Inhibiting Multidrug Resistance with Transferrin-Targeted Polymersomes through Optimization of Ligand Density.

Transferrin-conjugated polymersomes, transferrin-biotin/avidin/biotin-Pluronic F127-poly(lactic acid) (Tf-F127-PLA), were successfully prepared through a biotin-avidin bridging technique to study their ability to inhibit multidrug resistance of cancer cells. Hydrophilic doxorubicin (DOX) was selected as the model drug to be loaded into Tf-F127-PLA polymersomes. DOX loaded in Tf-F127-PLA polymersomes was released fast initially, followed by a slow release. The effect of the transferrin ligand density of Tf-F127-PLA/DOX polymersomes on their targeting properties was studied by both cytotoxicity and cellular uptake assays against A549 lung cancer cells. It was shown that Tf-F127-PLA/DOX polymersomes had better targeting ability than nontargeted drug-loaded polymersomes. Furthermore, Tf-F127-PLA/DOX polymersomes with 2% Tf molar content have more effective antitumor activity and a higher cellular uptake than those with 4 and 5% Tf molar content. 2% Tf-F127-PLA/DOX polymersomes also exhibited better anticancer ability in multidrug resistant cancer cells A549/ADR than nontargeted PLA-F127-PLA/DOX polymersomes. It was further proved that the endocytosis of polymersomes by A549/ADR cells was an energy-dependent endocytosis process, which was related to clathrin, macrocytosis, and caveolin. Also, the endocytosis of Tf-F127-PLA/DOX polymersomes was proven to be mediated by the transferrin receptor.

Risk factors of multidrug-resistant bacteria infection in patients with ventilator-associated pneumonia: A systematic review and meta-analysis.

BACKGROUND: Multidrug-resistant (MDR) bacteria-induced VAP often has high lethality. We present this systematic review and meta-analysis to assess the risk factors for MDR bacterial infection in patients with VAP. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library were searched for studies regarding MDR bacterial infection in VAP patients, from Jan 1996 to Aug 2022. Study selection, data extraction, and quality assessment of included studies were conducted by two reviewers independently, and potential risk factors for MDR bacterial infection were identified. RESULTS: Meta-analysis showed that the score of the Acute Physiology and Chronic Health Evaluation II (APACHE-II) [OR = 1.009, 95% (CI 0.732, 1.287)], Simplified Acute Physiology Score II (SAPS-II) [OR = 2.805, 95%CI (0.854, 4.755)], length of hospital-stay before VAP onset (days) [OR = 2.639, 95%CI (0.387, 4.892)], in-ICU duration [OR = 3.958, 95%CI (0.894, 7.021)], Charlson index [OR = 1.000, 95%CI (0.889, 1.111)], overall hospital-stay [OR = 20.742, 95%CI (18.894, 22.591)], Medication of Quinolones [OR = 2.017, 95%CI (1.339, 3.038)], medication of carbapenems [OR = 3.527, 95%CI (2.476, 5.024)], combination of more than 2 prior antibiotics [OR = 3.181, 95%CI (2.102, 4.812)], and prior use of antibiotics [OR 2.971, 95%CI (2.001, 4.412)] were independent risk factors of MDR bacterial infection in VAP patients. Diabetes and mechanical ventilation duration before VAP onset showed no association with risk for MDR bacterial infection. CONCLUSIONS: This study has identified 10 risk factors associated with MDR bacterial infection in VAP patients. Identification of these factors would be able to facilitate the treatment and prevention of MDR bacterial infection in clinical practice.

In-situ fabrication of zeolite imidazole framework@hydroxyapatite composite for dispersive solid-phase extraction of benzodiazepines and their determination with high-performance liquid chromatography-VWD detection.

A novel zeolite imidazole framework@hydroxyapatite composite (ZIF-8@HAP) was constructed via in-situ growth and developed for efficient dispersive solid-phase extraction (DSPE) of three benzodiazepines from urine samples. The prepared composite was characterized by scanning electron microscopy, energy-dispersive spectrometer, Fourier-transform infrared spectrometry, X-ray diffractometry, zeta potential analyzer, and nitrogen adsorption-desorption experiment. Characterization results showed typical dodecahedron ZIF-8 crystals that were uniformly located on the surface of rod-like HAP. The combination of ZIF-8 and HAP made the surface area significantly enhanced from 4.68 to 205.44 m2 g-1. Compared with a commercial C18 adsorbent, ZIF-8@HAP exhibited superior removal performance for interfering components from urine and offered better extraction properties for the analytes. The prepared ZIF-8@HAP was applied as an adsorbent in DSPE, and the main experimental parameters, including pH and ionic strength of solution, adsorbent amount, adsorption time, elution solvent, and volume, were investigated. Under optimal conditions, the adsorption for 250 ng mL-1 of each analyte in 4 mL of urine was accomplished within 2 min using 60 mg of adsorbent. The method of ZIF-8@HAP-based DSPE followed by high-performance liquid chromatography gave enhancement factors of 13.3-15.3, linear ranges of 2.5-500 ng mL-1, and limits of detection (S/N = 3) of 0.7-1.4 ng mL-1. The relative recoveries at three spiked levels ranged from 88.7 - 102% with intra-day and inter-day precisions from 3.0 - 10.3% and 2.3 - 12.3%, respectively. These results indicated that the proposed strategy had promising applicability for convenient, rapid, and efficient determination of benzodiazepines in urine samples.Graphical abstract In-situ fabrication of ZIF-8@HAP composite for dispersive solid-phase extraction of benzodiazepines in urine samples.

Determination of trace hydroxyl polycyclic aromatic hydrocarbons in urine using graphene oxide incorporated monolith solid-phase extraction coupled with LC-MS/MS.

The biomonitoring of hydroxy polycyclic aromatic hydrocarbons in urine, as a direct way to access multiple exposures to polycyclic aromatic hydrocarbons, has raised great concerns due to their increasing hazardous health effects on humans. Solid-phase extraction is an effective and useful technique to preconcentrate trace analytes from biological samples. Here, we report a novel solid-phase extraction method using a graphene oxide incorporated monolithic syringe for the determination of six hydroxy polycyclic aromatic hydrocarbons in urine coupled with liquid chromatography-tandem mass spectrometry. The effect of graphene oxide amount, washing solvent, eluting solvent, and its volume on the extraction performance were investigated. The fabricated monoliths gave higher adsorption efficiency and capacity than the neat polymer monolith and commercial C18 sorbent. Under the optimum conditions, the developed method provided the detection limits (S/N = 3) of 0.02-0.1 ng/mL and the linear ranges of 0.1-1500 ng/mL for six analytes in urine sample. The recoveries at three spiked levels ranged from 77.5 to 97.1%. Besides, the intra column-to-column (n = 3) and inter batch-to-batch (n = 3) precisions were ≤ 9.8%. The developed method was successfully applied for the determination of hydroxy polycyclic aromatic hydrocarbons in urine samples of coke oven workers.

Synergistic antitumor effect of folate-targeted Pluronic™ F-127/poly(lactic acid) polymersomes for codelivery of doxorubicin and paclitaxel.

Aim: Folate-targeted Pluronic™ F-127/poly(lactic acid) (FA-F127-PLA) polymersomes were used as codelivery carriers of doxorubicin hydrochloride (DOX) and paclitaxel (PTX) to achieve a targeted synergistic antitumor effect. Materials & methods: The cytotoxicity of PTX/DOX polymersomes against OVCAR-3 cells was determined by methyl thiazolyl tetrazolium assay. The cellular uptake of PTX/DOX polymersomes was examined by HPLC and micro-bicinchoninic acid techniques. Results: The polymersomes showed a bilayer core-shell structure with negative charge and good dispersion. PTX1/DOX5 polymersomes with a mass ratio of PTX to DOX of 1:5 showed the best synergistic effect and the highest cellular uptake. Conclusion: FA-F127-PLA polymersomes have the great promise for codelivery of multiple chemotherapeutics to achieve a targeted antitumor synergistic effect.

Hydrophilic doxorubicin hydrochloride (DOX) and hydrophobic paclitaxel (PTX) are two well-known anticancer drugs. Coadministration of DOX and PTX as a free drug cocktail has been widely used in clinical treatment to further improve their anticancer effect. However, this free drug cocktail often causes a lot of side effects such as cardiotoxicity and nephrotoxicity. In order to reduce the side effects of the drug cocktail and enhance their targeted delivery, folic acid-targeted Pluronic™ F-127 / poly(lactic acid) (FA-F127-PLA) polymersomes were used to load the drug cocktail. Both the cytotoxicity and cellular uptake data showed that PTX/DOX coloaded FA-F127-PLA polymersomes had better synergistic anticancer ability than a DOX and PTX free-drug cocktail.

Co-Delivery of paclitaxel and doxorubicin in folate-Targeted pluronic/ploy (D,L-lactide-b-glycolide) polymersomes.

Drugs with different solubility can be selectively embedded into polymersomes with the hydrophilic core and hydrophobic bilayer. Novel folate-targeted Pluronic/poly (D,L-lactide-b-glycolide) polymersomes were constructed and used for the co-delivery of paclitaxel (PTX) and doxorubicin (DOX) to improve their inhibitory effect over cancer cells. The particle size of blank polymersomes was mainly distributed below 125 nm. The release of PTX and DOX from polymersomes showed an initial burst release followed by a sustained and slow release. The in vitro cytotoxicity data showed that the targeted co-loaded polymersomes (PTX&DOX FA-Ps) exhibited better inhibitory effect than single-loaded polymersomes and free drugs did. Furthermore, PTX&DOX FA-Ps showed the synergistic therapeutic effect over OVCAR-3 cancer cells. The cellular uptake results also showed that folate modified polymersomes had excellent targeting performance. Therefore, the folate-targeted Pluronic/poly (D,L-lactide-b-glycolide) polymersomes have potential application value as novel drug carriers to co-deliver PTX and DOX.

Perioperative Risk Factors for Post-operative Pneumonia after Type A Acute Aortic Dissection Surgery.

OBJECTIVE: Type A acute aortic dissection (TAAAD) is a dangerous and complicated condition with a high death rate before hospital treatment. Patients who are fortunate to receive prompt surgical treatment still face high in-hospital mortality. A series of post-operative complications further affects the prognosis. Post-operative pneumonia (POP) also leads to great morbidity and mortality. This study aimed to identify the prevalence as well as the risk factors for POP in TAAAD patients and offer references for clinical decisions to further improve the prognosis of patients who survived the surgical procedure. METHODS: The study enrolled 89 TAAAD patients who underwent surgical treatment in Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei province, China from December 2020 to July 2021 and analyzed the perioperative data and outcomes of these patients. Logistic regression analyses were used to identify the risk factors for POP. RESULTS: In the study, 31.5% of patients developed POP. Patients with POP had higher proportions of severe oxygenation damage, pneumothorax, reintubation, tracheotomy, renal replacement therapy, arrhythmia, gastrointestinal bleeding, and longer duration of mechanical ventilation, fever, ICU stay, and length of stay (all with P<0.05). The in-hospital mortality was 2.3%. Smoking, preoperative white blood cells, and intraoperative transfusion were the independent risk factors for POP in TAAAD. CONCLUSION: Patients who underwent TAAAD surgery suffered poorer outcomes when they developed POP. Furthermore, patients with risk factors should be treated with caution.

Tuberculosis combined with Burkitt lymphoma in a kidney transplant recipient: A case report and literature review.

RATIONALE: Tuberculosis (TB) and post-transplant lymphoproliferative disorder are serious complications affecting the long-term survival of kidney transplant recipients (KTRs). Both of complications have overlapping clinical symptoms, signs, and high similar imaging presentation, which make early clinical diagnosis challenging. In this paper, we reported a rare case of post-transplant pulmonary TB combined with Burkitt lymphoma (BL) in KTR. PATIENT CONCERNS: A 20-year-old female KTR presented to our hospital with abdominal pain and multiple nodules throughout the body. DIAGNOSES: TB is diagnosed based on the lung histopathology showed fibrous connective tissue hyperplasia with number of chronic inflammatory changes, localized necrosis, granuloma formation and multinucleated giant cells were seen in the lung tissue. Moreover, lung histopathology specimen tested positive for TB gene. TB The culture for tuberculosis was positive. BL was diagnosed as metastatic after completion of liver and bone marrow biopsy. INTERVENTIONS: After an early diagnosis of TB, the patient received intensification of anti-tubercular therapy. Because the patient was diagnosed with BL, rituximab, cardioprotection, hepatoprotection and alkalinization of urine were added. OUTCOMES: After an early diagnosis of TB, the patient received anti-tubercular therapy and her clinical symptoms and imaging manifestations improved. After the diagnosis of BL was made, the patient's condition progressed rapidly, followed by multi-organ damage and died 3 months later. LESSONS: Therefore, in organ transplant patients, who present with multiple nodules and normal tumor markers, they should be alerted to the possibility of concurrent TB and post-transplant lymphoproliferative disorder, and perfect tests such as Epstein-Barr virus, ß2-microglobulin, lactate dehydrogenase, γ-interferon release test and Xpert Mycobacterium TB/rifampicin test and perform early lesion site biopsy to clarify the diagnosis with a view to improving the prognosis.

Transferrin/folate dual-targeting Pluronic F127/poly(lactic acid) polymersomes for effective anticancer drug delivery.

A novel dual-targeting Pluronic/poly(lactic acid) polymersome containing transferrin and folic acid ligands (Tf/FA-F127-PLA) has been designed to study its application in the targeted drug delivery system. Both biotin and folic acid conjugated Biotin/FA-F127-PLA polymersomes (Ps) were prepared as the precursor. The dual-targeting behaviors of Tf/FA-F127-PLA over C6 glioma cells were then fulfilled through connecting the precursor with biotinylated transferrin by using a three-step biotin-avidin technique. Paclitaxel (PTX) was loaded successfully into Biotin/FA-F127-PLA and showed a burst release followed by a slow-release process in vitro. It was also obtained that Tf/FA-F127-PLA had higher cytotoxicity and cellular uptake amount than non-targeted and single-targeted Ps did. These results could be because more PTX-loaded Tf/FA-F127-PLA Ps entered C6 cells through both FA-folate receptor (FR) and Tf-transferrin receptor (TfR) specific affinity and thus possessed the better anti-tumor ability. It was further proved that the uptake of Ps by C6 cells was through the endocytosis related to clathrin, caveolae, lysosome, etc. Furthermore, it was demonstrated that the uptake of dual-targeting Tf/FA-F127-PLA Ps by C6 cells was related to the endocytosis mediated by both FR and TfR. These findings indicated that dual-targeting Tf/FA-F127-PLA Ps could be a potential carrier in targeted drug delivery systems.

Monodispersed CaCO3@hydroxyapatite/magnetite microspheres for efficient and selective extraction of benzoylurea insecticides in tea beverages samples.

A novel monodispersed CaCO3@hydroxyapatite/magnetite microsphere (CaCO3 @HAP/Fe3O4) was prepared via an in-situ growth strategy, and applied as an adsorbent for efficient and selective adsorption of benzoylurea insecticides (BUs) in various tea beverages samples. The sorbent exhibited uniformity in particle size, good mono-dispersibility and excellent solvent stability. The adsorption equilibrium of BUs (100 ng/mL) in 10 mL of tea beverages samples was achieved on 20 mg of CaCO3 @HAP/Fe3O4 within 10 min. The adsorption followed pseudo-second-order kinetics and Langmuir models and the maximum adsorption capacities of 131.9-161.3 mg/g were accomplished via hydrophobic interactions, hydrogen bonding, and the affinity of F atom and Ca2+. Coupled with high performance liquid chromatography, the method offered wide linear ranges of 0.8-1000 ng/mL with correlation coefficients (r) ≥ 0.9995, low limits of detection of 0.2-0.3 ng/mL and large enrichment factors of 75.7-102. The recoveries ranged from 75.7%- 102% with intra- and inter-day precisions of 1.9%- 9.3% and 1.6%- 11.8%, respectively. In addition, CaCO3 @HAP/Fe3O4 could be easily regenerated and reused at least 10 times with no significant loss of recovery. These results revealed an alternative strategy for fast and convenient determination of BUs in tea beverages samples and proved the great feasibility of CaCO3 @HAP/Fe3O4 in the application for the selective adsorption of BUs.

Study on the Influencing Factors of Hypoglycemic Effect of Folate Targeted Polymersomes Encapsulating Insulin.

PURPOSE: To study the effects of the density of folic acid (FA) on the hypoglycemic ability of FA-targeted polymersomes as oral insulin carriers. Also to study the change of the hypoglycemic effect of FA-targeted mixed polymersomes added with various mass ratio of d-α-tocopherol polyethylene glycol 1000 succinate (TPGS). METHODS: The FA-targeted polymersomes with different FA molar contents were prepared. The in vitro insulin release experiments in different media for FA-targeted polymersomes with various FA contents were studied. Their quantitative cellular uptake in Caco-2 cells was examined. The in vivo hypoglycemic activity of FA-targeted polymersomes was also studied with diabetic rats. The polymersomes with the optimal FA molar content was chosen to prepare mixed polymersomes with various TPGS contents. RESULTS: Among insulin-loaded FA-targeted polymersomes with four different FA molar contents, insulin-loaded polymersomes with 10% FA molar content (insulin-loaded 10%FA-Ps) showed the hightest cellular uptake and the best hypoglycemic response. In addition, the insulin-loaded FA-Ps/TPGS5:1 mixed polymersomes exhibited higher cellular uptake and better hypoglycemic response than the other two insulin-loaded mixed polymersomes adding TPGS did. CONCLUSIONS: FA-Ps/TPGS5:1 could be a promising formulation for the oral administration of insulin.

Four-microRNA signature for detection of type 2 diabetes.

BACKGROUND: Sensitive, novel, and accurate biomarkers for the detection of physiological changes in type 2 diabetes (T2DM) at an early stage are urgently needed. AIM: To build a multi-parameter diagnostic model for the early detection of T2DM. METHODS: MiR-148b, miR-223, miR-130a, and miR-19a levels were detected by real-time polymerase chain reaction in serum of healthy controls, individuals with impaired glucose regulation, and T2DM patients. The diagnostic value of miR-148b, miR-223, miR-130a, and miR-19a, alone or in combination, was analyzed. RESULTS: The area under the curve (AUC) of miR-223, which had the best diagnostic value for discriminating the impaired glucose regulation and T2DM groups, was 0.84, and the sensitivity and specificity were 73.37% and 81.37%, respectively. The AUC of the four-miRNA signature was 0.90, and the sensitivity and specificity were 78.82% and 88.23%, respectively. In the validation set, the AUC was 0.88, and the sensitivity and specificity were 78.36% and 87.63%, respectively. CONCLUSION: In summary, we have built a multi-parameter diagnostic model consisting of miR-148b, miR-223, miR-130a, and miR-19a for the detection of T2DM. It may be a potential tool for the early detection of T2DM.

Folate-conjugated pluronic/polylactic acid polymersomes for oral delivery of paclitaxel.

Cancer chemotherapy and the patient's life will be more convenient if oral administration of anti-cancer drugs can be achieved. The feasibility of folate-targeted Pluronic F127/polylactic acid (FA-F127-PLA) polymersomes as the oral delivery carriers of paclitaxel (PTX) has been explored in this study. PTX loaded in FA-F127-PLA and PLA-F127-PLA polymersomes showed biphasic release behaviors in simulated gastric and intestinal fluids. PTX loaded in FA-F127-PLA polymersomes exhibited higher cytotoxicity and cellular uptake than PTX loaded in PLA-F127-PLA polymersomes. In vivo pharmacokinetic studies in rats showed that oral PTX loaded in FA-F127-PLA polymersomes had a higher bioavailability than oral PTX loaded in PLA-F127-PLA polymersomes. D-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS or Vitamin E TPGS) was also added to the FA-F127-PLA polymersomes as an optimization agent. Compared with PTX-loaded FA-F127-PLA polymersome, PTX-loaded FA-F127-PLA/TPGS mixed polymersomes showed even better cytotoxic ability, more cellular uptake and higher bioavailability. The above results indicate that FA-F127-PLA and FA-F127-PLA/TPGS mixed polymersomes could be good candidates for the oral delivery carrier of anti-cancer drugs.

Effect of the Folate Ligand Density on the Targeting Property of Folated-Conjugated Polymeric Nanoparticles.

Targeted drug delivery systems have attracted increasing attention due to their ability for delivering anticancer drugs selectively to tumor cells. Folic acid (FA)-conjugated targeted block copolymers, FA-Pluronic-polycaprolactone (FA-Pluronic-PCL) are synthesized in this study. The anticancer drug paclitaxel (PTX) is loaded in FA-Pluronic-PCL nanoparticles by nanoprecipitation method. The in vitro release of PTX from FA-Pluronic-PCL nanoparticles shows slow and sustained release behaviors. The effect of FA ligand density of FA-Pluronic-PCL nanoparticles on their targeting properties is examined by both cytotoxicity and fluorescence methods. It is shown that FA-Pluronic-PCL nanoparticles indicated better targeting ability than non-targeted PCL-Pluronic-PCL nanoparticles. Furthermore, FA-F127-PCL nanoparticle with 10% FA molar content has more effective antitumor activity and higher cellular uptake than those with 50% and 91% FA molar content. These results prove that FA-F127-PCL nanoparticle with 10% FA molar content can be a better candidate as the drug carrier in targeted drug delivery systems.

[A study of the histopathological characteristics of nontuberculous mycobacteria lymphadenitis].

OBJECTIVE: To describe the distinctive histopathological changes of nontuberculous mycobacteria lymphadenitis. METHODS: An experimental animal model of nontuberculous mycobacteria lymphadenitis was established and the histopathological changes were observed by light microscope. The paraffin imbedded tissue samples from patients suspected of having lymphoid tuberculosis were also detected by triplex polymerase chain reaction and studied by light microscope. RESULTS: The distinctive histopathological changes of nontuberculous mycobacteria lymphadenitis in the animal model were as follows: (1) Tubercular granuloma formation in lymph nodes which were infected with nontuberculous mycobacteria. Coagulation necrosis was located at the center of the granuloma, and the necrosis looked different from the caseation necrosis caused by mycobacterium tuberculosis. Many neutrophils and their nuclear debris were distributed over the necrosis area. Surrounding the central necrosis area, many epithelioid cells, lymph cells and mononuclear cells could be found. The periphery of the granuloma was surrounded by fibrous tissues. Langhans giant cells could be found in the granuloma and outside the granuloma, while these cells were usually found only in the granuloma of tuberculosis. (2) Serpiginous necrosis was found in the lymph nodes infected with nontuberculous mycobacteria. Many neutrophils and their nuclear debris were distributed over the necrosis area. Around the central necrosis area, many epithelioid cells, lymph cells and mononuclear cells could be found. The fibrous tissues were in the borderline. (3) Star-like necrosis and aristiform necrosis were also found in lymph nodes infected with nontuberculous mycobacteria. A paraffin imbedded tissue sample was detected by triplex polymerase chain reaction and the diagnosis of nontuberculous mycobacteria lymphadenitis was made. In this sample, epithelioid granuloma, serpiginous necrosis and star-like necrosis were found. Neutrophils and their nuclear debris were found distributed over the necrosis area, while epithelioid cells, lymph cells, mononuclear cells and Langhans giant cells were found around the central necrosis area. Polar arrangement of the nuclei of epithelioid cells was evident. The lesion was surrounded by fibrous and collagen tissues. CONCLUSION: Serpiginous, star-like and aristiform necrosis were the distinctive histopathological changes of nontuberculous mycobacteria lymphadenitis. Neutrophils and their nuclear debris were abundant over the necrosis area. Polar arrangement of the nuclei of epithelioid cells was also a distinctive histopathological manifestation.

Pluronics modified liposomes for curcumin encapsulation: Sustained release, stability and bioaccessibility.

The present work evaluated the feasibility of different pluronics (F127, F87 and P85) utilized as modifiers to improve the stability and bioaccessibility of curcumin liposomes (cur-Lps). Pluronics modified curcumin liposomes (cur-pluronic-Lps) were prepared by thin film evaporation combined with dynamic high pressure microfluidization. The particle size and polydispersity index of cur-pluronic-Lps was significantly lower than cur-Lps. Fourier transform infrared spectroscopy analysis revealed that curcumin was loaded in liposomes successfully and X-ray diffraction suggested that curcumin in the liposomes was in an amorphous state. In vitro release studies demonstrated that 73.4%, 63.9%, 66.7% and 58.9% curcumin released from cur-Lps, cur-F127-Lps, cur-F87-Lps and cur-P85-Lps, respectively. Compared with cur-Lps, cur-pluronic-Lps showed a slower release rate and lower cumulative release percentage for curcumin. Non-Fickian transport was the main release mechanism for cur-Lps, cur-F127-Lps and cur-F87-Lps, and typically the first-order model fitted cur-P85-Lps release. Stability studies (exposure to solutions of different pH and heat treatment) indicated that pluronics modification could enhance their pH stability and thermal stability. In vitro simulated gastrointestinal tract studies suggested that pluronics modification could significantly improve the absorption of cur-Lps. Bioaccessibility of curcumin liposomes increased in the following order: cur-Lps < cur-F87-Lps < cur-P85-Lps < cur-F127-Lps. These results may guide the potential application of pluronics modified liposomes as carriers of curcumin in nutraceutical and functional foods.

[Metalloproteinase-9/tissue inhibitor of metalloproteinase-1 in induced sputum in patients with asthma and chronic obstructive pulmonary disease and their relationship to airway inflammation and airflow limitation].

OBJECTIVE: To investigate the levels of metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in induced sputum in patients with asthma and chronic obstructive pulmonary disease (COPD), and its relationship to the number of inflammation cells and lung function. METHODS: Fourteen patients with asthma in remission stages, 12 patients with stable COPD and 10 normal control subjects were included in this study. Lung function was measured. Induced sputum was obtained and processed for cell differential and the supernatant was assayed for the concentrations of interleukin-4 (IL-4), MMP-9 and TIMP-1 by enzyme-linked immunosorbent assay (ELISA). RESULTS: The percentage of eosinophils in induced sputum in asthmatics (0.181 +/- 0.067) was significantly higher than that in normal control subjects (0.007 +/- 0.005) and in COPD (0.042 +/- 0.017, F = 4.32, P < 0.05). The percentage of neutrophils in induced sputum in patients with COPD (0.500 +/- 0.101) was significantly higher than that in asthmatics (0.30 +/- 0.07) and in normal control subjects (0.26 +/- 0.06, F = 4.13, P < 0.05). The concentrations of IL-4 in asthmatics, COPD and normal control subjects [respectively, (19 +/- 7) x 10(-3) g/L, (14 +/- 6) x 10(-3) g/L, (11 +/- 4) x 10(-3) g/L] did not show significant difference (F = 1.56, all P > 0.05) and did not correlate with the number of eosinophils (r = 0.33, 0.11, 0.19, all P > 0.05) and neutrophil (r = 0.25, 0.39, 0.40, all P > 0.05) and FEV(1) values (predicted r = 0.21, 0.35, 0.17, all P > 0.05). The concentrations of MMP-9 and TIMP-1 in induced sputum in asthmatics [(15.9 +/- 6.0) g/L, (19.8 +/- 8.5) g/L, respectively] and COPD [(13.4 +/- 5.1) g/L, (16.7 +/- 7.6) g/L, respectively] were significantly higher than those in normal control subjects [(1.8 +/- 1.1) g/L, (1.3 +/- 0.9) g/L, respectively] (F = 2.99, 4.22, respectively, all P < 0.05). Increased concentration of MMP-9 correlated positively with the percentage of eosinophils in asthmatics (r = 0.71, P < 0.05) and with the percentage of neutrophils in COPD (r = 0.59, P < 0.05), but did not correlate with FEV(1) values (predicted r = 0.22, 0.16, all P > 0.05) and FEV(1)/FVC (r = 0.25, 0.30, all P > 0.05). Increased concentration of TIMP-1 did not correlate with the number of eosinophils (r = 0.27, 0.31, all P > 0.05) and neutrophil (r = 0.20, 0.35, all P > 0.05) in asthmatics and COPD, but correlated inversely with FEV(1) values (predicted, respectively, r = -0.58, -0.62, all P < 0.05). The ratio of MMP-9/TIMP-1 was significantly lower in asthmatics 0.8 +/- 0.7 and COPD 0.8 +/- 0.6 than that in normal control subjects (1.5 +/- 0.6, F = 3.70, P < 0.05). The ratio was not statistically different between asthmatics and COPD (F = 1.78, P > 0.05). In asthmatics and COPD patients, the ratio of MMP-9/TIMP-1 in induced sputum correlated positively with FEV(1%) (respectively, r = 0.56, 0.61, all P < 0.05). CONCLUSION: An imbalance between MMP-9 and TIMP-1 in induced sputum in asthmatics and COPD is associated with airway inflammation and airflow limitation, which may play a role in the pathogenesis of extracellular matrix remodeling and airflow limitation.

Enhanced effect of folated pluronic F87-PLA/TPGS mixed micelles on targeted delivery of paclitaxel.

Targeted drug delivery systems have great potential to overcome the side effect and improve the bioavailability of conventional anticancer drugs. In order to further improve the antitumor efficacy of paclitaxel (PTX) loaded in folated Pluronic F87/poly(lactic acid) (FA-F87-PLA) micelles, D-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS or Vitamin E TPGS) were added into FA-F87-PLA to form FA-F87-PLA/TPGS mixed micelles. The LE of PTX-loaded mixed micelles (13.5%) was highest in the mass ratio 5 to 3 of FA-F87-PLA to TPGS. The in vitro cytotoxicity assays indicated that the IC50 values for free PTX injections, PTX-loaded FA-F87-PLA micelles and PTX-loaded FA-F87-PLA/TPGS mixed micelles after 72h of incubation were 1.52, 0.42 and 0.037mg/L, respectively. The quantitative cellular uptake of coumarin 6-loaded FA-F87-PLA/TPGS and FA-F87-PLA micelles showed that the cellular uptake efficiency of mixed micelles was higher for 2 and 4h incubation, respectively. In vivo pharmacokinetic studies found that the AUC of PTX-loaded FA-F87-PLA/TPGS mixed micelles is almost 1.4 times of that of PTX-loaded FA-F87-PLA micelles. The decreased particle size and inhibition of P-glycoprotein effect induced by the addition of TPGS could result in enhancing the cellular uptake and improving the antitumor efficiency of PTX-loaded FA-F87-PLA/TPGS mixed micelles.

The targeting properties of folate-conjugated Pluronic F127/poly (lactic-co-glycolic) nanoparticles.

Novel Folated Pluronic F127/poly (lactic-co-glycolic) (FA-F127-PLGA) and PLGA-F127-PLGA block copolymer were synthesized and nanoparticles self-assembled from these two copolymers were prepared by dialysis method. Paclitaxel (PTX) was successfully encapsulated in these two nanoparticles. According to in vitro release studies of PTX-loaded nanoparticles, after an initial burst release during the first 11h, the entrapped PTX released slowly in the following 82h. The cytotoxicity studies demonstrated that the in vitro antitumor effect of PTX could be improved by encapsulating PTX into PLGA-F127-PLGA nanoparticles. Moreover, folate-targeted FA-F127-PLGA nanoparticles were more effective than PLGA-F127-PLGA when delivering PTX in folate receptor overexpressing OVCAR-3 cells, which mainly due to the FA-receptor-meditated endocytosis. As the treatment time became longer, the targeting effects were more obvious. The targeting effect of FA-F127-PLGA nanoparticles was also investigated in vitro by measuring the cellular uptake of the nanoparticles. The results showed that FA-F127-PLGA nanoparticles were more easily to be uptaken by OVCAR-3 cells in comparison with PLGA-F127-PLGA nanoparticles. In vivo pharmacokinetic studies indicated that FA-F127-PLGA nanoparticles prolong the circulation time of PTX in plasma, and delay the blood clearance of PTX. These results indicated that Folated FA-F127-PLGA could be a potential carrier in long-term PTX delivery.

A review of biodegradable polymeric systems for oral insulin delivery.

Currently, repeated routine subcutaneous injections of insulin are the standard treatment for insulin-dependent diabetic patients. However, patients' poor compliance for injections often fails to achieve the stable concentration of blood glucose. As a protein drug, the oral bioavailability of insulin is low due to many physiological reasons. Several carriers, such as macromolecules and liposomes have been used to deliver drugs in vivo. In this review article, the gastrointestinal barriers of oral insulin administration are described. Strategies for increasing the bioavailability of oral insulin, such absorption enhancers, enzyme inhibitors, enteric coatings are also introduced. The potential absorption mechanisms of insulin-loaded nanoparticles across the intestinal epithelium, including intestinal lymphatic route, transcellular route and paracellular route are discussed in this review. Natural polymers, such as chitosan and its derivates, alginate derivatives, γ-PGA-based materials and starch-based nanoparticles have been exploited for oral insulin delivery; synthetic polymers, such as PLGA, PLA, PCL and PEA have also been developed for oral administration of insulin. This review focuses on recent advances in using biodegradable natural and synthetic polymers for oral insulin delivery along with their future prospects.