Anagliptin twice-daily regimen improves glycaemic variability in subjects with type 2 diabetes: A double-blind, randomized controlled trial.

AIM: To determine whether the twice-daily (BID) regimen is superior to the once-daily (QD) regimen for managing glycaemic variability by comparing the effects of anagliptin 100 mg BID versus sitagliptin 100 mg QD. MATERIALS AND METHODS: A double-blinded, randomized, multicentre study was performed in 89 patients with type 2 diabetes treated with metformin alone (6.5% < HbA1c < 8.5%). Subjects were randomly assigned to anagliptin 100 mg BID or sitagliptin 100 mg QD in a 1:1 ratio for 12 weeks. Continuous glucose monitoring was used to measure the mean amplitude of glycaemic excursion (MAGE) and postprandial time in range (TIR) before and after dipeptidyl peptidase-4 (DPP-4) inhibitor treatment to compare glycaemic variability. RESULTS: The decrease from baseline in MAGE at 12 weeks after DPP-4 inhibitor treatment was significantly greater in the anagliptin BID group than in the sitagliptin QD group (P < .05); -30.4 ± 25.6 mg/dl (P < .001) in the anagliptin group versus -9.5 ± 38.0 mg/dl (P = .215) in the sitagliptin group. The TIR after dinner increased by 33.0% ± 22.0% (P < .001) in the anagliptin group and by 14.6% ± 28.2% (P = .014) in the sitagliptin group, with a statistically significant difference (P = .009). No statistically significant differences were observed between the groups in the changes in HbA1c and fasting plasma glucose (FPG). CONCLUSIONS: The anagliptin BID regimen for the treatment of type 2 diabetes was superior in blood glucose control after dinner to improve glycaemic variability, as indicated by MAGE and TIR, but was equivalent to the QD regimen in terms of HbA1c and FPG.

Efficacy and safety of lobeglitazone versus sitagliptin as an add-on to metformin in patients with type 2 diabetes with two or more components of metabolic syndrome over 24 weeks.

We aimed to evaluate the efficacy and safety profile of lobeglitazone compared with sitagliptin as an add-on to metformin in patients with type 2 diabetes as well as other components of metabolic syndrome. Patients inadequately controlled by metformin were randomly assigned to lobeglitazone (0.5 mg, n = 121) or sitagliptin (100 mg, n = 126) for 24 weeks. The mean changes in HbA1c of the lobeglitazone and sitagliptin groups were -0.79% and -0.86%, respectively; the between-group difference was 0.08% (95% confidence interval, -0.14% to 0.30%), showing non-inferiority. The proportion of patients having two or more factors of other metabolic syndrome components decreased to a greater extent in the lobeglitazone group than in the sitagliptin group (-11.9% vs. -4.8%; P < .0174). Favourable changes in the lipid metabolism were also observed with lobeglitazone, which had a similar safety profile to sitagliptin. Lobeglitazone was comparable with sitagliptin as an add-on to metformin in terms of efficacy and safety.

Efficacy and safety of evogliptin monotherapy in patients with type 2 diabetes and moderately elevated glycated haemoglobin levels after diet and exercise.

AIMS: To evaluate the efficacy and safety of evogliptin, a newly developed dipeptidyl peptidase-4 inhibitor, in patients with type 2 diabetes (T2D) inadequately controlled by diet and exercise. MATERIALS AND METHODS: In this randomized, double-blind, placebo-controlled, parallel-group, multicentre, phase III study, 160 patients with T2D were assigned to either evogliptin 5 mg or placebo for 24 weeks. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) from baseline to week 24. RESULTS: The mean baseline HbA1c levels were similar in the evogliptin and the placebo groups (7.20% ± 0.56% vs 7.20% ± 0.63%, respectively). At week 24, evogliptin significantly reduced HbA1c levels from baseline compared with placebo (-0.23% vs 0.05%, respectively, P < .0001). Additionally, the proportion of patients achieving HbA1c <6.5% was significantly higher in the evogliptin group than in the placebo group (33.3% vs 15.2%; P = .008). The overall incidence of adverse events, including hypoglycaemia, was similar in the 2 groups. CONCLUSIONS: In this 24-week study, once-daily evogliptin monotherapy significantly improved glycaemic control and was well tolerated in patients with T2D.

Impact of carotid atherosclerosis detection on physician and patient behavior in the management of type 2 diabetes mellitus: a prospective, observational, multicenter study.

BACKGROUND: This study compared carotid ultrasound (CUS) and traditional risk calculations in determining cardiovascular disease (CVD) risk in patients with type 2 diabetes mellitus (DM) and investigated whether awareness of CVD affects patient and/or physician behavior. METHODS: In this prospective, observational, multicenter study, 797 participants with type 2 diabetes were assessed using CUS, the United Kingdom Prospective Diabetes Study Risk Engine (UKPDSRE) calculator, and the Framingham Risk Score (FRS) algorithm. Health-related behaviors and physician treatments were compared at baseline and at 6 months after assessment. RESULTS: According to CUS, 43.5 % of the participants were at high risk (compared to 10.6 % and 4.3 % using the UKPDSRE and FRS approaches, respectively). Interestingly, 31.5 % of the patients with low risk scores according to the UKPDSRE calculator and 35.8 % of the patients with low risk scores according to the FRS algorithm were found to be at high risk according to CUS. The proportion of patients who achieved target LDL-C levels significantly increased after CUS. Moreover, increased awareness of atherosclerosis through CUS findings significantly altered physician treatment patterns and patient health-related behaviors. CONCLUSIONS: Carotid atherosclerosis was detected in more than 30 % of all participants with low or intermediate risk stratification scores. Improved awareness of atherosclerosis through CUS findings had a positive impact on both patient and physician behavior, resulting in improved CV risk management.

A randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of anagliptin in drug-naïve patients with type 2 diabetes.

The aim of this study was to evaluate the efficacy and safety of anagliptin in drug-naïve patients with type 2 diabetes in a double-blind randomized placebo-controlled study. A total of 109 patients were randomized to 100 mg (n=37) or 200 mg (n=33) anagliptin twice daily or placebo (n=39). The primary objective was to alter HbA1c levels from baseline at a 24-week endpoint. The overall baseline mean age and body mass index were 56.20 ± 9.77 years and 25.01 ± 2.97 kg/m(2), respectively, and the HbA1c level was of 7.14 ± 0.69 %. Anagliptin at 100 mg and 200 mg produced significant reductions in HbA1c (-0.50 ± 0.45 % and -0.51 ± 0.55%, respectively), and the placebo treatment resulted in an increase in HbA1c by 0.23 ± 0.62 %. Both doses of anagliptin produced significant decreases in fasting plasma glucose (-0.53 ± 1.25 mmol/L and -0.72 ± 1.25 mmol/L, respectively) and the proinsulin/insulin ratio (-0.04 ± 0.15 and -0.07 ± 0.18, respectively) compared with placebo. No meaningful body weight changes from baseline were observed in three groups. Plasma dipeptidyl peptidase (DPP)-4 activity was significantly inhibited after 24 weeks of anagliptin treatment, and >75% and >90% inhibitions were observed during the meal tolerance tests with 100 mg and 200 mg anagliptin, respectively. The incidences of adverse or serious adverse events were similar among the three study groups. Twice-daily anagliptin therapy effectively inhibited DPP-4 activity and improved glycemic control and was well-tolerated in patients with type 2 diabetes.

The effects of the Korean reference value on the prevalence of osteoporosis and the prediction of fracture risk.

BACKGROUND: Since the reference value is the core factor of the T-score calculation, it has a significant impact on the prevalence of osteoporosis. The purpose of this study was to determine the effects of using the Korean reference value on the prevalence of osteoporosis and on the prediction of fracture risk. METHODS: We used femoral neck bone mineral density (BMD) data from the Korea National Health and Nutrition Examination Survey (KNHANES) 2008-2011. The Korean reference was identified by the mean and standard deviation of men and women aged 20-29 years. We compared the prevalence and the fracture risk assessment tool (FRAX™) probability obtained from the Korean reference and the NHANES III reference. RESULTS: In men, the prevalence of osteoporosis increased when using the Korean men's reference, and the difference increased up to 9% for those in their 80s. In women, the prevalence increased when using the NHANES III reference, and the difference increased up to 17% for those in their 80s. The reference value also affected the fracture risk probability, and the difference from changing the reference value increased in women and in subjects with more clinical fracture risk factors. In major osteoporotic fractures, the difference of the risk probability was up to 6% in women aged 70-79 years with two clinical risk factors. For femoral neck fractures, the difference was up to 7% in women aged 50-59 years with two clinical risk factors. CONCLUSIONS: We confirmed that the reference value had significant effects on the prevalence of osteoporosis and on the fracture risk probability. The KNHANES 2008-2011 BMD data reflected the characteristics of the Korean BMD status well with regard to data size and study design; therefore, these data can be used as reference values.

Unprotected daily sun exposure is differently associated with central adiposity and ß-cell dysfunction by gender: the Korean National Health and Nutrition Examination Survey (KNHANES) V.

BACKGROUND: Ultraviolet irradiation by sun exposure has been associated with both harms and benefits to metabolic health. OBJECTIVE: The objective of this study was to determine whether unprotected daily sun exposure is associated with the prevalence of diabetes and explore the underlying mechanism. METHODS: We analyzed the Korean National Health and Nutrition Survey V from 2010 to 2011. Participants 19-60 years of age were asked about the average amount of time they had been exposed to direct sunlight per day since the age of 19. We categorized participants into three groups with different levels of lifetime daily sun exposure and explored the association of sun exposure with the prevalence of diabetes. RESULTS: The risk of diabetes was higher in subjects with more than 5h of unprotected sun exposure per day, with an odds ratio of 2.39 (95% CI 1.75-3.25), compared to those with less than 2h of sun exposure, and the association remained significant after adjusting for diabetes risk factors. Long-term sun exposure was associated with increased central obesity and the possibility of an increase in visceral adiposity, especially among women, and with decrease in beta cell function and peripheral adiposity or percent body fat in men. CONCLUSIONS: Our study provides a cutoff for upper limit of sun exposure and suggests unprotected daily sun exposure for more than 5h should be avoided to prevent diabetes. Increased central adiposity and decreased beta cell function were observed in women and men, respectively, who had long-term unprotected daily sun exposure.

Comparison of acarbose and voglibose in diabetes patients who are inadequately controlled with basal insulin treatment: randomized, parallel, open-label, active-controlled study.

We studied the efficacy and safety of acarbose in comparison with voglibose in type 2 diabetes patients whose blood glucose levels were inadequately controlled with basal insulin alone or in combination with metformin (or a sulfonylurea). This study was a 24-week prospective, open-label, randomized, active-controlled multi-center study. Participants were randomized to receive either acarbose (n=59, 300 mg/day) or voglibose (n=62, 0.9 mg/day). The mean HbA1c at week 24 was significantly decreased approximately 0.7% from baseline in both acarbose (from 8.43% ± 0.71% to 7.71% ± 0.93%) and voglibose groups (from 8.38% ± 0.73% to 7.68% ± 0.94%). The mean fasting plasma glucose level and self-monitoring of blood glucose data from 1 hr before and after each meal were significantly decreased at week 24 in comparison to baseline in both groups. The levels 1 hr after dinner at week 24 were significantly decreased in the acarbose group (from 233.54 ± 69.38 to 176.80 ± 46.63 mg/dL) compared with the voglibose group (from 224.18 ± 70.07 to 193.01 ± 55.39 mg/dL). In conclusion, both acarbose and voglibose are efficacious and safe in patients with type 2 diabetes who are inadequately controlled with basal insulin. (ClinicalTrials.gov number, NCT00970528).

Resistant starch and type 2 diabetes mellitus: Clinical perspective.

The immediate and well-documented benefits of carbohydrate restriction include improved glycemic control in individuals with diabetes mellitus. Starch, a significant source of carbohydrates, is categorized as rapidly digestible, slowly digestible, or resistant starch (RS). RS, which is a non-viscous fermentable fiber, has shown promise in animal studies for antidiabetic effects by improving glucose metabolism. Although the exact mechanism by which RS affects glucose metabolism remains unclear, it is expected to positively impact glucose tolerance and insulin sensitivity. The fermentation of RS by colonic microbiota in the large bowel produces short-chain fatty acids, which exert multiple metabolic effects on glucose regulation and homeostasis. Moreover, RS may influence glucose metabolism via bile acid modulation, independent of its fermentation. Diets rich in RS could aid in blood glucose homeostasis. However, it is uncertain whether they can alter the metabolic pathology associated with glucose regulation. In essence, RS has the potential to lower postprandial glucose levels similarly to a low-glycemic index diet. Yet, its efficacy as a medical nutrition therapy for type 2 diabetes needs further investigation. To confirm the role of RS in glycemic control and to possibly recommend it as an additional dietary approach for people with type 2 diabetes mellitus, a well-designed, large-scale intervention is required.

Efficacy and Safety of Metformin and Atorvastatin Combination Therapy vs. Monotherapy with Either Drug in Type 2 Diabetes Mellitus and Dyslipidemia Patients (ATOMIC): Double-Blinded Randomized Controlled Trial.

BACKGRUOUND: It is well known that a large number of patients with diabetes also have dyslipidemia, which significantly increases the risk of cardiovascular disease (CVD). This study aimed to evaluate the efficacy and safety of combination drugs consisting of metformin and atorvastatin, widely used as therapeutic agents for diabetes and dyslipidemia. METHODS: This randomized, double-blind, placebo-controlled, parallel-group and phase III multicenter study included adults with glycosylated hemoglobin (HbA1c) levels >7.0% and <10.0%, low-density lipoprotein cholesterol (LDL-C) >100 and <250 mg/dL. One hundred eighty-five eligible subjects were randomized to the combination group (metformin+atorvastatin), metformin group (metformin+atorvastatin placebo), and atorvastatin group (atorvastatin+metformin placebo). The primary efficacy endpoints were the percent changes in HbA1c and LDL-C levels from baseline at the end of the treatment. RESULTS: After 16 weeks of treatment compared to baseline, HbA1c showed a significant difference of 0.94% compared to the atorvastatin group in the combination group (0.35% vs. -0.58%, respectively; P<0.0001), whereas the proportion of patients with increased HbA1c was also 62% and 15%, respectively, showing a significant difference (P<0.001). The combination group also showed a significant decrease in LDL-C levels compared to the metformin group (-55.20% vs. -7.69%, P<0.001) without previously unknown adverse drug events. CONCLUSION: The addition of atorvastatin to metformin improved HbA1c and LDL-C levels to a significant extent compared to metformin or atorvastatin alone in diabetes and dyslipidemia patients. This study also suggested metformin's preventive effect on the glucose-elevating potential of atorvastatin in patients with type 2 diabetes mellitus and dyslipidemia, insufficiently controlled with exercise and diet. Metformin and atorvastatin combination might be an effective treatment in reducing the CVD risk in patients with both diabetes and dyslipidemia because of its lowering effect on LDL-C and glucose.

Efficacy and Safety of Enavogliflozin versus Dapagliflozin as Add-on to Metformin in Patients with Type 2 Diabetes Mellitus: A 24-Week, Double-Blind, Randomized Trial.

BACKGRUOUND: Enavogliflozin is a novel sodium-glucose cotransporter-2 inhibitor currently under clinical development. This study evaluated the efficacy and safety of enavogliflozin as an add-on to metformin in Korean patients with type 2 diabetes mellitus (T2DM) against dapagliflozin. METHODS: In this multicenter, double-blind, randomized, phase 3 study, 200 patients were randomized to receive enavogliflozin 0.3 mg/day (n=101) or dapagliflozin 10 mg/day (n=99) in addition to ongoing metformin therapy for 24 weeks. The primary objective of the study was to prove the non-inferiority of enavogliflozin to dapagliflozin in glycosylated hemoglobin (HbA1c) change at week 24 (non-inferiority margin of 0.35%) (Clinical trial registration number: NCT04634500). RESULTS: Adjusted mean change of HbA1c at week 24 was -0.80% with enavogliflozin and -0.75% with dapagliflozin (difference, -0.04%; 95% confidence interval, -0.21% to 0.12%). Percentages of patients achieving HbA1c <7.0% were 61% and 62%, respectively. Adjusted mean change of fasting plasma glucose at week 24 was -32.53 and -29.14 mg/dL. An increase in urine glucose-creatinine ratio (60.48 vs. 44.94, P<0.0001) and decrease in homeostasis model assessment of insulin resistance (-1.85 vs. -1.31, P=0.0041) were significantly greater with enavogliflozin than dapagliflozin at week 24. Beneficial effects of enavogliflozin on body weight (-3.77 kg vs. -3.58 kg) and blood pressure (systolic/diastolic, -5.93/-5.41 mm Hg vs. -6.57/-4.26 mm Hg) were comparable with those of dapagliflozin, and both drugs were safe and well-tolerated. CONCLUSION: Enavogliflozin added to metformin significantly improved glycemic control in patients with T2DM and was non-inferior to dapagliflozin 10 mg, suggesting enavogliflozin as a viable treatment option for patients with inadequate glycemic control on metformin alone.

Current status of diabetic kidney disease and latest trends in management.

Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetes and is leading cause of end-stage renal disease (ESRD) and one of major risk factors of cardiovascular disease (CVD).

Effects of glucagon-like peptide-1 receptor agonists on kidney function and safety in type 2 diabetes patients.

Glucagon-like peptide-1 receptor agonists have been recommended in diabetic kidney disease patients.

A Multicentre, Multinational, Open-Label, 52-Week Extension Study of Gemigliptin (LC15-0444) Monotherapy in Patients with Type 2 Diabetes Mellitus.

The purpose of this extension study was to assess the long-term efficacy and safety of gemigliptin 50 mg in patients with type 2 diabetes mellitus (T2DM). Patients with T2DM who had completed the initial 24-week study comparing gemigliptin monotherapy with placebo were eligible to enrol. In the open-label, 28-week extension study, all enrolled patients received gemigliptin, regardless of the treatment received during the initial 24-week study period. The mean reduction±standard deviation (SD) in glycosylated hemoglobin (HbA1c) observed after 24 weeks of treatment (-0.6%±1.1%) was further decreased for the gemi-gemi group and the mean change in HbA1c at week 52 from baseline was -0.9%±1.2% (P<0.0001). For the pbo-gemi group, HbA1c decreased after they were switched to gemigliptin, and the mean change in HbA1c at week 52 from baseline was -0.7%±1.2% (P<0.0001). Furthermore, the overall incidence of adverse events demonstrated that gemigliptin was safe and well tolerated up to 52 weeks.

Diabetes and COVID-19: IDF perspective in the Western Pacific region.

The World Health Organization (WHO) declared a pandemic, the highest risk level in the infectious disease alert phase, on 11 March 2020. In the Western Pacific Region (WPR), 192,016 confirmed cases with 7125 deaths had been reported as of 8 June 2020. In people with diabetes COVID-19 can be more difficult to treat due to the wide fluctuations in blood glucose levels or presence of comorbidities such as diabetes complications, including cardiovascular disease and renal damage, which are recognized risks for adverse outcomes. National diabetes associations and governments have established guidelines for subjects with diabetes in relation to COVID-19, and are trying to supply emergency and their regularly required medical products for them. The WPR is so large and composed of such diverse countries and COVID-19 situations, no one conclusion or program applies. Instead we could see a diverse COVID-19 pandemic profile in the WPR, and several creative diagnostic and therapeutic measures undertaken. This includes drive-through screening facilities, high-speed RT-PCR technologies, convalescent patients' plasma therapy, which potentially had some positive contributions in combatting COVID-19 in the WPR as well as globally. Although the numbers of confirmed cases are currently decreasing in the region, the COVID-19 pandemic is not over, and many experts are recommending to prepare measures for potential second or third waves of COVID-19.

Changes in the Quality of Life in Patients with Type 2 Diabetes Mellitus According to Physician and Patient Behaviors.

BACKGROUND: Diabetes mellitus (DM) is the most common chronic metabolic disorder with an increasing prevalence worldwide. According to a previous study, physicians' treatment patterns or patients' behaviors change when they become aware of the risk for cardiovascular (CV) disease in patients with DM. However, there exist controversial reports from previous studies in the impact of physicians' behaviors on the patients' quality of life (QoL) improvements. So we investigate the changes in QoL according to physicians and patients' behavioral changes after the awareness of CV risks in patients with type 2 DM. METHODS: Data were obtained from a prospective, observational study where 799 patients aged ≥40 years with type 2 DM were recruited at 24 tertiary hospitals in Korea. Changes in physicians' behaviors were defined as changes in the dose/type of antihypertensive, lipid-lowering, and anti-platelet therapies within 6-month after the awareness of CV risks in patients. Changes in patients' behaviors were based on lifestyle modifications. Audit of Diabetes Dependent Quality of Life comprising 19-life-domains was used. RESULTS: The weighted impact score change for local or long-distance journey (P=0.0049), holidays (P=0.0364), and physical health (P=0.0451) domains significantly differed between the two groups; patients whose physician's behaviors changed showed greater improvement than those whose physician's behaviors did not change. CONCLUSION: This study demonstrates that changes in physicians' behaviors, as a result of perceiving CV risks, improve QoL in some domains of life in DM patients. Physicians should recognize the importance of understanding CV risks and implement appropriate management.

When should antithyroid drug therapy to reduce the relapse rate of hyperthyroidism in Graves' disease be discontinued?

OBJECTIVE: The use of antithyroid drug (ATD) therapy in patients with Graves' disease (GD) hyperthyroidism has been increasing, but ATD therapy is associated with a higher relapse rate. We aimed to evaluate clinical factors for predicting relapse of GD after ATD therapy. METHODS: Patients (n = 149) with newly diagnosed GD who achieved remission of hyperthyroidism after ATD therapy (≥6 months) were followed up for >18 months after ATD withdrawal. We evaluated the predictive factors of relapse during a median of 6.9 years of follow-up. RESULTS: Disease relapse occurred in 52 patients (34.9%). By multivariate analyses, a duration of the minimum maintenance dose therapy (MMDT) of <6 months was a significant factor in disease relapse (hazard ratio [HR], 2.58; 95% confidence interval [CI], 1.47-4.52; p < 0.001), and a T3/free T4 (fT4) ratio > 120 at ATD withdrawal was significantly more frequent in patients with relapse (HR 2.43; 95% CI, 1.36-4.34; p = 0.002). In the prediction-of-relapse model, the likelihood of relapse was greater in the high-risk group, which had a short MMDT duration and a T3/fT4 ratio ≥120 (HR, 5.81; 95% CI, 2.52-13.39; p < 0.001) and the intermediate-risk group, which had a short MMDT duration or a T3/fT4 ratio < 120 (HR, 2.77; 95% CI, 1.26-6.13; p < 0.001), than in the low-risk group, which had a long MMDT duration and a T3/fT4 ratio < 120. CONCLUSION: An MMDT longer than 6 months and a high T3/fT4 ratio at ATD withdrawal were independent predictors of relapse in patients who achieved initial remission after ATD for GD. These factors could be used to determine the optimal time to withdraw ATD during the treatment of GD hyperthyroidism.

CD44 Receptor-Specific and Redox-Sensitive Nanophotosensitizers of Hyaluronic Acid-Chlorin e6 Tetramer Having Diselenide Linkages for Photodynamic Treatment of Cancer Cells.

For reactive oxygen species (ROS)-sensitive and CD44 receptor-mediated delivery of photosensitizers, chlorin e6 (ce6) tetramer was synthesized using tetra acid (TA) via selenocystamine linkages and then conjugated with hyaluronic acid (HA) (abbreviated as HAseseCe6TA). HAseseCe6TA nanophotosensitizers were fabricated by dialysis procedure. HAseseCe6TA nanophotosensitizers showed spherical morphology with small particle sizes less than 100 nm and monomodal pattern. When H2O2 was added, size distribution was changed to multimodal pattern and morphological observation showed disintegration of nanophotosensitizers, indicating that HAseseCe6TA nanophotosensitizers have ROS sensitivity. Furthermore, H2O2 addition resulted in acceleration of Ce6 release from HAseseCe6TA nanophotosensitizers. In vitro cell culture study, HAseseCe6TA nanophotosensitizers increase Ce6 uptake ratio, ROS production efficiency, and photodynamic therapy efficacy in both B16F10 cells and CT26 cells. Especially, CD44-receptor blocking of cancer cells by pretreatment of HA showed that fluorescence intensity in B16F10 cells was significantly decreased while fluorescence intensity in CT26 cells was not significantly changed, indicating that HAseseCe6TA nanophotosensitizers can be delivered by CD44 receptor-mediated pathway. In vivo animal tumor xenograft study, HAseseCe6TA nanophotosensitizers was selectively delivered to B16F10 tumor rather than CT26 tumor. These results indicated that HAseseCe6TA nanophotosensitizers have ROS sensitivity and have CD44 receptor-recognition properties.

Hyaluronic Acid-Conjugated with Hyperbranched Chlorin e6 Using Disulfide Linkage and Its Nanophotosensitizer for Enhanced Photodynamic Therapy of Cancer Cells.

The main purpose of this study is to synthesize novel types of nanophotosensitizers that are based on hyperbranched chlorin e6 (Ce6) via disulfide linkages. Moreover, hyperbranched Ce6 was conjugated with hyaluronic acid (HA) for CD44-receptor mediated delivery and redox-sensitive photodynamic therapy (PDT) against cancer cells. Hyperbranched Ce6 was considered to make novel types of macromolecular photosensitizer since most of the previous studies regarding nanophotosensizers are concerned with simple conjugation between monomeric units of photosensitizer and polymer materials. Hyperbranched Ce6 was synthesized by conjugation of Ce6 each other while using disulfide linkage. To synthesize Ce6 tetramer, carboxyl groups of Ce6 were conjugated with cystamine and three equivalents of Ce6 were then conjugated again with the end of amine groups of Ce6-cystamine. To synthesize Ce6 decamer as a hyperbranched Ce6, six equivalents of Ce6 was conjugated with the end of Ce6 tetramer via cystamine linkage. Furthermore, HA-cystamine was attached with Ce6 tetramer or Ce6 decamer to synthesize HA-Ce6 tetramer (Ce6tetraHA) or HA-Ce6 decamer (Ce6decaHA) conjugates. Ce6tetraHA and Ce6decaHA nanophotosensitizers showed small diameters of less than 200 nm. The addition of dithiothreitol (DTT) and hyaluronidase (HAse) induced a faster Ce6 release rate in vitro drug release study, which indicated that Ce6tetraHA nanophotosensitizers possess redox-sensitive and HAse-sensitive release properties. Ce6tetraHA nanophotosensitizers showed higher intracellular Ce6 accumulation, higher ROS generation, and higher PDT efficacy than that of Ce6 alone. Ce6tetraHA nanophotosensitizers responded to the CD44 receptor of cancer cell surface, i.e., the pre-treatment of HA blocked CD44 receptor of U87MG or HCT116 cells and then inhibited delivery of nanophotosensitizers in vitro cell culture study. Furthermore, in vivo tumorxenograft study showed that fluorescence intensity in the tumor tissues was stronger than those of other organs, while CD44 receptor blocking by HA pretreatment induced a decrease of fluorescence intensity in tumor tissues when compared to liver. These results indicated that Ce6tetraHA nanophotosensitizers delivered to tumors by redox-sensitive and CD44-sensitive manner.

Piperlongumine-Eluting Gastrointestinal Stent Using Reactive Oxygen Species-Sensitive Nanofiber Mats for Inhibition of Cholangiocarcinoma Cells.

BACKGROUND: The aim of this study is to fabricate drug-eluting gastrointestinal (GI) stent using reactive oxygen species (ROS)-sensitive nanofiber mats for treatment of cholangiocarcinoma (CCA) cell. A ROS-producing agent, piperlongumine (PL)-incorporated nanofiber mats were investigated for drug-eluting stent (DES) application. METHODS: Selenocystamine-conjugated methoxy poly(ethylene glycol) (MePEG) was conjugated with poly(L-lactide) (PLA) to produce block copolymer (LEse block copolymer). Various ratios of poly(ε-caprolactone) (PCL) and LEse block copolymer were dissolved in organic solvent with PL, and then nanofiber mats were fabricated by electro-spinning techniques. RESULTS: The higher amount of LEse in the blend of PCL/LEse resulted in the formation of granules while PCL alone showed fine nanofiber structure. Nanofiber mats composed of PCL/LEse polymer blend showed ROS-sensitive drug release, i.e., PL release rate from nanofiber mats was accelerated in the presence of hydrogen peroxide (H2O2) while nanofiber mats of PCL alone have small changes in drug release rate, indicating that PL-incorporated nanofiber membranes have ROS responsiveness. PL itself and PL released from nanofiber mats showed almost similar anticancer activity against various CCA cells. Furthermore, PL released from nanofiber mats properly produced ROS generation and induced apoptosis of CCA cells as well as PL itself. In HuCC-T1 cell-bearing mice, PL-incorporated nanofiber mats showed improvement in anticancer activity. CONCLUSION: PL-incorporated ROS-sensitive nanofiber mats were coated onto GI stent and showed improved anticancer activity with ROS responsiveness. We suggested PL-incorporated ROS-sensitive nanofiber mats as a promising candidate for local treatment of CCA cells.