Hierarchically Porous Implants Orchestrating a Physiological Viscoelastic and Piezoelectric Microenvironment for Bone Regeneration.

The extracellular matrix microenvironment of bone tissue comprises several physiological cues. Thus, artificial bone substitute materials with a single cue are insufficient to meet the demands for bone defect repair. Regeneration of critical-size bone defects remains challenging in orthopedic surgery. Intrinsic viscoelastic and piezoelectric cues from collagen fibers play crucial roles in accelerating bone regeneration, but scaffolds or implants providing integrated cues have seldom been reported. In this study, it is aimed to design and prepare hierarchically porous poly(methylmethacrylate)/polyethyleneimine/poly(vinylidenefluoride) composite implants presenting a similar viscoelastic and piezoelectric microenvironment to bone tissue via anti-solvent vapor-induced phase separation. The viscoelastic and piezoelectric cues of the composite implants for human bone marrow mesenchymal stem cell line stimulate and activate Piezo1 proteins associated with mechanotransduction signaling pathways. Cortical and spongy bone exhibit excellent regeneration and integration in models of critical-size bone defects on the knee joint and femur in vivo. This study demonstrates that implants with integrated physiological cues are promising artificial bone substitute materials for regenerating critical-size bone defects.

A 90-day rodent feeding study with grain for genetically modified maize L4 conferring insect resistance and glyphosate tolerance.

A 90-day rat feeding study was performed to conduct a safety assessment on L4, a multi-gene genetically modified maize, conferring "Bt" insect resistance and glyphosate tolerance. A total of 140 Wistar rats were assigned to seven groups, 10 animals/group/sex, which comprised three genetically modified groups fed diets containing different concentrations of L4, three corresponding non-genetically modified groups fed diets containing different concentrations of zheng58 (parent plants), and a basal diet group fed the standard basal diet for 13 weeks. The fed diets contained L4 and Zheng58 at w/w% percentages of 12.5%, 25.0%, and 50% of the total. Animals were evaluated on some research parameters, including general behaviour, body weight/gain, feed consumption/efficiency, ophthalmology, clinical pathology, organ weights, and histopathology. Throughout the feeding trial, all animals were in good condition. No mortality and no biologically relevant effects or toxicologically significant alterations were observed in the total research parameters of the rats in the genetically modified groups compared with those in the basal diet group or their corresponding non-genetically modified groups. No adverse effects were observed in any of the animals. The results indicated that L4 is as safe and wholesome as conventional, non-genetically modified control maize.

Antihyperlipidemic and Hepatoprotective Properties of Vitamin B6 Supplementation in Rats with High-Fat Diet-Induced Hyperlipidemia.

BACKGROUND: The incidence and mortality of hyperlipidemia are increasing year by year, showing a younger trend. At present, the treatment of hyperlipidemia is mainly dependent on western medicine, but its side effects on liver and kidney function are common in clinics. Therefore, it is necessary to study the treatment of hyperlipidemia by augmenting effective dietary nutrition supplements. Vitamin B6 (VitB6), as an essential cofactor for enzymes, participates in lipid metabolism. The effects of VitB6 on hyperlipidemia, however, have not been reported until now. AIM: The present study was to investigate the influence of VitB6 on hepatic lipid metabolism in hyperlipidaemia rats induced by a High-Fat Diet (HFD). METHODS: Male Sprague-Dawley rats were kept on HFD for two weeks to establish the hyperlipidemia model. The rats in low-dosage and high-dosage groups were received 2.00 and 3.00 mg/kg/- day of VitB6 for eight weeks, respectively. RESULTS: The results showed that both doses of VitB6 reduced HFD-induced hepatic Low-Density Lipoprotein Cholesterol (LDL-C); decreased blood cholesterol (TC), triglycerides, LDL-C, atherogenic index (AI), Atherogenic Index of Plasma (AIP), apolipoprotein B (ApoB) and ApoB/apolipoprotein A-1(ApoA1) ratio; increased liver High-Density Lipoprotein Cholesterol (HDL-C) and serum ApoA1; reduced hepatic steatosis and triglyceride accumulation, lowered fat storage, and recovered heart/body and brain/body ratio to a normal level. In addition, VitB6 supplementation markedly decreased HMGR level, increased the mRNA abundance of LDLR and CYP7A1, and protein expression of SIRT1, following the downregulation of SREBP-1 and PPARγ protein expression in the liver of hyperlipidemia rats. CONCLUSION: In summary, oral VitB6 supplementation can ameliorate HFD-induced hepatic lipid accumulation and dyslipidemia in SD rats by inhibiting fatty acid and cholesterol synthesis, promoting fatty acid decomposition and cholesterol transport.

Rapid Electrochemical Screening of Phenylketonuria Maker Depending on Dehydrogenase Attached to the Pt-Doped Reduced Graphene Oxide Nanocomposites.

Phenylketonuria (PKU) is a common disease associated with amino acid metabolism, and usually occurs in newborns. It can cause serious neurological diseases and even death. However, owing to inadequate-effective treatment, it can only be slowed by a low-phenylalanine (Phe) diet. In addition, PKU screening is essential for newborns in many countries. Therefore, rapid screening is crucial for preventing damage and meeting the large sample diagnosis demand. For confirmed patients, a convenient method to monitor their regular Phe levels is required. However, current clinical methods do not meet the rapid screening and convenient monitoring requirements. Herein, a rapid and facile electrochemical device based on platinum-doped reduced graphene oxide nanocomposites was developed to detect PKU biomarker-Phe. The results demonstrated that the developed electrode has great sensitivity, selectivity, and stability. The detection range was 0.0001 mM to 6 mM with a limit of detection of 0.01 µM. Therefore, this work offers a simple and rapid method for point-of-care PKU screening and daily monitoring.

Subchronic toxicity study in rats evaluating herbicide-tolerant soybean DAS-68416-4.

A subchronic toxicity study was conducted in Wistar rats to evaluate the potential health effects of genetically modified (GM) herbicide-tolerant soybean DAS-68416-4. Rats were fed with diets containing toasted meal produced from GM soybean engineered with aad-12 and pat genes or containing non-GM soybean at a dose of 30.0, 15.0, or 7.5%,w/w% and 0% (control group) for 90 consecutive days. Animals were evaluated for general behavior, body weight gain, food consumption, food use efficiency, etc. At the middle and end of the study, blood and serum samples were collected for routine and biochemical assays. Internal organs were taken for calculating relative weights and doing histopathological examination. The rats were active and healthy without any abnormal symptoms during the entire study period. No biological differences in hematological or biochemical indices were detected. No histopathological changes were observed. Under the conditions of this study, herbicide-tolerant soybean DAS-68416-4 did not cause any treatment-related effects in Wistar rats following 90 days of dietary administration.

Clinical characteristics and long-term prognosis of ischemic and non-ischemic cardiomyopathy.

OBJECTIVES: The different etiology of HF has different prognostic risk factors. Prognosis assessment of ICM and NICM has important clinical value. This study is aimed to explore the predicting factors for ICM and NICM. METHODS: 1082 HFrEF patients were retrospectively enrolled from Jan. 01, 2016 to Dec. 31, 2017. On Jan. 31, 2019, 873 patients were enrolled for analysis excluding incomplete, unfollowed, and unexplained data. The patients were divided into ischemic and non-ischemic group. The differences in clinical characteristics and long-term prognosis between the two groups were analyzed, and multivariate Cox analysis was used to predict the respective all-cause mortality, SCD and rehospitalization of CHF. RESULTS: 873 patients aged 64(53,73) were divided into two groups: ICM (403, 46.16%) and NICM. At the end, 203 died (111 in ICM, 54.68%), of whom 87 had SCD (53 in ICM, 60.92%) and 269 had rehospitalization for HF(134 in ICM, 49.81%). Independent risk factors affecting all-cause mortality in ICM: DM, previous hospitalization of HF, age, eGFR, LVEF; for SCD: PVB, eGFR, Hb, revascularization; for readmission of HF: low T3 syndrome, PVB, DM, previous hospitalization of HF, eGFR. Otherwise; factors affecting all-cause mortality in NICM: NYHA III-IV, paroxysmal AF/AFL, previous hospitalization of HF, ß-blocker; for SCD: low T3 syndrome, PVB, nitrates, sodium, ß-blocker; for rehospitalization of HF: paroxysmal AF/AFL, previous admission of HF, LVEF. CONCLUSIONS: Both all-cause mortality and SCD in ICM is higher than that in NICM. Different etiologies of CHF have different risk factors affecting the prognosis.

Advanced biomaterials for cancer immunotherapy.

Immunotherapy, as a powerful strategy for cancer treatment, has achieved tremendous efficacy in clinical trials. Despite these advancements, there is much to do in terms of enhancing therapeutic benefits and decreasing the side effects of cancer immunotherapy. Advanced nanobiomaterials, including liposomes, polymers, and silica, play a vital role in the codelivery of drugs and immunomodulators. These nanobiomaterial-based delivery systems could effectively promote antitumor immune responses and simultaneously reduce toxic adverse effects. Furthermore, nanobiomaterials may also combine with each other or with traditional drugs via different mechanisms, thus giving rise to more accurate and efficient tumor treatment. Here, an overview of the latest advancement in these nanobiomaterials used for cancer immunotherapy is given, describing outstanding systems, including lipid-based nanoparticles, polymer-based scaffolds or micelles, inorganic nanosystems, and others.

Subchronic feeding toxicity studies of drought-tolerant transgenic wheat MGX11-10 in Wistar Han RCC rats.

A subchronic toxicity study were conducted in Wistar Han RCC rats to evaluate the potential health effects of genetically modified (GM), drought-tolerant wheat MGX11-10. Rats were fed a rodent diet formulated with MGX11-10 and were compared with rats fed a diet formulated with its corresponding non-transgenic control Jimai22 and rats fed a basal diet. MGX11-10 and Jimai22 were ground into flour and formulated into diets at concentrations of 16.25, 32.5, or 65%, w/w% and fed to rats (10/sex/group) for 13 weeks. Compared with rats fed Jimai22 and the basal-diet group, no biologically relevant differences were observed in rats fed the GM diet with respect to body weight/gain, food consumption/efficiency, clinical signs, mortality, ophthalmology, clinical pathology (hematology, prothrombin time, urinalysis, clinical chemistry), organ weights, and gross and microscopic pathology. Under the conditions of this study, the MGX11-10 diets did not cause any treatment-related effects in rats following at least 90 days of dietary administration as compared with rats fed diets with the corresponding non-transgenic control diet and the basal-diet group. The MGX11-10 diets are considered equivalent to the diets prepared from conventional comparators. The results demonstrated that MGX11-10 wheat is as safe and wholesome as the corresponding non-transgenic control wheat.

Cardiac electrical and mechanical synchrony of super-responders to cardiac resynchronization therapy.

BACKGROUND: Super-responders (SRs) to cardiac resynchronization therapy (CRT) regain near-normal or normal cardiac function. The extent of cardiac synchrony of SRs and whether continuous biventricular (BIV) pacing is needed remain unknown. The aim of this study was to evaluate the cardiac electrical and mechanical synchrony of SRs. METHODS: We retrospectively analyzed CRT recipients between 2008 and 2016 in 2 centers to identify SRs, whose left ventricular (LV) ejection fraction was increased to ≥50% at follow-up. Cardiac synchrony was evaluated in intrinsic and BIV-paced rhythms. Electrical synchrony was estimated by QRS duration and LV mechanical synchrony by single-photon emission computed tomography myocardial perfusion imaging. RESULTS: Seventeen SRs were included with LV ejection fraction increased from 33.0 ±â€Š4.6% to 59.3 ±â€Š6.3%. The intrinsic QRS duration after super-response was 148.8 ±â€Š30.0 ms, significantly shorter than baseline (174.8 ±â€Š11.9 ms, P = 0.004, t = -3.379) but longer than BIV-paced level (135.5 ±â€Š16.7 ms, P = 0.042, t = 2.211). Intrinsic LV mechanical synchrony significantly improved after super-response (phase standard deviation [PSD], 51.1 ±â€Š16.5° vs. 19.8 ±â€Š8.1°, P < 0.001, t = 5.726; phase histogram bandwidth (PHB), 171.7 ±â€Š64.2° vs. 60.5 ±â€Š22.9°, P < 0.001, t = 5.376) but was inferior to BIV-paced synchrony (PSD, 19.8 ±â€Š8.1° vs. 15.2 ±â€Š6.4°, P = 0.005, t = 3.414; PHB, 60.5 ±â€Š22.9° vs. 46.0 ±â€Š16.3°, P = 0.009, t = 3.136). CONCLUSIONS: SRs had significant improvements in cardiac electrical and LV mechanical synchrony. Since intrinsic synchrony of SRs was still inferior to BIV-paced rhythm, continued BIV pacing is needed to maintain longstanding and synchronized contraction.

Microvolt T-wave alternans complemented with electrophysiologic study for prediction of ventricular tachyarrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy: a long-term follow-up study.

BACKGROUND: The long-term predicted value of microvolt T-wave alternans (MTWA) for ventricular tachyarrhythmia in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) remains unclear. Our study explored the characteristics of MTWA and its prognostic value when combined with an electrophysiologic study (EPS) in patients with ARVC. METHODS: All patients underwent non-invasive MTWA examination with modified moving average (MMA) analysis and an EPS. A positive event was defined as the first occurrence of sudden cardiac death, documented sustained ventricular tachycardia (VT), ventricular fibrillation, or the administration of appropriate implantable cardioverter defibrillator therapy including shock or anti-tachycardia pacing. RESULTS: Thirty-five patients with ARVC (age 38.6 ±â€Š11.0 years; 28 males) with preserved left ventricular (LV) function were recruited. The maximal TWA value (MaxValt) was 17.0 (11.0-27.0) µV. Sustained VT was induced in 22 patients by the EPS. During a median follow-up of 99.9 ±â€Š7.7 months, 15 patients had positive clinical events. When inducible VT was combined with the MaxValt, the area under the curve improved from 0.739 to 0.797. The receiver operating characteristic curve showed that a MaxValt of 23.5 µV was the optimal cutoff value to identify positive events. The multivariate Cox regression model for survival showed that MTWA (MaxValt, hazard ratio [HR], 1.06; 95% confidence interval [CI], 1.01-1.11; P = 0.01) and inducible VT (HR, 5.98; 95% CI, 1.33-26.8; P = 0.01) independently predicted positive events in patients with ARVC. CONCLUSIONS: MTWA assessment with MMA analysis complemented by an EPS might provide improved prognostic ability in patients with ARVC with preserved LV function during long-term follow-up.

Methotrexate-loaded biodegradable polymeric micelles for lymphoma therapy.

Drug resistance and recurrence are the main clinical challenges in chemotherapy of lymphoma. Methotrexate (MTX), especially high dose MTX (HD MTX), is extensively used to treat some aggressive subtypes of lymphoma, such as Burkitt's lymphoma, in order to overcome drug resistance. But poor solubility of the free drug and severe side effects of HD MTX limit its clinical application. Polymeric micelle, as an ideal nano delivery system, provides effective solutions to these problems. In this work, monomethyl poly (ethylene glycol)-poly (ε-caprolactone) (MPEG-PCL) was employed to load MTX through a one-step solid dispersion method. MTX loaded micelles had a small particle size of 25.64 ±â€¯0.99 nm and polydisperse index (PDI) of 0.176 ±â€¯0.05. Drug loading and encapsulation efficiency of MTX loaded micelles were 5.57 ±â€¯0.14% and 92.46 ±â€¯2.38%. Compared with free MTX, MTX loaded micelles demonstrated a much slower and sustained release behavior in vitro. MTT assay and cell apoptosis study suggested that MTX loaded micelles were more effective in inhibiting proliferation and inducing apoptosis on Raji lymphoma cells than MTX injection, which was especially distinct in high dose groups. Cellular uptake study indicated that MPEG-PCL micelle had a 1.5 times higher uptake rate in Raji cells. As for in vivo studies, MTX loaded micelles were more competent to suppress tumor growth and prolong survival time than MTX injection in the subcutaneous Raji lymphoma model. Notably, the high dose group of micelle formulation exhibited the strongest anti-tumor effect without additional toxicity. Furthermore, immunofluorescent and immunohistochemical studies showed that tumors of MPEG-PCL-MTX treated mice had more apoptotic cells and fewer proliferative cells. In conclusion, MPEG-PCL-MTX micelle is an excellent intravenously injectable formulation of MTX with both good solubility and enhanced anti-tumor activity, which perfectly meets clinical demands, especially for administration of HD MTX.

Effects of oral selenium and magnesium co-supplementation on lipid metabolism, antioxidative status, histopathological lesions, and related gene expression in rats fed a high-fat diet.

BACKGROUND: Supplementation with Selenium (Se) has been shown to lower blood cholesterol and increase tissue concentrations of the antioxidant glutathione (GSH); however, the effects of Se supplementation, in combination with supplemental magnesium, on high fat-induced hyperlipidemia have not been studied. This study was designed to elucidate the effects of oral selenium and magnesium co-supplementation on antihyperlipidemic and hepatoprotective, antioxidative activities, and related gene expression in a hyperlipidemic rat model. METHODS: Forty male Sprague Dawley rats were divided into 4 groups: one group served as control group (CT), provided control diet; The other groups were made hyperlipidemic with high-fat diet; specifically, a high-fat diet group (HF); low-dose selenium (0.05 mg/kg·bw) + low-dose magnesium (5.83 mg/kg·bw) supplement high-fat diet group (HF + LSe + LMg) and high-dose selenium (0.10 mg/kg·bw) + high-dose magnesium (58.33 mg/kg·bw) supplement high-fat diet group (HF + HSe + HMg). The first 4 weeks of the experiment was a hyperlipidemia inducing period using high-fat diet and the following 8 weeks involved in selenium and magnesium co-supplementation. On day 0, 20, 40 and 60 of the intervention, lipid profile was measured. At the end of the 12-week experiments, final blood and liver samples were collected for the measurements of lipid profile, antioxidative indexes, pathological examination, and liver lipid metabolism related gene expression. RESULTS: The elevated levels of serum and liver total cholesterol (TC) and serum LDL-C induced by feeding high-fat diets were significantly reduced by low-dose Se and Mg co-supplementation. Both doses of selenium and magnesium co-supplementation notably decreased the blood and liver TG levels, liver function indexes ALT and AST and the ratio of TC/HDL-C and TG/HDL-C. In contrast, Se and Mg supplementation showed a substantial increase in Se-dependent glutathione peroxidase (GSH-Px) and SOD activities and an significant reduce of level of MDA of hyperlipidemic rats. Oil Red O staining showed that selenium and magnesium co-supplementation significantly reduced hepatic intracellular triacylglycerol accumulation. H&E staining also showed that selenium and magnesium co-supplementation can attenuate liver steatosis. Selenium and magnesium co-supplementation remarkably inhibited the mRNA expression level of hepatic lipogenesis genes liver X receptor alpha (LXRα),SREBP-1c and FASN (fatty acid synthase), regulated the mRNA expression levels of liver enzymes related to cholesterol metabolism, including the down regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) and the upregulation of cholesterol 7α-hydroxylase (CYP7A1) and lecithin cholesterol acyltransferase (LCAT) in the liver of hyperlipidemia rats. CONCLUSIONS: Oral selenium and magnesium co-supplementation inhibited an increase of lipid and liver profile and liver function index induced by a high-fat diet, and enhanced the activity of the antioxidant enzymes. Selenium combined with magnesium is a promising therapeutic strategy with lipid-lowering and antioxidative effects that protects the liver against hyperlipidemia.

Pathway-based analysis of genome-wide association study of circadian phenotypes.

Sleepiness affects normal social life, which attracts more and more attention. Circadian phenotypes contribute to obvious individual differences in susceptibility to sleepiness. We aimed to identify candidate single nucleotide polymorphisms (SNPs) which may cause circadian phenotypes, elucidate the potential mechanisms, and generate corresponding SNP-gene-pathways. A genome-wide association studies (GWAS) dataset of circadian phenotypes was utilized in the study. Then, the Identify Candidate Causal SNPs and Pathways analysis was employed to the GWAS dataset after quality control filters. Furthermore, genotype-phenotype association analysis was performed with HapMap database. Four SNPs in three different genes were determined to correlate with usual weekday bedtime, totally providing seven hypothetical mechanisms. Eleven SNPs in six genes were identified to correlate with usual weekday sleep duration, which provided six hypothetical pathways. Our results demonstrated that fifteen candidate SNPs in eight genes played vital roles in six hypothetical pathways implicated in usual weekday bedtime and six potential pathways involved in usual weekday sleep duration.

Subchronic toxicity study in rats evaluating genetically modified DAS-81419-2 soybean.

A 90-day feeding study in rats was conducted to evaluate the subchronic oral toxicity of genetically modified (GM) DAS-81419-2 soybean. Wistar rats were fed with diets containing toasted soybean meal produced from DAS-81419-2 soybean grain that expresses the Cry1F, Cry1Ac, and Pat proteins or containing conventional soybean at doses of 30.0%, 15.0%, 7.5%, or 0% (control group) for 90 consecutive days. The general behavior, body weight and food consumption were observed. At the middle and end of the experiment, blood, serum, and urine samples were collected for biochemical assays. At the conclusion of the study, the internal organs were weighed and histopathological examination was completed. The rats exhibited free movement and shiny coats without any abnormal symptoms or abnormal secretions in their noses, eyes, or mouths. There were no adverse effects on body weight in GM soybean groups and conventional soybean groups. No biological differences in hematological, biochemical, or urine indices were observed. No significant differences in relative organ weights were detected between the experimental groups and the control group. No histopathological changes were observed. Under the conditions of this study, DAS-81419-2 soybean did not cause any treatment-related effects in Wistar rats following 90 days of dietary administration.

Effect of magnesium gluconate administration on lipid metabolism, antioxidative status, and related gene expression in rats fed a high-fat diet.

To explore the effect of magnesium gluconate (MgG) on lipid metabolism and its regulation mechanism through animal experiments, and to provide basis for MgG dietary intervention in hyperlipidemia. The first four weeks was hyperlipidemia-inducing period through high-fat diet and the following eight weeks was the MgG supplementation. At the end of the experiment, blood and liver samples were collected for the measurements of lipid profile, antioxidative indexes, pathological examination, and cholesterol metabolism-related gene expression. Oral administration of MgG notably decreased the blood levels of TC, TG, LDL-C and liver function index ALT and AST of hyperlipidemic rats. The rats supplemented with magnesium showed a huge increase in the GSH-Px and SOD activities, and reduced the heart weight and liver lipid accumulation of high-fat diet fed rats. MgG remarkably up-regulated the mRNA expression levels of LDLR and CYP7A1 of liver enzymes related to cholesterol metabolism. Oral magnesium supplementation inhibited an increase in lipid profile and liver function index by a high-fat diet, and enhanced the activity of the antioxidant enzymes. Magnesium has lipid-lowering and antioxidative effects that protect the liver against hyperlipidemia.

Toxicity Evaluation and Anti-Tumor Study of Docetaxel Loaded mPEG-Polyester Micelles for Breast Cancer Therapy.

In this work, docetaxel (DTX) was encapsulated in monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) micelles and monomethoxy poly(ethylene glycol)-poly(D, L-lactic acid) (mPEG-PLA) micelles, respectively. For the further application, the acute/genetic toxicity evaluation and pharmacokinetic/pharmacodynamic study of the two kinds of micellar nanomedicines were performed. In the study of anticancer activity in vitro and in vivo, DTX micelles showed better tumorgrowth inhibition than free DTX. The pharmacokinetic and tissue distribution studies showed that the DTX incorporated in micelles (especially in DTX-mPEG-PCL) retained significantly higher concentration in plasma and tumor tissue compared with free DTX. The acute toxicity and genotoxicity studies indicated that DTX micelles were safer than the docetaxel injection in cancer therapy and DTX-mPEG-PCL had less damage to DNA than DTX-mPEG-PLA. So the micelles had a pronounced effect on reducing acute toxicity and genotoxicity of docetaxel. In conclusion, DTX micelles were efficient and safe on breast carcinoma chemotherapy.

Biodegradable Self-Assembled Micelles Based on MPEG-PTMC Copolymers: An Ideal Drug Delivery System for Vincristine.

Despite advantageous properties, micelles using methoxy poly(ethylene glycol)-poly(trimethylene carbonate) (MPEGPTMC) have not been widely studied. In this work, we aim to develop a novel vehicle for vincristine (VCR) based on a MPEG-PTMC micelle system. MPEG-PTMC with a series of molecular weights were synthesized and screened for the appropriate range for forming stable VCR micelles. The prepared micelles were then characterized in vitro and in vivo . VCR micelles presented high stability and ideal sustained release profile. The passive targeting effect was also enhanced compared with liposomal VCR. These results provide critical data to give the first clues regarding novel VCR micelles which exhibit potential for clinical application.

Ovarian cancer treatment with a tumor-targeting and gene expression-controllable lipoplex.

Overexpression of folate receptor alpha (FRα) and high telomerase activity are considered to be the characteristics of ovarian cancers. In this study, we developed FRα-targeted lipoplexes loaded with an hTERT promoter-regulated plasmid that encodes a matrix protein (MP) of the vesicular stomatitis virus, F-LP/pMP(2.5), for application in ovarian cancer treatment. We first characterized the pharmaceutical properties of F-LP/pMP(2.5). The efficient expression of the MP-driven hTERT promoter in SKOV-3 cells was determined after an in-vitro transfection assay, which was significantly increased compared with a non-modified LP/pMP(2.5) group. F-LP/pMP(2.5) treatment significantly inhibited the growth of tumors and extended the survival of mice in a SKOV-3 tumor model compared with other groups. Such an anti-tumor effect was due to the increased expression of MP in tumor tissue, which led to the induction of tumor cell apoptosis, inhibition of tumor cell proliferation and suppression of tumor angiogenesis. Furthermore, a preliminary safety evaluation demonstrated a good safety profile of F-LP/pMP(2.5) as a gene therapy agent. Therefore, FRα-targeted lipoplexes with therapeutic gene expression regulated by an hTERT promoter might be a promising gene therapy agent and a potential translational candidate for the clinical treatment of ovarian cancer.

Synthesis, characterization, and application of reversible PDLLA-PEG-PDLLA copolymer thermogels in vitro and in vivo.

In this study, a series of injectable thermoreversible and thermogelling PDLLA-PEG-PDLLA copolymers were developed and a systematic evaluation of the thermogelling system both in vitro and in vivo was performed. The aqueous PDLLA-PEG-PDLLA solutions above a critical gel concentration could transform into hydrogel spontaneously within 2 minutes around the body temperature in vitro or in vivo. Modulating the molecular weight, block length and polymer concentration could adjust the sol-gel transition behavior and the mechanical properties of the hydrogels. The gelation was thermally reversible due to the physical interaction of copolymer micelles and no crystallization formed during the gelation. Little cytotoxicity and hemolysis of this polymer was found, and the inflammatory response after injecting the hydrogel to small-animal was acceptable. In vitro and in vivo degradation experiments illustrated that the physical hydrogel could retain its integrity as long as several weeks and eventually be degraded by hydrolysis. A rat model of sidewall defect-bowel abrasion was employed, and a significant reduction of post-operative adhesion has been found in the group of PDLLA-PEG-PDLLA hydrogel-treated, compared with untreated control group and commercial hyaluronic acid (HA) anti-adhesion hydrogel group. As such, this PDLLA-PEG-PDLLA hydrogel might be a promising candidate of injectable biomaterial for medical applications.

Recent Advances of Poly(ether-ether) and Poly(ether-ester) Block Copolymers in Biomedical Applications.

BACKGROUND: Poly(ether-ether) and poly(ether-ester) block copolymers have been widely applied in biomedical fields over two decades due to their good safety and biocompatibility. Poly(ethylene glycol), poly(ethylene glycol)-poly(propylene glycol) and poly(lactic-co-glycolic acid) have been approved as excipients by Food and Drug Administration. Because of the broad perspective in biomedical fields, many novel poly(etherether) and poly(ether-ester) block copolymers have been developed for drug delivery, gene therapy and tissue engineering in recent years. This review focuses on active targeting theranostic systems, gene delivery systems and tissue engineering based on poly(ether-ether) and poly(ether-ester) block copolymers. METHODS: We perform a structured search of bibliographic databases for peer-reviewed scientific reports using a focused review question and inclusion/exclusion criteria. The literatures related to the topics of this review are cataloged according to the developed copolymers or their applications such as active targeting theranostic systems, gene delivery systems and tissue engineering. Some important advances and new trends are summarized in this review. RESULTS: Some commercial poly(ether-ether) copolymers have been used as excipients for drug research and development. Amphiphilic and biodegradable poly(ether-ester) diblock copolymers are capable of formulating biomedical nanoparticulate theranostic systems, and targeting moiety-functionalized poly(ether-ester) diblock copolymers will be further developed and applied in biomedical nanotechnology fields in the near future. Meanwhile, triblock or multiblock poly(ether-ether) and poly(ether-ester) copolymers with environmentsensitive properties are suitable for gene delivery and tissue engineering. Poly(ether-ether) and poly(ether-ester) copolymers are being extensively applied in active targeting theranostic systems, gene delivery systems and tissue engineering. CONCLUSIONS: Biodegradable, environment-sensitive and targeting moiety-functionalized block copolymers, which are being applied in active targeting theranostic systems, gene delivery systems and tissue engineering, are promising candidates for treatment of various diseases.