Nanoparticle drug delivery systems responsive to tumor microenvironment: Promising alternatives in the treatment of triple-negative breast cancer.

The conventional therapeutic treatment of triple-negative breast cancer (TNBC) is negatively influenced by the development of tumor cell drug resistant, and systemic toxicity of therapeutic agents due to off-target activity. In accordance with research findings, nanoparticles (NPs) responsive to the tumor microenvironment (TME) have been discovered for providing opportunities to selectively target tumor cells via active targeting or Enhanced Permeability and Retention (EPR) effect. The combination of the TME control and therapeutic NPs offers promising solutions for improving the prognosis of the TNBC because the TME actively participates in tumor growth, metastasis, and drug resistance. The NP-based systems leverage stimulus-responsive mechanisms, such as low pH value, hypoxic, excessive secretion enzyme, concentration of glutathione (GSH)/reactive oxygen species (ROS), and high concentration of Adenosine triphosphate (ATP) to combat TNBC progression. Concurrently, NP-based stimulus-responsive introduces a novel approach for drug dosage design, administration, and modification of the pharmacokinetics of conventional chemotherapy and immunotherapy drugs. This review provides a comprehensive examination of the strengths, limitations, applications, perspectives, and future expectations of both novel and traditional stimulus-responsive NP-based drug delivery systems for improving outcomes in the medical practice of TNBC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Protective effects of psoralen polymer lipid nanoparticles on doxorubicin - induced myocardial toxicity

Abstract Doxorubicin (DOX) induced myocardial toxicity may limit its therapeutic use in clinic. Psoralen (PSO), a major active tricyclic furocoumarin extracted from Psoralea corylifolia, is widely used as an antineoplastic agent in treatment of leukemia and other cancers. This study is aim to find the protective effect of psoralen polymer lipid nanoparticles (PSO-PLN) on doxorubicin-induced myocardial toxicity in mice. The model of myocardial toxicity induced by DOX was established. The experiment was divided into 6 groups: normal saline group, DOX + Sulfotanshinone Sodium, DOX + PSO-PLN (3 mg/kg), DOX + PSO-PLN (6 mg/kg), DOX + PSO-PLN (9 mg/ kg), DOX group. DOX alone treated mice lead to a significant decrease in the body weight, heart weight, and increase in the serum levels of lactate dehydrogenase (LDH), creatine kinase (CK) and malondialdehyde (MDA) markers of cardiotoxicity. However, DOX reduced glutathione (GSH) content and activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPX), were recovered by PSO-PLN. And PSO-PLN also decreased markers of cardiotoxicity in the serum. Western blotting data showed that the protective effects of PSO-PLN might be mediated via regulation of protein kinase A (PKA) and p38. Our study suggest that PSO-PLN possesses antioxidant activities, inactivating PKA and p38 effect, which in turn protect the heart from the DOX-induced cardiotoxicity.

Polymeric-based microneedle arrays as potential platforms in the development of drugs delivery systems.

BACKGROUND: Microscopic patches as quite promising platforms in transdermal drug delivery suffer from conventional injections. In other hand, a wide range of pharmacokinetics, ranging from fast oral administration to sustained drug delivery, can be implemented with the help of microneedle arrays (MNAs). AIM OF REVIEW: Hence, in this paper, we overviewed different kinds of MNAs such as solid/coated, hollow, porous, hydrogel/swellable, and merged-tip geometry followed by introducing different types of material (silicon, glass, ceramics, dissolving and biodegradable polymers, and hydrogel) used for fabrication of MNAs. Afterwards, some conventional and brand-new simple and customizable MN mold fabrication techniques were surveyed. Polymeric MNAs have received a great deal of attention due to their potential biocompatibility and biodegradability in comparison to other materials. Therefore, we also covered different kinds of polymers such as hydrogel/swellable, dissolving and biodegradable analogues used for the development of MNAs as potential candidates in drug delivery systems (DDSs). Finally, we discussed different challenges and future perspectives in the aspect of MNAs-based drug delivery platforms. KEY SCIENTIFIC CONCEPTS OF REVIEW: This review may provide guidelines for the rational design of polymeric MNAs-based DDSs for promising programmable drug release and enhanced therapeutic effect.

Application of the Cobas 4800 System for the Detection of High-Risk Human Papillomavirus in 5650 Asymptomatic Women.

High-risk papillomavirus (HR-HPV) testing combined with cytology improves the detection of cervical lesions and increases length of screening intervals. For a population-based HR-HPV survey, testing automation is in great need. The Cobas 4800 HPV Test System is a fully automated assay that can simultaneously detect HPV16, HPV18, and other 12 pooled HR-HPV genotypes. This system has been employed for HR-HPV screening in a number of countries; however, such application in a large population in China has not been documented. In this study, we employed the Cobas 4800 HPV Test System to detect HR-HPV in cervical cytology specimens collected from a total of 5650 asymptomatic women from a region of South China. We reported the following: (1) the prevalence of the 14 genotypes of HR-HPV was 12.96%; (2) for those with HR-HPV infection, 2.25% were positive for HPV16, 0.50% for HPV18, 9.15% for pooled 12 HPV types, and 1.06% for multiple HPV infection; and (3) there was no significant difference in the HR-HPV prevalence among different age groups. HPV16 and HPV18 have been shown to be the predominant HPV types found in cervical cancer patients in some regions in China, indicating that a fully automated assay like the Cobas 4800 HPV Test System is especially valuable for population-based HR-HPV screening in these regions as this assay can concurrently detect HPV16 and HPV18.

Nanotargeted agents: an emerging therapeutic strategy for breast cancer.

Breast cancer is the most common female cancer worldwide and represents 12% of all cancer cases. Improvements in survival rates are largely attributed to improved screening and diagnosis. Conventional chemotherapy remains an important treatment option but it is beset with poor cell selectivity, serious side effects and resistance. Nanoparticle drug delivery systems bring promising opportunities to breast cancer treatment. They may improve chemotherapy by targeting drugs to tumors, generating high drug concentrations at tumors providing slow release of the drug, increased drug stability and concomitant reductions in side effects. The nanotechnology-based drug delivery approaches and the current research and application status of nano-targeted agents for breast cancer are discussed in this review to provide a basis for further study on targeted drug delivery systems.

A review of pharmacological and clinical studies on the application of Shenling Baizhu San in treatment of Ulcerative colitis.

ETHNOPHARMACOLOGICAL RELEVANCE: The prescription of Shenling Baizhu San (SLBZS) was derived from the Song Dynasty "Taiping Huimin Heji Ju Fang", which was a representative prescription for treating spleen asthenic diarrhea. The prescription comprised of 10 herbs for treating weak spleen and stomach. It describes symptoms like eating less, loose stools, cough, shortness of breath and tired limbs. SLBZS has been reported to be capable of eliminating discomfort when it is administered for treating irritable bowel syndrome and diarrhea. This traditional Chinese medicine (TCM) formula has been widely used for improving gastrointestinal dysfunction and modifying the immune response to inflammation. AIM OF THE STUDY: This review is aimed to provide the up-to-date information on the pharmacology and clinical research of SLBZS in the treatment of ulcerative colitis (UC), and to discuss the research findings and possible deficiencies, hoping to better guide the clinical application and scientific research of SLBZS in the treatment of UC. MATERIALS AND METHODS: Relevant studies from 2004 to 2018 on SLBZS in the treatment of UC mechanism and curative effect were collected from ancient books, pharmacopoeia, reports, thesis via library and Digital databases (PubMed, CNKI, Google Scholar, Web of Science, SciFinder, Springer, Elsevier, etc). RESULTS: SLBZS could regulate inflammatory factors and intestinal flora, and ERK/p38 MAPK signaling pathway may be one of its targets. In addition, clinical research results show that SLBZS has a good therapeutic effect on UC, and the adverse reactions are small. CONCLUSION: Although SLBZS has achieved some success in the treatment of UC, there are still some scientific gaps. There is a lack of uniform standards for constructing UC animal models, and some methods of modeling through environmental and dietary interventions are not reproducible, and there is a lack of uniform dosing regimen standards. SLBZS doses follow the tradition and lack toxicological validation. Therefore, more specific toxicological research models are essential. The clinical application of SLBZS requires reassessment and standardization. Although all clinical research reports randomly assigned patients to different groups, most did not describe a detailed method of randomization and no description of the analysis data. In addition, extensive in vitro studies and further in-depth molecular studies are essential for the determination of mechanisms that have been performed in all in vivo experiments on animal models and patients.

Polymer-lipid hybrid nanoparticles: A novel drug delivery system for enhancing the activity of Psoralen against breast cancer.

A polymer-lipid hybrid nanocarrier was developed to encapsulate psoralen (PSO) to improve its water solubility and bioavailability. The effects of PSO-loaded polymer-lipid hybrid nanoparticles (PSO-PLNs) on breast cancer MCF-7 cells were investigated. PSO-PLNs were prepared through a nanoprecipitation method and were optimized by a central composite design-response surface methodology using particle size and entrapment efficiency as indices. Dynamic light scattering and transmission electron microscopy analysis confirmed the physicochemical characterizations of PSO-PLNs, which had an average size of 93.44 ±â€¯2.39 nm and a zeta potential of -27.63 ±â€¯0.31 mV. In vitro drug release of PSO-PLNs was evaluated using dialysis and showed a delayed release compared with free PSO. The in vivo anticancer efficiency of PSO-PLNs was appreciated using a MCF-7 breast tumor model. Administration of PSO-PLNs showed similar antitumor efficacy but lower toxicity compared with doxorubicin. Our designed nanocarriers successfully optimized the pharmacokinetics of PSO via improved systemic delivery.

Effect of Xuefu Zhuyu Decoction Pretreatment on Myocardium in Sepsis Rats.

Xuefu Zhuyu Decoction (XFZYD), the classical recipe for promoting blood circulation by removing blood stasis, has been used in China for a long history clinically. XFZYD has been found to improve cardiac function through reducing inflammation. However, the effect of XFZYD on myocardial apoptosis remains unclear. Herein, we investigated the mechanism of XFZYD preconditioning on myocardial injury in sepsis rats. The rats were treated with XFZYD one week, followed with intraperitoneal injection of lipopolysaccharide (LPS: 10 mg/kg) to induce sepsis. Pretreatment with XFZYD could reverse the effects of LPS-induced decreased mean arterial pressure (MAP) and increased heart rate (HR). XFZYD decreased the levels of malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) in serum or in heart. TUNEL staining revealed that the apoptotic index of XFZYD was significantly lower compared with the LPS group (P<0.05). Western blot results showed that the high doses of pretreatment XFZYD group can reduce the Bax expression of myocardial tissue in rats (P<0.05, P<0.01). The expression of Bcl-2 in XFZYD group was significantly higher than that in the LPS group (P<0.01), while the expression of caspase-3 in treatment group was significantly lower than that in the LPS group only after 12 h modeling (P<0.01). In addition, caspase-3 activity in rat cardiomyocytes of XFZYD-treated animals was significantly decreased. These findings suggest that pretreatment with XFZYD exerts a protective effect in the myocardium of septic rats by inhibiting myocardial cell apoptosis and antioxidation.

Proteomic analysis and identification of intestinal FBP as a predictor of gut dysfunction during heatstroke in mice.

BACKGROUND: Gut-derived endotoxin and pathogenic bacteria have been proposed to be an important causative factor of morbidity and death during heatstroke. However, the molecular changes underlying heat stress-induced small intestine lesions have not yet been well characterized. MATERIALS AND METHODS: A heatstroke model was established in mice, and the thermal response and pathologic changes in the small intestine were examined during heat stress. Proteins extracted from the small intestine of the heated and control mice were separated by two-dimensional (2D) gel electrophoresis, and different protein spots were further identified by peptide mass fingerprint. Targeted proteins were further verified by Western blot and immunohistochemistry analysis. RESULTS: Pathologic changes in the small intestine during heat stress were found to be substantial. Using 2 D gel proteomics we identified 14 proteins that were regulated differentially in the small intestine of the mice subjected to heat stress. These 14 identified proteins, seven were down-regulated and the other seven were up-regulated, appeared to be involved in metabolism, chaperone, cell skeleton, defense, signal transduction, DNA repair, and recombination. Using Western blot and immunohistochemical analysis, we further confirmed that down-regulated expression of intestinal fructose 1,6-bisphosphatase (FBP) correlated to the severity of small intestine lesions during heat stress and cooling treatment. CONCLUSIONS: Our results identified 14 differentially expressed proteins, which may contribute to the understanding of molecular mechanisms underlying intestinal injury during heatstroke. Furthermore, intestinal FBP, one of the seven down-regulated proteins, may function as a potential marker for prognosis of gut dysfunction.

Curcumin protects intestinal mucosal barrier function of rat enteritis via activation of MKP-1 and attenuation of p38 and NF-κB activation.

BACKGROUND: Intestinal mucosa barrier (IMB) dysfunction results in many notorious diseases for which there are currently few effective treatments. We studied curcumin's protective effect on IMB and examined its mechanism by using methotrexate (MTX) induced rat enteritis model and lipopolysaccharide (LPS) treated cell death model. METHODOLOGY/PRINCIPAL FINDINGS: Curcumin was intragastrically administrated from the first day, models were made for 7 days. Cells were treated with curcumin for 30 min before exposure to LPS. Rat intestinal mucosa was collected for evaluation of pathological changes. We detected the activities of D-lactate and diamine oxidase (DAO) according to previous research and measured the levels of myeloperoxidase (MPO) and superoxide dismutase (SOD) by colorimetric method. Intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß) were determined by RT-PCR and IL-10 production was determined by ELISA. We found Curcumin decreased the levels of D-lactate, DAO, MPO, ICAM-1, IL-1ß and TNF-α, but increased the levels of IL-10 and SOD in rat models. We further confirmed mitogen-activated protein kinase phosphatase-1 (MKP-1) was activated but phospho-p38 was inhibited by curcumin by western blot assay. Finally, NF-κB translocation was monitored by immunofluorescent staining. We showed that curcumin repressed I-κB and interfered with the translocation of NF-κB into nucleus. CONCLUSIONS/SIGNIFICANCE: The effect of curcumin is mediated by the MKP-1-dependent inactivation of p38 and inhibition of NF-κB-mediated transcription. Curcumin, with anti-inflammatory and anti-oxidant activities may be used as an effective reagent for protecting intestinal mucosa barrier and other related intestinal diseases.

[Role of assessment and monitoring of human leucocyte antigen-DR on CD14+ monocyte in postoperative infection in patients after orthotopic liver transplantation].

OBJECTIVE: To investigate the changes in expression level of human leucocyte antigen-DR (HLA-DR) on CD14(+) monocyte (CD14(+)/HLA-DR) in the patients after orthotopic liver transplantation, and its role in monitoring postoperative infection. METHODS: Sixty-three patients with liver transplantation were divided into three groups, non-infection group with 47 cases, infection group with 10 cases and septic shock group with 6 cases [according to the definition of septic shock of American College of Chest Physicians/Society for Critical Care Medicine (ACCP/SCCM)]. CD14(+)/HLA-DR expression ratio was assessed with flow cytometer, and its clinical implication was evaluated by receiver operating characteristic (ROC) curve assay. RESULTS: CD14(+)/HLA-DR expression ratio in infection group [(29.6+/-7.2)%] and septic shock group [(16.3+/-10.5)%] were significantly lower than that in non-infection group [(62.3+/-18.3)%, both P<0.01], but no significant difference of CD14(+)/HLA-DR expression ratio was found between infection group and septic shock group (P=0.128). Total area under ROC curve of CD14(+)/HLA-DR expression ratio for the infection was 0.965, its sensitivity and specificity at 36.35% cut off were 100.0% and 93.6%, respectively. Total area under ROC curve of CD14(+)/HLA-DR expression ratio to predict septic shock was 0.968, its sensitivity and specificity at 31.97% cut off were 100.0% and 87.7%, respectively. Comparing the change of CD14(+)/HLA-DR expression, it was lower in the infection group and septic shock group (P<0.05 and P<0.01), and the expression rate was lowest during period of serious infection in the two groups [infection group: (29.6+/-7.2)%, septic shock group: (16.3+/-0.5)%, all P<0.01]. CONCLUSION: For the patients with possible infection after liver transplantation, sequential assessment of CD14(+)/HLA-DR expression ratio would be a good marker for the judgment of patient's conditions and outcome. CD14(+)/HLA-DR expression ratio below 36.35% could be used as the prewarning value for the diagnosis of postoperative infection, and 31.97% could be used as the critical value for the diagnosis of septic shock.

[Combined effect of high mobile group box-1 protein and lipopolysaccharide on release of cytokines from human HepG2 cells].

OBJECTIVE: To study the effects of high mobile group box-1 protein (HMGB1) and lipopolysaccharide (LPS) singly or in combination on release of cytokines from human liver carcinoma cell line (HepG2). METHODS: HepG2 cells were cultured, and purified HMGB1 protein was prepared by chromatography on Ni(2+)-NTA Sepharose column under natural conditions with recombinant expression plasmid pET14b-HMGB1. Different concentrations of HMGB1 (0, 0.01, 0.1, 1, 10 mg/L) and LPS (0, 0.1, 1, 10, 100 mg/L) were added into the cultured cells for 24 hours, respectively. Then the supernatant were collected to detect the levels of granulocyte/macrophage colony stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 beta (IL-1 beta), IL-2, IL-4, IL-6, IL-8, IL-10, and IL-12 by using LiquiChip system. Lastly, HepG2 cells were co-stimulated with 10 mg/L LPS and 1 mg/L HMGB1 for 24 hours. The supernatant were collected to determine the levels of above ten of cytokines . RESULTS: The expression and release of IL-6 and IL-8 increased from HepG2 cells after being stimulated by LPS in a dose-dependent manner, but there were no changes in other eight kinds of cytokines (P<0.05 or P<0.01). Low concentration of HMGB1 could up-regulate the expression of IL-6 and IL-8 in HepG2 cells (both P<0.01). But the extent of induction decreased with higher concentration of HMGB1. Similar to LPS, there was no effect of HMGB1 on the expression of other eight kinds of cytokines from cultured HepG2 cells. Furthermore, high concentration of HMGB1 could obviously inhibit the upregulation of IL-6 and IL-8 by high concentration of LPS when the HepG2 cells were co-stimulated with LPS and HMGB1 (both P<0.01). CONCLUSION: HepG2 cells could only express and release a few kinds of cytokines when the cells were stimulated with pro-inflammatory agents, such as LPS or HMGB1. Two kinds of cytokines, IL-6 and IL-8 could be up-regulated by LPS and low concentration of HMGB1, and HMGB1 acted as an inhibitor of LPS to down-regulate the expression and release of IL-6 and IL-8 from HepG2 cells.

[Clinical effects of ulinastatin and thymosin alpha1 on immune-modulation in septic patients].

OBJECTIVE: To analyze clinical effect of immuno-modulatory therapy with ulinastatin and thymosin alpha1 on patients with sepsis. METHODS: Two hundred and forty-two septic patients admitted to Guangzhou General Hospital of Guangzhou Military Command intensive care unit (ICU) during 2004.10-2008.6 were included, and they were randomly divided into treatment group (128 cases) and control group (114 cases). The patients in control group were given regular conventional treatment according to Surviving Sepsis Campaign (SSC) in 2004, including early fluid resuscitation, antibiotic therapy, mechanical ventilation (MV) and blood purification. The treatment group received conventional treatment plus immuno-modulation therapy including ulinastatin (first 200 kU injection intravenous twice a day for 4 days and 100 kU for another 6 days) and thymosin alpha1 (1.6 mg subcutaneous twice a day for 4 days, followed by 1.6 mg per day subcutaneous for another 6 days). The total treatment course was 10 days. General demographics were observed, and acute physiology and chronic health evaluation II (APACHE II) scores were recorded. Serum interleukin-6 (IL-6), IL-10 levels of peripheral blood were detected by enzyme linked immunosorbent assay (ELISA). Peripheral blood CD14(+) monocyte human leucocyte antigen DR (HLA-DR) expression, and ratio of helper T lymphocyte 1 (Th1) cytokines interferon-gamma (CD4(+)IFN-gammaww(+)), and Th2 cytokines (CD4(+) IL-4(+)) were assessed with flow cytometer. Duration of infection and MV, length of ICU stay, rate of development of multiple organ dysfunction syndrome (MODS) and mortality rate on 28 days were observed as end-point. RESULTS: Before treatment, there was no difference in all biomarkers between two groups (all P>0.05). After treatment, peripheral blood CD14ww+ monocyte HLA-DR expression and the ratio of CD4(+)IFN-gamma (+)/CD4(+) IL-4(+) increased significantly in the treatment group (both P<0.05), with serum IL-6, IL-10 levels and APACHE II scores all reduced remarkably (all P<0.05). The values showed significant differences compared with those of control group (all P<0.05). The MODS development rate in the treatment group was much lower than that of control group (21% vs. 47%, P<0.05), and the length of use of MV was significantly reduced [(6.08+/-2.46) days vs. (8.23+/-3.47) days, P<0.05]. There was no difference in the infection duration and length of ICU stay (both P>0.05). The mortality rate on 28 days in the treatment group was much lower than that in control group (20% vs. 33%, P<0.05). CONCLUSION: The immuno-modulation therapy of ulinastatin and thymosin alpha1 can remarkably improve the duration of MV and the development rate of MODS and mortality rate on 28 days in the patients with sepsis, probably due to its effect in ameliorating the immuno-imbalance state of the patients. However, the duration of infection and length of ICU stay are not effected.

Serum procalcitonin at the time of admission to the ICU as a predictor of short-term mortality.

OBJECTIVE: This purpose of this study was to determine if serum procalcitonin (PCT) concentration at the time of admission to the ICU is a predictor of all-cause short-term mortality. DESIGN AND METHODS: This prospective cross-sectional study was conducted over a 16-month period with 86 consecutive critically ill patients. The semi-quantitative PCT-Q test was performed and APACHE II scores and C-reactive protein (CRP) concentrations were determined within 24 h of admission. RESULTS: PCT-Q test value was a better predictor of all-cause short-term mortality than CRP value or APACHE II score. PCT > or = 10 ng/mL was highly and independently correlated with mortality. Use of PCT-Q > or = 10 ng/mL was superior to use of APACHE II > or = 25 or CRP > or = 10 mg/dL as a predictor of poor outcome. CONCLUSIONS: A PCT-Q value > or = 10 ng/mL obtained at the time of admission to the ICU is a strong predictor of short-term mortality.

[Clinical value of monitoring CD14+ monocyte human leukocyte antigen (locus) DR levels in the early stage of sepsis].

OBJECTIVE: To explore the relationship of monitoring CD14(+) monocyte human leucocyte antigen (locus) DR (HLA-DR) and the outcome in the early stage of sepsis. METHODS: Thirty-six definitely diagnosed septic patients in intensive care unit (ICU) were included. CD14(+) monocyte HLA-DR levels were detected by flow cytometer on the first day of the study, and acute physiology and chronic health evaluation II (APACHE II) scores were evaluated. Their clinical values in predicting the outcome of the disease were assessed through correlation analysis. RESULTS: Among 36 sepsis patients CD14(+) monocyte HLA-DR level<30% was found in 6 patients (16.67%). The average APACHE II score was 24.17+/-4.45 (r=0.212, P=0.687), all of them die, CD14(+) monocyte HLA-DR level <40% was 27.78% (10/36), the scores of APACHE II score was 23.50+/-4.30 (r=-0.0251, P=0.484), and the mortality rate was 80% (8/10). CONCLUSION: CD14(+) monocyte HLA-DR level <30% is an immunosuppressive index. In predicting the outcome of sepsis, it might be better than APACHE II scores. Immunosuppression is primarily found in the early stage of sepsis, suggesting that the classical compensatory anti-inflammatory response syndrome (CARS) hypothesis needs to be revised and improved.