluating the mechanism of nipple dicharge from the tumor. Although phyllodes tumor must be differentiated from fibroadenoma, the present case was histopathologically identical to phyllodes tumor.

A comb-shaped polymeric modifier, SMA [poly(styrene comaleic anhydride)], which binds to plasma albumin in blood was used to modify the synthetic cell-adhesive laminin peptide YIGSR, and its inhibitory effect on experimental lung metastasis of B16-BL6 melanoma cells was examined. YIGSR was chemically conjugated with SMA via formation of an amide bond between the N-terminal amino group of YIGSR and the carboxyl anhydride of SMA. The antimetastatic effect of SMA-conjugated YIGSR was approximately 50-fold greater than that of native YIGSR. When injected intravenously, SMA-YIGSR showed a 10-fold longer plasma half-life than native YIGSR in vivo. In addition, SMA-YIGSR had the same binding affinity to plasma albumin as SMA, while native YIGSR did not bind to albumin. These findings suggested that the enhanced antimetastatic effect of SMA-YIGSR may be due to its prolonged plasma half-life by binding to plasma albumin, and that bioconjugation of in vivo unstable peptides with SMA may facilitate their therapeutic use.

Several cancer gene therapy strategies involve suicide genes to kill the neoplasm, or to regulate effector cells such as lymphocytes. We have developed an inducible apoptosis system with a Fas-estrogen receptor fusion protein (MfasER) for rapid elimination of transduced cells. In the present study, we further improved this molecular switch for estrogen-inducible apoptosis to overcome concerns with the wild-type estrogen receptor and its natural ligand, 17beta-estradiol (E2). The ligand-binding domain of MfasER was replaced with that of a mutant estrogen receptor which is unable to bind estrogen yet retains affinity for a synthetic ligand, 4-hydroxytamoxifen (Tm). The resultant fusion protein (MfasTmR) and MfasER were expressed in L929 cells for examination of their ligand specificities. Tm induced apoptosis in MfasTmR-expressing cells (L929MfasTmR) at 10(-8) M or higher concentrations, but induced no apoptosis in MfasER-expressing cells (L929MfasER) at up to 10(-6) M. On the other hand, E2 induced apoptosis in L929MfasER at concentrations as low as 10(-10)-10(-9) M, while it did so partially in L929MfasTmR at concentrations greater than 10(-7) M. Thus, L929MfasTmR cells were highly susceptible to Tm, but refractory to E2, with 100-1,000 times more tolerance than L929MfasER. These results suggest that the MfasTmR/Tm system would induce apoptosis in the target cells more safely in vivo, working independently of endogenous estrogen.

In order to achieve optimum drug delivery for clinical application, the bioconjugated drugs with polymeric modifiers must be designed to show desirable biopharmaceutical characteristics. Pharmacokinetics of bioconjugated drugs is greatly affected by physicochemical characteristics of polymeric modifiers themselves. Therefore, it is very important to study the relationships between pharmacokinetics of polymeric modifiers and their physicochemical properties typified with molecular weight, electric charge, and hydrophilic-lipophilic balance and so on. In the present study, we synthesized two anionized polyvinylpyrrolidone (PVP) by radical copolymerization between vinylpyrrolidone monomer and acrylic acid or vinylsulfonic acid co-monomer to assess the influence of anionic groups on pharmacokinetics of polymeric modifiers. The resulting anionized PVPs were eliminated from the circulation more rapidly than nonionic PVP. An increase of negative charge on polymeric modifier occurred a decrease of circulation life-time. In addition, though PVP showed no specific tissue distribution, anionized PVP was markedly accumulated to kidney at 3 hr after iv injection. These fundamental approach will enable to chose the optimum polymeric modifiers for features of drugs or for purposes of bioconjugation.

The objective of this study was to elucidate the range of abilities of nonclinical safety assessment for predicting adverse drug reactions (ADRs) in humans. The dataset included 1256 ADRs with an incidence rate of 5% or more collected from 142 drugs approved in Japan from 2001 to 2010 (excluding anticancer agents and vaccines). Gastrointestinal, neurological and hepatobiliary ADRs were relatively common, followed by hematological, cutaneous, systemic and cardiovascular ADRs in the dataset. The analysis revealed that 48% of ADRs were predictable based on a comprehensive nonclinical safety assessment considering animal toxicity. Hematological and ocular ADRs, infection, and application site reactions showed a correlation of more than 70%, while musculoskeletal, respiratory and neurological ADRs showed a correlation of less than 30%. In addition to subjective patient perceptions, several laboratory parameters routinely monitored both in animals and humans showed a lower correlation, e.g., abnormalities in hepatobiliary and metabolic parameters, and blood pressure increase. Large molecule drugs showed lower correlation than small molecule drugs; ADRs were observed in various organs and consideration of pharmacological action did not significantly contribute to the prediction. It was also confirmed that the current standard of toxicology testing regarding dosing duration and dose level is adequate to detect concordant animal toxicity. This study collectively demonstrated a significant value of nonclinical safety assessment in predicting ADRs in humans. It also identified the subset of ADRs with poor predictability, highlighting the need for advanced testing that enables successful translation of animal toxicity to clinical settings with better accuracy and sensitivity.

SummaryTo clarify the role of c-Mpl ligand (thrombopoietin: TPO) in liver cirrhosis (LC), we examined serum TPO levels (sTPO) in patients with LG (N = 44), chronic hepatitis (CH; N = 13) and healthy controls (N = 41) by an enzyme-linked immunosorbent assay. Although platelet counts of all LC patients (89 ± 59 × 109/1; mean ± SD) were lower than those of controls and CH patients, sTPO levels in LC patients (1.23 ± 0.51 fmol/ml) were the same as those in controls (1.22 ± 0.37) and CH patients (1.18 ± 0.36). Platelet counts were significantly higher in splenectomized patients than in unsplenectomized patients, but the sTPO level did not differ between these two groups. In LC patients, the sTPO level was not correlated with the platelet count, but was correlated with prothrombin time, activated partial thromboplastin time, and total bilirubin, indicating that production of TPO in the liver decreases slightly with the development of liver dysfunction. Our findings suggest that production of TPO is maintained in LC patients and their thrombocytopenia is not due to a defect in platelet production.

We experienced a case of Sipple's syndrome which was suggestive of familial occurorence. A 27-year-old man was admitted to the hospital because of hypertention and palpitation. He had been aware of palpitation in the morning since the age of about 17 and was under treatment of diabetes on an ambulant base for about 5 years. Examinations showed increases in the values of serum adrenalin, noradrenalin, calcitonin and urine catecholamine. Ultrasonogram and CT scan revealed a 4.1×3.2cm mass in the right adrenal gland and a 1.3×7cm mass in the left thyroid. A diagnosis of Sipple's syndrome was made and right adrenalectomy for the adrenal tumor and left hemithyroidectomy with modified neck dissection were performed. Histological examination revealed benign pheochromocytoma in the adrenal gland and medullary carcinoma of the thyroid. His postoperative course was uneventful and currently he is under routine check-up. Blood examination of his family members revealed elevations in serum calcitonin and CEA levels for his brother and sister and medullary carcinoma of the thyroid was detected in both of them. Since Sipple's syndrome is a hereditary autosomal dominant disease, it is mandotory to follow up the family periodically by routine blood examinations including serum CEA and calcitonin.

This study investigated the impact of the active efflux mediated by P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) at the blood-brain barrier (BBB) on the predictability of the unbound brain concentration (C(u,brain)) by the concentration in the cerebrospinal fluid (CSF) (C(u,CSF)) in rats. C(u,brain) is obtained as the product of the total brain concentration and unbound fraction in the brain (f(u,brain)) determined in vitro in brain slices. Twenty-five compounds, including P-gp and/or Bcrp substrates, were given a constant intravenous infusion, and their plasma, brain, and CSF concentrations were determined. P-gp and/or Bcrp substrates, such as verapamil, loperamide, flavopiridol, genistein, quinidine, dantrolene, daidzein, cimetidine, and pefloxacin, showed a higher CSF-to-brain unbound concentration ratio (K(p,uu,CSF/brain)) compared with non-P-gp and non-Bcrp substrates. K(p,uu,CSF/brain) values of P-gp-specific (quinidine and verapamil) and Bcrp-specific (daidzein and genistein) substrates were significantly decreased in Mdr1a/1b(-/-) and Bcrp(-/-) mice, respectively. Furthermore, consistent with the contribution of P-gp and Bcrp to the net efflux at the BBB, K(p,uu,CSF/brain) values of the common substrates (flavopiridol and erlotinib) were markedly decreased in Mdr1a/1b(-/-)/Bcrp(-/-) mice, but only moderately or weakly in Mdr1a/1b(-/-) mice and negligibly in Bcrp(-/-) mice. In conclusion, predictability of C(u,brain) by C(u,CSF) decreases along with the net transport activities by P-gp and Bcrp at the BBB. C(u,CSF) of non-P-gp and non-Bcrp substrates can be a reliable surrogate of C(u,brain) for lipophilic compounds.

The antitumor effect of IHL-305, a novel pegylated liposome containing irinotecan, was investigated in human xenograft models. After subcutaneous transplantation of several human cancer cell lines (colorectal, non-small cell lung, small cell lung, prostate, ovarian and gastric cancer cells) to nude mice, IHL-305 or CPT-11 was administered intravenously 3 times at 4-day intervals. In all xenograft models tested, IHL-305 showed superior antitumor activity to that of CPT‑11 and a comparable tumor-growth-inhibitory effect at one-eighth or less of the dose of CPT-11, even against HT-29 colorectal and NCI-H460 non-small cell lung cancer cell lines, which show intrinsic resistance to CPT-11. A single injection or 2 injections of IHL-305 on several dosing schedules also resulted in a significant antitumor effect compared to that of vehicle control in a dose-dependent manner and showed comparable antitumor activity at about one-fifth the dose of the maximum tolerated dose of CPT-11. The analysis of the concentrations of irinotecan and SN-38, an active metabolite of CPT-11, in plasma and tumors revealed that irinotecan was maintained at high concentrations, and the prolonged presence of SN-38 in plasma and tumors in IHL-305 treated mice compared with CPT-11-treated mice. Therefore, the stronger tumor inhibitory effect of IHL-305, as compared to CPT-11, was associated with the difference in the concentration of irinotecan in plasma or tumors after each agent was administered and with the maintainance of a higher concentration of SN-38. These results indicate that IHL-305 demonstrated superior antitumor activity against a wide range of tumors at lower doses than CPT-11.

Breast cancer resistance protein (BCRP/ABCG2) confers resistance to anticancer drugs such as 7-ethyl-10-hydroxycamptothecin (SN-38, an active metabolite of irinotecan), mitoxantrone, and topotecan. In this study, we examined the reversing effects of YHO-13177, a novel acrylonitrile derivative, and its water-soluble diethylaminoacetate prodrug YHO-13351 on the BCRP-mediated drug resistance. YHO-13177 potentiated the cytotoxicity of SN-38, mitoxantrone, and topotecan in both BCRP-transduced human colon cancer HCT116 (HCT116/BCRP) cells and SN-38–resistant human lung cancer A549 (A549/SN4) cells that express BCRP, but had little effect in the parental cells. In addition, YHO-13177 potentiated the cytotoxicity of SN-38 in human lung cancer NCI-H460 and NCI-H23, myeloma RPMI-8226, and pancreatic cancer AsPC-1 cells that intrinsically expressed BCRP. In contrast, it had no effect on P-glycoprotein–mediated paclitaxel resistance in MDR1-transduced human leukemia K562 cells and multidrug resistance-related protein 1–mediated doxorubicin resistance in MRP1-transfected human epidermoid cancer KB-3-1 cells. YHO-13177 increased the intracellular accumulation of Hoechst 33342, a substrate of BCRP, at 30 minutes and partially suppressed the expression of BCRP protein at more than 24 hours after its treatment in both HCT116/BCRP and A549/SN4 cells. In mice, YHO-13351 was rapidly converted into YHO-13177 after its oral or intravenous administration. Coadministration of irinotecan with YHO-13351 significantly increased the survival time of mice inoculated with BCRP-transduced murine leukemia P388 cells and suppressed the tumor growth in an HCT116/BCRP xenograft model, whereas irinotecan alone had little effect in these tumor models. These findings suggest that YHO-13351, a prodrug of YHO-13177, could be clinically useful for reversing BCRP-mediated drug resistance in cancer chemotherapy. Mol Cancer Ther; 10(7); 1252–63. ©2011 AACR.

A synergistic effect of P-glycoprotein (P-gp)/Abcb1a and breast cancer resistance protein (Bcrp)/Abcg2 was reported to limit the brain penetration of their common substrates. This study investigated this based on pharmacokinetics using Mdr1a/1b(-/-), Bcrp(-/-), and Mdr1a/1b(-/-)/Bcrp(-/-) mice. Comparison of the brain- and testis-to-plasma ratios (C(brain)/C(plasma) and C(testis)/C(plasma), respectively) of the reference compounds quinidine and dantrolene for P-gp and Bcrp, respectively, indicates that impairment of either P-gp and Bcrp did not cause any change in the efflux activities of Bcrp or P-gp, respectively, at both the blood-brain barrier (BBB) and blood-testis barrier (BTB). The C(brain)/C(plasma) and C(testis)/C(plasma) of the common substrates erlotinib, flavopiridol, and mitoxantrone were markedly increased in Mdr1a/1b(-/-)/Bcrp(-/-) mice even compared with Mdr1a/1b(-/-) and Bcrp(-/-) mice. Efflux activities by P-gp and Bcrp relative to passive diffusion at the BBB and BTB were separately evaluated based on the C(brain)/C(plasma) and C(testis)/C(plasma) in the knockout strains to the wild-type strain. P-gp made a larger contribution than Bcrp to the net efflux of the common substrates, but Bcrp activities were also significantly larger than passive diffusion. These parameters could reasonably account for the marked increase in C(brain)/C(plasma) and C(testis)/C(plasma) in the Mdr1a/1b(-/-)/Bcrp(-/-) mice. In conclusion, the synergistic effect of P-gp and Bcrp on C(brain)/C(plasma) and C(testis)/C(plasma) can be explained by their contribution to the net efflux at the BBB and BTB without any interaction between P-gp and Bcrp.

子宮内膜妊娠様変化, 特にArias-Stella reactionの細胞像を検索するために, 子宮内膜吸引細胞診と内膜全掻爬術を行い, 病理学的にArias-Stella reactionの診断がついた, 妊娠2ヵ月遷延流産2例 (過分泌型1, 再生増殖型1), 侵入奇胎1例 (再生増殖型), 右卵管の絨毛癌1例 (過分泌型) の子宮内膜細胞像を検討し, 以下の細胞学的所見を得た.(1) 核は大型核である.(2) 核型は円, 卵円形が多いが, 不整形や陥入像を有するものまである.(3) 核内所見は, 核膜に溝やしわをもち, 大小不同を認めるが, 核膜肥厚がなく, クロマチン顆粒が微細顆粒状で, 核小体のめだたない軽度異型をもつもの (過分泌型, 再生増殖型) から, 核膜肥厚, 明瞭な核小体を認め, クロマチン顆粒の増量のある悪性細胞と鑑別が必要な高度異型をもつもの (再生増殖型) まで出現する.(4) 細胞質は豊富でシート状または蜂巣状である.また, 軽度重積を示すものも認められるが, 細胞質境界明瞭なモザイク配列を示す.(5) 過分泌型では, 背景に赤色粘液顆粒が豊富にある.

We have developed a system to analyze the specific protein kinase activity of herpes simplex virus 1 Us3 in vitro and shown that Us3 directly phosphorylates viral proteins UL34, ICP22, and Us9 and the cellular protein Bad, previously reported to be putative substrates. Using this system, we determined the phosphorylation sites of UL34 and identified UL31 as a previously unreported, novel substrate of Us3. This system will be useful for further identification of Us3 substrates and their phosphorylation sites, clarification of the role of Us3 in viral replication, and identification of additional Us3 function(s).

SummaryPlatelet membrane glycoprotein Iba has at least two polymorphisms which affect phenotype. One is the dimorphism at codon 145, and the other is a molecular weight polymorphism due to variable numbers of tandem repeats (TR) in the macroglycopeptide region. These two polymorphisms are in linkage disequilibrium. The frequencies of these polymorphisms differ considerably depending on race, and the largest variant with four TR is almost exclusively present in the Japanese population. We examined the genotypes of HPA-2 and TR polymorphism in three different races from Eastern Asia; the Japanese (n = 103), Korean (n = 101) and Chinese population (n = 177). The gene frequency of HPA-2 differed significantly among these three populations. Among HPA-2b-positive individuals, the A isoform with four TR and B with three TR were present in all three populations and A dominated over B. Individuals homozygous for the A isoform were found in both Japanese and Korean populations. These findings indicate that the largest haplotype is common in the Eastern Asian region.

We describe a patient with eosinophilia and an abnormal CD3 + 4 - 8 - αβ + T-cell population. Chromosomal analysis of sorted CD3 + 4 - 8 - cells revealed abnormal karyotypes on chromosome 16. In the presence of IL-2 the production of IL-5 from CD3 + 4 - 8 - cells was higher than that from CD3 + 4 + /8 + cells. Eosinophil survival-enhancing activity in the patient serum was inhibited by a combination of anti-IL-5 and anti-GM-CSF monoclonal antibodies. These data suggest that increased production of IL-5 and GM-CSF from the abnormal CD3 + 4 - 8 - cells might cause eosinophilia.

We reported that the co-polymer composed of vinylpyrrolidone and maleic acid selectively distributed into the kidneys after i.v. injection. To further optimize the renal drug delivery system, we assessed the renal targeting capability of anionized polyvinylpyrrolidone (PVP) derivatives after intravenous administration in mice. The elimination of anionized PVP derivatives from the blood decreased with increasing anionic groups, and the clearance of carboxylated PVP and sulfonated PVP from the blood was almost similar. But carboxylated PVP efficiently accumulated in the kidney, whereas sulfonated PVP was rapidly excreted in the urine. The renal levels of carboxylated PVP were about five-fold higher than sulfonated PVP. Additionally, carboxylated PVP was effectively taken up by the renal proximal tubular epithelial cells in vivo after i.v. injection. These anionized PVP derivatives did not show any cytotoxicity against renal tubular cells and endothelial cells in vitro. Thus, these carboxylated and sulfonated PVPs may be useful polymeric carriers for drug delivery to the kidney and bladder, respectively.

To achieve an optimum drug delivery such as targeting or controlled release utilizing bioconjugation with polymeric modifier, the conjugate between drugs and polymeric modifiers must be designed to show desirable pharmacokinetic characteristics in vivo. In this study, we assessed the biopharmaceutical properties of various nonionic water-soluble polymers as polymeric drug carriers. Polyvinylpyrrolidone (PVP) showed the longest mean resident time (MRT) after i.v. injection of all nonionic polymers with the same molecular size. In fact, tumor necrosis factor- α (TNF- α ) bioconjugated with PVP (PVP-TNF- α ) circulated longer than TNF- α bioconjugated with polyethylene glycol (PEG-TNF- α ) with the same molecular size. Each nonionic polymeric modifier showed a different tissue distribution. Dextran was accumulated in the spleen and liver. Polydimethylacrylamide (PDAAm) tended to distribute in the kidney. However, PVP showed the minimum volume of tissue distribution. These results suggested that PVP is the most suitable polymeric modifier for prolonging the circulation lifetime of a drug and localizing the conjugated drug in blood.

Background: Accumulating evidence reveals effectiveness of histone deacetylase (HDAC) inhibition in various types of cancer, and resminostat is a novel and oral HDAC inhibitor. In this study, we investigated the preclinical activity of resminostat in human non-small-cell lung cancer (NSCLC) cells, especially in combination with docetaxel (DTX). Materials and Methods: Anti-proliferative activity of resminostat was evaluated in 9 human NSCLC cell lines in vitro. Monolayers of cultured cells were exposed to resminostat and cell viability was determined. The amount of p21, acetylated histone H3 and α-tublin were analyzed by Western blotting in NCI-H460 cells exposed to resminostat. In addition, caspase-3 activity was measured. In a drug combination study, cells were simultaneously exposed to resminostat and DTX, and the synergistic effects of this drug combination were analyzed using the Combination Index, calculated by the median-effect method. For in vivo studies, a suspension of NCI-H460 cells was subcutaneously inoculated into the flank of male nude mice. The antitumor efficacies of oral resminostat alone or in combination with intravenous DTX were evaluated in this NSCLC xenograft model. Results: Resminostat exhibited antiproliferative activity in all tested cell lines. Sensitivity to resminostat was not influenced by the genetic status of KRAS among the cell lines (IC50 from 9 cell lines: 0.4-8.7 μmol/L). The treatment of cells with resminostat alone increased the levels of total p21 protein and acetylated histone H3. α-tublin was also acetylated by resminostat treatment and the level of acetylation was enhanced by the combination treatment with DTX. The amount of polymerized α-tubulin was increased by DTX treatment and this effect was greater in the combination treatment with resminostat than with DTX alone. Caspase-3 was more significantly activated by the combination treatment than with each mono-treatment. The Combination Index showed synergistic or additive effects in the resminostat plus DTX combination. The antitumor activities of resminostat were demonstrated in NCI-H460 tumor-bearing mice, where an up-regulation of p21 was accompanied by acetylation of histone H3 in the tumor tissues. The tumor growth inhibition ratio (IR) in the combination treatment was 2.6 and 1.8 times higher than with DTX alone or with resminostat alone, respectively, following a tolerable drug application schedule. Conclusion: These results demonstrated the potent activity of resminostat in NSCLC. The combination of resminostat and DTX appears to be a promising regimen to be tested in clinical trials in NSCLC patients. Based on this study, we initiated a phase I/II study in NSCLC patients to examine the safety and efficacy of this combination. Citation Format: Akimitsu Takagi, Hiroaki Konishi, Momomi Tsugane, Keisuke Taniguchi, Hiroyuki Takahashi, Yu Inutake, Akinobu Watanabe, Hiroshi Kodaira, Takeshi Matsuzaki. A novel and oral histone deacetylase inhibitor, resminostat, effectively suppresses the growth of non-small cell lung cancer in a xenograft mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5534. doi:10.1158/1538-7445.AM2014-5534

Background We have developed a novel system for expansion of gene-modified hematopoietic stem/progenitor cells to overcome the low efficiency of current gene transfer methodology. This system involves ‘selective amplifier genes’, that encode fusion proteins between the granulocyte colony-stimulating factor receptor (GCR) and the hormone-binding domain of estrogen receptor (ER). Hematopoietic progenitors expressing the chimeras showed estrogen-responsive growth in a controllable manner. However, endogenous estrogen may activate the fusion proteins in vivo, depending on the hormonal status of the subjects. Methods We replaced ER with a mutant receptor (TmR) which specifically binds to 4-hydroxytamoxifen (Tm), to overcome limitations with wild-type ER. Interleukin-3 (IL-3)-dependent Ba/F3 cells and hematopoietic progenitor cells transduced with the resultant fusion proteins (GCRTmR and ΔGCRTmR) were examined for ligand-inducible growth. Results GCRTmR- and ΔGCRTmR-expressing Ba/F3 showed IL-3-independent growth in response to Tm, while the cells were unresponsive to estrogen at concentrations up to 10−7–10−6 M. Furthermore, murine bone marrow cells transduced with GCRTmR and ΔGCRTmR formed colonies in methylcellulose medium in response to Tm, while virtually no colonies appeared with 10−7 M estrogen or without cytokines. Conclusions These results suggest that influences of the endogenous estrogen can be almost eliminated by using the GCRTmR/Tm or ΔGCRTmR/Tm system to expand gene-modified hematopoietic stem/progenitor cells. Copyright © 1999 John Wiley & Sons, Ltd.

Polyvinyl pyrrolidone (PVP) which can be radically synthesized and have a long blood residency was used to modify the laminin-related peptide YIGSR, and its inhibitory effect on experimental lung metastasis of B16-BL6 melanoma cells was examined. The antimetastatic effect of PVP-conjugated YIGSR (PVP-YIGSR) was more than 100-fold greater than that of native YIGSR. When injected intravenously, PVP-YIGSR showed more than a 15-fold longer plasma half-life relative to native YIGSR. In addition, the stability of YIGSR in plasma was increased by conjugation with PVP. These findings suggest that PVP is a useful polymeric modifier for increasing the antimetastatic activity of YIGSR.

We investigated the prevalence of the factor V (FV) Arg 506 Gin mutation in healthy subjects from three eastern Asian countries (Japan, n = 270; China, n = 113; and Korea, n = 93) and in 26 Japanese patients showing venous thromboembolic events. The patients were also examined for activated protein C (APC) resistance by using the Coatest® APC resistance kit. The FV mutation was investigated by polymerase chain reaction and restricted enzyme digestion with MnlIRFLP assay of the FV gene. None of the patients showed APC resistance, while all subjects examined were homozygous for Arg at position 506 of the FV gene. Our results imply that FV mutation and APC resistance contribute little to venous thrombotic diseases in eastern Asia.

Background: Perifosine is an oral anticancer compound that inhibits the PH-domain of AKT, which is frequently activated in human cancers including gastric cancer. In this study, the mode of action of perifosine, especially in association with mTOR, and the antitumor activity in combination with paclitaxel were examined in human gastric cancer cell lines. Materials and Methods: The following human gastric cancer cell lines were used in this study: MKN1, MKN45, MKN74, AGS, and NCI-N87. Monolayers of cultured cells were exposed to perifosine for 48 hours and the antiproliferative activity was measured. The phosphorylated (p-)AKT status and its downstream molecules (e.g., PRAS40, TSC2, mTOR, 4E-BP1, and p70S6K) were analyzed using immunoblotting. In perifosine-treated cells, the induction of autophagy-like cell death was detected using LC3. With or without perifosine, the p-AKT (S473) levels were examined in rapamycin-treated cells. In a drug combination study, perifosine was used in combination with paclitaxel, and the synergistic effects of these drugs were quantified using the median-effect method to estimate the Combination Index. The antitumor efficacy of daily oral perifosine alone or in combination with intravenous paclitaxel was evaluated at various doses for 4 weeks in xenografted mice. The tumors at the time of necropsy were immunohistochemically examined for TUNEL, Ki-67 and AKT signal-related molecules. Results: Perifosine exhibited antiproliferative activity in the tested cell lines (GI50: 4.7-18.0 μmol/L), reducing p-AKT. The perifosine-induced inhibition of phosphorylation was also seen in molecules downstream of AKT, such as PRAS40, mTOR, and p70S6K. Perifosine also induced autophagy-like cell death, observed as the induction of type II LC3 along with cleaved PARP. The phosphorylation of AKT (S473) was induced by rapamycin treatment. While this phosphorylation was not induced by perifosine, the rapamycin-dependent phosphorylation of AKT was inhibited by perifosine. The Combination Index showed synergistic or additive effects when perifosine was used in combination with paclitaxel. The antitumor activities of perifosine were demonstrated in a dose-dependent manner in the 3 cell lines tested in mice. When perifosine was administered with paclitaxel to NCI-N87 cells in mice, the inhibitory ratio of the tumor increased to 78.8% from 61.7% for perifosine monotherapy and from 50.0% for paclitaxel monotherapy. The population of TUNEL-positive cells was higher in the combination therapy group than in the monotherapy group in the tumor tissues. This combination decreased the number of positive cells with Ki-67 and AKT signal molecules in the tissue. Conclusion: These results demonstrated that perifosine downregulates the mTOR function. The combination of perifosine and paclitaxel appears to be a promising regimen for the treatment of gastric cancer. Citation Format: Akimitsu Takagi, Momomi Tsugane, Hiroaki Konishi, Satoru Ishii, Ken-ichi Sata, Hiroshi Kodaira, Takeshi Matsuzaki. Perifosine, an AKT inhibitor, downregulates mTOR function and suppresses the growth of human gastric cancer cells in mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3994. doi:10.1158/1538-7445.AM2013-3994

Background: Irinotecan (CPT-11) is a prodrug of SN-38 that has antitumor activity in a wide range of solid tumors. IHL-305 is a PEGylated-liposomal formulation of CPT-11. The PK of liposomal agents is highly complex due to the variability in the disposition of the inactive-encapsulated drug and the release of active-drug from the liposome. We previously reported that age, body weight, and monocytes affect the PK and PD of PEGylated liposomal agents. Thus, we evaluated the effect of these factors on the PK and PD of IHL-305 as part of a phase I study. Methods: IHL-305 was administered IV over 1 h at 3.5, 7, 10.5, 14, 28, 33.5, 37, 50, 67, 80, 88, 120, 160, and 210 mg/m2 q 28 d. Serial plasma samples were obtained prior to infusion, at the end of infusion (EOI), and from 1 to 192 h after EOI. Plasma samples were processed to measure sum total (encapsulated + released) CPT-11, released CPT-11, SN-38 and SN-38 glucuronide (SN-38G). The total (lactone + hydroxy acid) forms were measured by HPLC. The area under the plasma concentration versus time curve (AUC) for each form was calculated from 0 to last sampling time and from 0 to ∞. The ratio of total body weight to ideal body weight (TBW/IBW) was calculated. Results: 39 patients (pts) (13 male) were treated. Median (range) of age and TBW/IBW were 60 years old (yo) (42–75 yo) and 1.16 (0.81–2.7), respectively. There was high inter-patient variability in the PK disposition of sum total CPT-11, released CPT-11, SN-38 and SN-38G. Sum total CPT-11 is associated with linear and non-linear clearance. The ratio of SN-38 to released CPT-11 and SN-38G to SN-38 were similar to those reported after irinotecan. Pts whose age and TBW/IBW were greater than the median of the study had a 1.7- to 2.6-fold higher ratio of released CPT-11 AUC to sum total CPT-11 AUC. In pts < 60 yo and in pts ≥ 60 yo, the ratio of % decrease in monocytes at nadir to % decrease in ANC at nadir were 1.65 ± 1.36 and 1.24 ± 0.68, respectively. There was an inverse relationship between pts age and % decrease in monocytes at nadir with younger pts having a higher % decrease in monocytes. Pts with a higher % decrease in monocytes at nadir have an increased clearance of sum total CPT-11 and increased exposure of released CPT-11 and ratio of released CPT-11 AUC to sum total CPT-11 AUC. Conclusions: PK and PD of IHL-305 are consistent with a PEGylated-liposomal carrier. IHL-305 has pharmacological advantages compared with irinotecan. The inter-patient variability in the PK and PD of IHL-305 was associated with age, body composition, and monocytes. Sponsored by Yakult Honsha Co., Ltd., Tokyo, Japan Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C127.

To optimize polymer-conjugated drugs as a polymeric drug delivery system, it is essential to design polymeric carriers with tissue-specific targeting capacity. Previously, we showed that polyvinylpyrrolidone (PVP) was the most suitable polymeric carrier for prolonging the blood-residency of drugs, and was one of the best parent polymers to design the polymeric carriers with targeting capacity. In this study, we synthesized some hydrophobic PVP derivatives, poly(vinylpyrrolidone-co-styrene) [poly(VP-co-S)] and poly(vinylpyrrolidone-co-vinyl laurate) [poly(VP-co-VL)], and assessed their biopharmaceutical properties after intravenous administration in mice. The elimination of hydrophobic PVP derivatives from blood was the same as PVP, and the plasma half-lives of poly(VP-co-S) were almost similar to that of poly(VP-co-VL). Poly(VP-co-VL) efficiently accumulated in the spleen, whereas poly(VP-co-S) effectively accumulated in the liver. The level of poly(VP-co-VL) in the spleen was about 20 times higher than PVP and poly(VP-co-S). These hydrophobic PVP derivatives did not show any cytotoxicity against endothelial cells in vitro. Thus, poly(VP-co-VL) may be a useful polymeric carrier for drug delivery to the spleen. This study will provide useful information to design optimal polymeric carriers with targeting capacity to the spleen and liver.