Breast cancer surgery in patients with schizophrenia: short-term outcomes from a nationwide cohort.

BACKGROUND: Although patients with schizophrenia have a higher risk of developing breast cancer than the general population, studies that have investigated postoperative complications after breast cancer surgery in patients with schizophrenia are scarce. This study examined associations between schizophrenia and short-term outcomes following breast cancer surgery. METHODS: Patients who underwent surgery for stage 0-III breast cancer between July 2010 and March 2017 were identified from a Japanese nationwide inpatient database. Multivariable analyses were conducted to compare postoperative complications and hospitalization costs between patients with schizophrenia and those without any psychiatric disorder. Three sensitivity analyses were performed: a 1 : 4 matched-pair cohort analysis with matching for age, institution, and fiscal year at admission; analyses excluding patients with schizophrenia who were not taking antipsychotic medication; and analyses excluding patients with schizophrenia who were admitted to hospital involuntarily. RESULTS: The study included 3660 patients with schizophrenia and 350 860 without any psychiatric disorder. Patients with schizophrenia had a higher in-hospital morbidity (odds ratio (OR) 1.37, 95 per cent c.i. 1.21 to 1.55), with more postoperative bleeding (OR 1.34, 1.05 to 1.71) surgical-site infections (OR 1.22, 1.04 to 1.43), and sepsis (OR 1.20, 1.03 to 1.41). The total cost of hospitalization (coefficient €743, 95 per cent c.i. 680 to 806) was higher than that for patients without any psychiatric disorder. All sensitivity analyses showed similar results to the main analyses. CONCLUSION: Although causal inferences remain premature, multivariable regression analyses showed that schizophrenia was associated with greater in-hospital morbidity and higher total cost of hospitalization after breast cancer surgery than in the general population.

The Double Burden of COVID-19 and Dengue in Nepal: The challenges ahead.

Coronavirus disease 2019 (COVID-19) pandemic has caused significant impact on the health care system. As a consequence, diagnosis and treatment of vector borne diseases including dengue has been equally affected. Nepal is no exception to this, where COVID-19 cases is exponentially increased and all resources are concentrated on its prevention, control and management. Dengue, one of the major vector-borne diseases in Nepal, is apparently overlooked despite approaching the peak season of the disease. The aim of this paper is to describe the double burden of COVID-19 and dengue in Nepal, particularly highlighting the co-circulation and possible coinfections. This has posed higher risk of increased severity, more severe cases and deaths in Nepal. Moreover, potential misdiagnosis of these viral diseases may lead to delayed or, inappropriate treatment and poor allocation of resources.

Study of Quasielastic Barrier Distributions as a Step towards the Synthesis of Superheavy Elements with Hot Fusion Reactions.

The excitation functions for quasielastic scattering of ^{22}Ne+^{248}Cm, ^{26}Mg+^{248}Cm, and ^{48}Ca+^{238}U are measured using a gas-filled recoil ion separator. The quasielastic barrier distributions are extracted for these systems and are compared with coupled-channel calculations. The results indicate that the barrier distribution is affected dominantly by deformation of the actinide target nuclei, but also by vibrational or rotational excitations of the projectile nuclei, as well as neutron transfer processes before capture. From a comparison between the experimental barrier distributions and the evaporation residue cross sections for Sg (Z=106), Hs (108), Cn (112), and Lv (116), it is suggested that the hot fusion reactions take advantage of a compact collision, where the projectile approaches along the short axis of a prolately deformed nucleus. A new method is proposed to estimate the optimum incident energy to synthesize unknown superheavy nuclei using the barrier distribution.

Image quality and radiation dose of renal perfusion CT with low-dose contrast agent: a comparison with conventional CT using a 320-row system.

AIM: To compare perfusion computed tomography (CT) with reconstructed image from source data using low-dose contrast agent and conventional 320-row CT for the evaluation of renal tumours. MATERIALS AND METHODS: Twenty-eight patients underwent conventional CT (C-CT) and 26 patients underwent perfusion CT with low-dose (40 ml) contrast agent. Image noise, arterial visualisation, the sharpness of the corticomedullary junction (CMJ), and overall image quality were each assessed using a four-point scale. The tumour detection rate for lesions <4 cm (n=66) was also evaluated. Quantitative image parameters including image noise and the contrast-to-noise ratios (CNRs) of the renal artery and CMJ were measured. The volume CT dose index (CTDI), dose-length product (DLP), and size-specific dose estimate (SSDE) were also recorded. RESULTS: Although the image noise of perfusion CT was higher than that of C-CT and the overall image quality of perfusion CT was lower than that of C-CT, the arterial visualisation score of perfusion CT was significantly higher than that of C-CT. The CMJ sharpness scores of the two techniques were equivalent. Sensitivity and positive predictive values were also equivalent with respect to tumour detection. The CNRs of both the left and right renal arteries were significantly higher on perfusion CT than on C-CT. The CTDI, DLP, and SSDE of perfusion CT were significantly lower than those of C-CT. CONCLUSION: Perfusion CT using low-dose contrast agent preserved arterial visualisation and the tumour detection rate and achieved a low radiation dose despite image quality degradation and image noise.

Oral function and vertical jump height among healthy older people in Japan.

OBJECTIVE: Vertical jump height and oral function affect the general muscle condition. This study aimed to evaluate the association between vertical jump height and oral function among healthy older individuals. BASIC RESEARCH DESIGN: Cross-sectional analytic study. PARTICIPANTS: 231 independent older people (mean age, 74.4 ± 5.6 years) who participated in the Kyoto Elders Physical Fitness Measurement Research Project. Individuals with partial or complete edentulousness who did not use a prosthetic device or complained of oral/maxillofacial pain were excluded from the study. INTERVENTIONS: Grip strength was measured using a Smedley Hand Dynamometer. To measure masticatory performance, the participants were instructed to chew a gummy jelly on their habitual chewing side (left or right) for 20 s. Occlusal force, contact area, and pressure were also assessed. MAIN OUTCOME MEASURES: The outcome variable was vertical jump height. The predictor variables were physical status (age, body mass index, and grip strength), oral status (number of present teeth and denture use), and oral function (masticatory performance, occlusal force, occlusal contact area, occlusal pressure, and tongue pressure). These relationships were evaluated with univariate analysis, and then multiple regression analysis was performed with age as the covariate for each male and female participant. RESULTS: Vertical jump height was significantly associated with grip strength in both men and women. Moreover, in women, it was associated with masticatory performance, occlusal force, and occlusal contact area. CONCLUSIONS: Vertical jump height was closely associated with oral function among healthy older women.

Preoperative oral care and effect on postoperative complications after major cancer surgery.

BACKGROUND: Improving patients' oral hygiene is an option for preventing postoperative pneumonia that may be caused by aspiration of oral and pharyngeal secretions. Whether preoperative oral care by a dentist can decrease postoperative complications remains controversial. A retrospective cohort study was undertaken to assess the association between preoperative oral care and postoperative complications among patients who underwent major cancer surgery. METHODS: The nationwide administrative claims database in Japan was analysed. Patients were identified who underwent resection of head and neck, oesophageal, gastric, colorectal, lung or liver cancer between May 2012 and December 2015. The primary outcomes were postoperative pneumonia and all-cause mortality within 30 days of surgery. Patient background was adjusted for with inverse probability of treatment weighting using propensity scoring. RESULTS: Of 509 179 patients studied, 81 632 (16·0 per cent) received preoperative oral care from a dentist. A total of 15 724 patients (3·09 per cent) had postoperative pneumonia and 1734 (0·34 per cent) died within 30 days of surgery. After adjustment for potential confounding factors, preoperative oral care by a dentist was significantly associated with a decrease in postoperative pneumonia (3·28 versus 3·76 per cent; risk difference - 0·48 (95 per cent c.i. -0·64 to-0·32) per cent) and all-cause mortality within 30 days of surgery (0·30 versus 0·42 per cent; risk difference - 0·12 (-0·17 to -0·07) per cent). CONCLUSION: Preoperative oral care by a dentist significantly reduced postoperative complications in patients who underwent cancer surgery.

First Direct Mass Measurements of Nuclides around Z=100 with a Multireflection Time-of-Flight Mass Spectrograph.

The masses of ^{246}Es, ^{251}Fm, and the transfermium nuclei ^{249-252}Md and ^{254}No, produced by hot- and cold-fusion reactions, in the vicinity of the deformed N=152 neutron shell closure, have been directly measured using a multireflection time-of-flight mass spectrograph. The masses of ^{246}Es and ^{249,250,252}Md were measured for the first time. Using the masses of ^{249,250}Md as anchor points for α decay chains, the masses of heavier nuclei, up to ^{261}Bh and ^{266}Mt, were determined. These new masses were compared with theoretical global mass models and demonstrated to be in good agreement with macroscopic-microscopic models in this region. The empirical shell gap parameter δ_{2n} derived from three isotopic masses was updated with the new masses and corroborates the existence of the deformed N=152 neutron shell closure for Md and Lr.

Impact of renal transplantation on glucose tolerance in Japanese recipients with impaired glucose tolerance.

AIMS: To investigate changes in glucose tolerance, insulin secretion and insulin sensitivity in Japanese recipients before and 1 year after renal transplantation. METHODS: We conducted a study of Japanese recipients without diabetes who underwent renal transplantation at Hokkaido University Hospital. A 75-g oral glucose tolerance test was performed before and 1 year after renal transplantation in these recipients. Insulin sensitivity was estimated using the Matsuda index and homeostasis model assessment of insulin resistance (HOMA-IR). Insulin secretion was evaluated based on the insulin secretion sensitivity index-2 (ISSI-2). RESULTS: Of the 62 renal transplant recipients, 31 were diagnosed as having impaired glucose tolerance before transplantation. Among these 31 recipients, after 1 year, four had developed new-onset diabetes after transplantation, and nine had impaired glucose tolerance. Unexpectedly, 18 changed from impaired to normal glucose tolerance. When these recipients with impaired glucose tolerance were classified into a non-amelioration group and an amelioration group, the ISSI-2 was significantly reduced, with no significant changes in the Matsuda index or HOMA-IR, in the non-amelioration group 1 year after renal transplantation. By contrast, ISSI-2 and Matsuda index values were significantly increased, with no significant changes in HOMA-IR values in the amelioration group. CONCLUSIONS: More than half of Japanese renal transplant recipients with impaired glucose tolerance had normal glucose tolerance 1 year after renal transplantation. These results suggest that an increase in insulin secretion and whole insulin sensitivity was associated with improvement in glucose tolerance in these recipients.

Temporal variability of glucocorticoid receptor activity is functionally important for the therapeutic action of fluoxetine in the hippocampus.

Previous studies have shown inconsistent results regarding the actions of antidepressants on glucocorticoid receptor (GR) signalling. To resolve these inconsistencies, we used a lentiviral-based reporter system to directly monitor rat hippocampal GR activity during stress adaptation. Temporal GR activation was induced significantly by acute stress, as demonstrated by an increase in the intra-individual variability of the acute stress group compared with the variability of the non-stress group. However, the increased intra-individual variability was dampened by exposure to chronic stress, which was partly restored by fluoxetine treatment without affecting glucocorticoid secretion. Immobility in the forced-swim test was negatively correlated with the intra-individual variability, but was not correlated with the quantitative GR activity during fluoxetine therapy; this highlights the temporal variability in the neurobiological links between GR signalling and the therapeutic action of fluoxetine. Furthermore, we demonstrated sequential phosphorylation between GR (S224) and (S232) following fluoxetine treatment, showing a molecular basis for hormone-independent nuclear translocation and transcriptional enhancement. Collectively, these results suggest a neurobiological mechanism by which fluoxetine treatment confers resilience to the chronic stress-mediated attenuation of hypothalamic-pituitary-adrenal axis activity.

Clinical, virological and epidemiological characterization of dengue outbreak in Myanmar, 2015.

Hospital-based surveillance was conducted at two widely separated regions in Myanmar during the 2015 dengue epidemic. Acute phase serum samples were collected from 332 clinically diagnosed dengue patients during the peak season of dengue cases. Viremia levels were measured by quantitative real-time PCR and plaque assays using FcγRIIA-expressing and non-FcγRIIA-expressing BHK cells to specifically determine the infectious virus particles. By serology and molecular techniques, 280/332 (84·3%) were confirmed as dengue patients. All four serotypes of dengue virus (DENV) were isolated from among 104 laboratory-confirmed patients including two cases infected with two DENV serotypes. High percentage of primary infection was noted among the severe dengue patients. Patients with primary infection or DENV IgM negative demonstrated significantly higher viral loads but there was no significant difference among the severity groups. Viremia levels among dengue patients were notably high for a long period which was assumed to support the spread of the virus by the mosquito vector during epidemic. Phylogenetic analyses of the envelope gene of the epidemic strains revealed close similarity with the strains previously isolated in Myanmar and neighboring countries. DENV-1 dominated the epidemic in 2015 and the serotype (except DENV-3) and genotype distributions were similar in both study sites.

Retrospective seroepidemiological study of chikungunya infection in South Asia, Southeast Asia and the Pacific region.

Chikungunya virus (CHIKV) and Ross River virus (RRV) of the genus Alphavirus, family Togaviridae are mainly transmitted by Aedes mosquitoes and the symptoms they cause in patients are similar to dengue. A chikungunya (CHIK) outbreak re-emerged in several Asian countries during 2005-2006. This study aimed to clarify the prevalence of CHIKV infection in suspected dengue patients in six countries in South Asia and Southeast Asia. Seven hundred forty-eight serum samples were from dengue-suspected patients in South Asia and Southeast Asia, and 52 were from patients in Fiji. The samples were analysed by CHIKV IgM capture ELISA, CHIKV IgG indirect ELISA and focus reduction neutralization test against CHIKV or RRV. CHIK-confirmed cases in South Asia, particularly Myanmar and Sri Lanka, were 4·6%, and 6·1%, respectively; and in Southeast Asia, particularly Indonesia, the Philippines and Vietnam, were 27·4%, 26·8% and 25·0%, respectively. It suggests that CHIK was widely spread in these five countries in Asia. In Fiji, no CHIK cases were confirmed; however, RRV-confirmed cases represented 53·6% of suspected dengue cases. It suggests that RRV is being maintained or occasionally entering from neighbouring countries and should be considered when determining a causative agent for dengue-like illness in Fiji.

Heterogeneity of non-cancerous liver parenchyma on gadoxetic acid-enhanced MRI: an imaging biomarker for hepatocellular carcinoma development in chronic liver disease.

AIM: To clarify whether the heterogeneity of non-cancerous liver parenchyma (NLP) in the hepatobiliary phase on gadoxetic acid enhanced magnetic resonance imaging (MRI) is correlated with hepatocellular carcinoma (HCC) development. MATERIALS AND METHODS: Institutional review board approval was obtained, and the requirements for informed consent were waived for this retrospective study. The imaging characteristics of 84 patients with chronic liver disease who underwent gadoxetic acid-enhanced 3T MRI between January 2013 and October 2014 were examined retrospectively. For the evaluation of the heterogeneity of the intensity in the hepatobiliary phase, the largest possible region of interest was placed on the NLP, and the skewness and kurtosis were calculated using ImageJ software. Skewness is the degree of asymmetry of a histogram, and kurtosis is a measure of the peak. Based on the median values of kurtosis and skewness, the patients were classified into four categories and the categories were compared between the 49 patients with HCC (HCC group) and the 35 patients without HCC (non-HCC group). RESULTS: Kurtosis was significantly higher in the HCC group compared to the non-HCC group (1.19±1.15 versus 0.43±0.83; p=0.0006). Skewness was significantly lower in the HCC group than in the non-HCC group (1.19±1.15 versus 0.43±0.83; p=0.0152). In a multivariate logistic analysis, the category showing lower-than-the-median (-0.1185) skewness and higher-than-the-median (0.547) kurtosis was significantly and independently associated with HCC development (p=0.0031). CONCLUSION: The heterogeneity of NLP in the hepatobiliary phase on gadoxetic acid enhanced MRI may reflect the development of HCC.

Impact of a ß-blocker and/or acute hemodilution on cerebral oxygenation during apneic hypoxia.

BACKGROUND: ß-blockers reduce the tolerance for acute hemodilution by decreasing cerebral oxygenation and may contribute to the incidence of stroke. We hypothesized that ß-blockers also increase the risk for cerebral hypoxia when apneic hypoxia occurs. METHODS: After induction of isoflurane, 14 swine (mean ± SD =25.3 ± 0.8 kg) were studied using 200 µg/kg/min of landiolol or saline (control group) in three sequential stages: before, during, and after landiolol (saline) infusion. In each stage, after 5 min of mechanical ventilation with 100% oxygen, apnea was induced until the time to < 70% oxygen saturation. Hemodynamic and blood gas variables were measured, and the cerebral tissue oxygenation index (TOI) was recorded by near infrared spectroscopy (apnea experiment). After these steps, hemodilution was induced by hemorrhage of 600 ml and infusion of the same volume of hydroxyethylstarch, and the apnea experiments were then conducted before, during, and after landiolol (saline) infusion similarly to before hemodilution. RESULTS: Landiolol decreased TOI at 1 min after apnea and at SpO2 < 70% by 3.3% and 7.0% from each corresponding value at baseline, and by 13.1% and 20.3% during hemodilution. Landiolol shifted the relationship between TOI and arterial hemoglobin oxygen saturation (SaO2 ) or arterial partial pressure of oxygen (PaO2 ) to the left; and reduced TOI at similar arterial blood oxygenation. This phenomenon was marked during hemodilution. CONCLUSIONS: Landiolol reduces cerebral tissue oxygenation during apneic hypoxia. ß-blockers increase the risk for cerebral hypoxia when apneic hypoxia occurs, especially during acute hemodilution.

Japanese encephalitis.

Japanese encephalitis (JE) is an inflammation of the central nervous system in humans and animals, specifically horses and cattle. The disease, which can sometimes be fatal, is caused by the flavivirus Japanese encephalitis virus (JEV), of which there are five genotypes (genotypes 1, 2, 3, 4 and 5). The transmission cycle of the virus involves pigs and wild birds as virus amplifiers and mosquitoes as vectors for transferring the virus between amplifying hosts and to dead- end hosts, i.e. humans, horses and cattle. In horses and cattle the disease is usually asymptomatic, but when clinical signs do occur they include fever, decreased appetite, frothing at the mouth, rigidity of the legs and recumbency, and neurological signs, such as convulsive fits, circling, marked depression and disordered consciousness. In pigs, it can cause abortion and stillbirths. At present, the virus is detected in a wide area covering eastern and southern Asia, Indonesia, northern Australia, Papua New Guinea and Pakistan. JEV RNA has also been detected in Italy, first in dead birds in 1997 and 2000 and then in mosquitoes in 2010. Genotype shift, i.e. a change of genotype from genotype 3 to genotype 1, has occurred in some countries, namely Japan, South Korea, Chinese Taipei and Vietnam. Laboratory methods are available for confirming the causative agent of the disease. There are control measures to prevent or minimise infection and, among them, vaccination is one of the most important and one which should be adopted in endemic and epidemic areas.

Temperature seasonality during fry out-migration influences the survival of hatchery-reared chum salmon Oncorhynchus keta.

Among years, fry-to-adult survival of hatchery-reared chum salmon Oncorhynchus keta was positively correlated with the length (in days) of the fry out-migration period with temperatures suitable for migration. Furthermore, survival decreased with increasing difference in mean temperature between May and June. Thus, prolonged out-migration periods increased the probability of survival from fry to adult, lending support to the hypothesis that long migration periods decrease the risk of mortality (bet-hedging), and increase the probability of migration when environmental conditions in fresh water and the ocean are suitable (match-mismatch).

Influence of cardiac output on the pseudo-steady state remifentanil and propofol concentrations in swine.

BACKGROUND: The propofol concentration during constant infusion is affected by a change in cardiac output, but the effect of this change on remifentanil, which is frequently used in combination with propofol, is unclear. METHODS: Ten swine were anaesthetised through inhalation of isoflurane and maintained with 1.5% isoflurane. After infusion of remifentanil (0.5 µg/kg/min) and propofol (6 mg/kg/h after 2 mg/kg bolus infusion) for 60 min (baseline 1), cardiac output was increased by continuous infusion of dobutamine and termination of isoflurane (high cardiac output state). Dobutamine infusion was then stopped, 1.5% isoflurane was restarted, and cardiac output was allowed to return to baseline (baseline 2). Finally, cardiac output was decreased by administration of 3% isoflurane (low cardiac output state). Blood samples were collected from the femoral artery at 10, 30, and 60 min after the change to each haemodynamic state. RESULTS: An inverse relationship was found between cardiac output and the plasma remifentanil and propofol concentrations. The plasma drug concentrations were given by the following equations: [remifentanil] (ng/ml) = 17.5/cardiac output (l/min) + 4.52; and [propofol] (µg/ml) = 3.34/cardiac output + 1.17. The influence of changes in cardiac output on remifentanil were similar to those for coadministered propofol and the influence on the concentration of each drug was greater with decreasing cardiac output. CONCLUSIONS: The plasma remifentanil concentration is influenced by cardiac output in a similar manner to that of propofol during remifentanil and propofol anaesthesia, although the metabolic sites are different.

Observation of an exotic insulator to insulator transition upon electron doping the Mott insulator CeMnAsO.

A promising route to discover exotic electronic states in correlated electron systems is to vary the hole or electron doping away from a Mott insulating state. Important examples include quantum criticality and high-temperature superconductivity in cuprates. Here, we report the surprising discovery of a quantum insulating state upon electron doping the Mott insulator CeMnAsO, which emerges below a distinct critical transition temperature, TII. The insulator-insulator transition is accompanied by a significant reduction in electron mobility as well as a colossal Seebeck effect and slow dynamics due to decoupling of the electrons from the lattice phonons. The origin of the transition is tentatively interpreted in terms of many-body localization, which has not been observed previously in a solid-state material.

Impact of human T cell leukemia virus type 1 in living donor liver transplantation.

Human T cell leukemia virus type 1 (HTLV-1) is an endemic retrovirus in southwestern Japan, which causes adult T cell leukemia (ATL) or HTLV-1 associated myelopathy in a minority of carriers. Here, we investigated the impact of HTLV-1 status in living donor liver transplantation (LDLT). Twenty-six of 329 (7.9%) HTLV-1 carriers underwent primary LDLT. One recipient negative for HTLV-1 before LDLT received a graft from an HTLV-1 positive donor. Eight donors were HTLV-1 positive. Twenty-seven recipients (13 male and 14 female; mean age 52.5 years) were reviewed retrospectively. ATL developed in four recipients who ultimately died. The intervals between LDLT and ATL development ranged from 181 to 1315 days. Of the four ATL recipients, two received grafts from HTLV-1 positive donors and two from negative donors. The 1-, 3- and 5-year HTLV-1 carrier survival rates were 91.3%, 78.3% and 66.3%, respectively. Fulminant hepatic failure as a pretransplant diagnosis and a pretransplant MELD score ≥ 15 was identified as risk factors for ATL development in this study (p = 0.001 and p = 0.041, respectively). In conclusion, LDLT can be performed for HTLV-1 positive recipients. However, when fulminant hepatic failure is diagnosed, LDLT should not be performed until further studies have revealed the mechanisms of ATL development.

Virtual magnetic resonance lumbar spine images generated from computed tomography images using conditional generative adversarial networks.

INTRODUCTION: The aim of this study was to generate virtual Magnetic resonance (MR) from computed tomography (CT) using conditional generative adversarial networks (cGAN). METHODS: We selected examinations from 22 adults who obtained their CT and MR lumbar spine examinations. Overall, 4 examinations were used as test data, and 18 examinations were used as training data. A cGAN was trained to generate virtual MR images from the CT images using the corresponding MR images as targets. After training, the generated virtual MR images from test data in epochs 1, 10, 50, 100, 500, and 1000 were compared with the original ones using the mean square error (MSE) and structural similarity index (SSIM). Additionally, two radiologists also performed qualitative assessments. RESULTS: The MSE of the virtual MR images decreased as the epoch of the cGANs increased from the original CT images: 8876.7 ± 1192.9 (original CT), 1567.5 ± 433.9 (Epoch 1), 1242.4 ± 442.0 (Epoch 10), 1065.8 ± 478.1 (Epoch 50), 1276.1 ± 718.9 (Epoch 100), 1046.7 ± 488.2 (Epoch 500), and 1031.7 ± 400.0 (Epoch 1000). No considerable differences were observed in the qualitative evaluation between the virtual MR images and the original ones, except in the structure of the spinal canal. CONCLUSION: Virtual MR lumbar spine images using cGANs could be a feasible technique to generate near-MR images from CT without MR examinations for evaluation of the vertebral body and intervertebral disc. IMPLICATIONS FOR PRACTICE: Virtual MR lumbar spine images using cGANs can offer virtual CT images with sufficient quality for attenuation correction for PET or dose planning in radiotherapy.

Synthesis and characterization of biodegradable and thermosensitive polymeric micelles with covalently bound doxorubicin-glucuronide prodrug via click chemistry.

Doxorubicin is an anthracycline anticancer agent that is commonly used in the treatment of a variety of cancers, but its application is associated with severe side effects. Biodegradable and thermosensitive polymeric micelles based on poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-lactate] (mPEG-b-p(HPMAmLac(n))) have been studied as drug delivery systems for therapeutic and imaging agents and have shown promising in vitro and in vivo results. The purpose of this study was to investigate the covalent coupling of a doxorubicin-glucuronide prodrug (DOX-propGA3) to the core of mPEG-b-p(HPMAmLac(2)) micelles. This prodrug is specifically activated by human ß-glucuronidase, an enzyme that is overexpressed in necrotic tumor areas. To this end, an azide modified block copolymer (mPEG(5000)-b-p(HPMAmLac(2)-r-AzEMA)) was synthesized and characterized, and DOX-propGA3 was coupled to the polymer via click chemistry with a high (95%) coupling efficiency. Micelles formed by this DOX containing polymer were small (50 nm) and monodisperse and released 40% of the drug payload after 5 days incubation at 37 °C in the presence of ß-glucuronidase, but less than 5% in the absence of the enzyme. In vitro cytotoxicity experiments demonstrated that DOX micelles incubated with 14C cells showed the same cytotoxicity as free DOX only in the presence of ß-glucuronidase, indicating full conversion of the polymer-bound DOX into the parent drug. Overall, this novel system is very promising for enzymatically responsive anticancer therapy.