Association between two different lipid injectable emulsions and parenteral nutrition-associated cholestasis in very low birth weight infants: A retrospective cohort study.

BACKGROUND: Using soybean oil-based lipid emulsions (Intralipid), which contain higher amounts of ω-6 fatty acids and phytosterols in parenteral nutrition, is a risk factor for cholestasis (parenteral nutrition-associated cholestasis [PNAC]). An alternative form of a mixed lipid emulsion (SMOFlipid) has been developed to reduce the risk of PNAC, but significant benefits over Intralipid in very low birth weight (VLBW) infants have yet to be demonstrated. The aim of this study was to compare the differences in PNAC incidence in VLBW infants receiving SMOFlipid vs Intralipid. METHODS: The study was conducted in Sir Run Run Shaw Hospital of the Zhejiang University School of Medicine, Hangzhou, China, from January 2016 to March 2022. In total, 235 VLBW infants were administered SMOFlipid or Intralipid for ≥21 days and were included in the study. The primary outcome was the incidence of PNAC. Secondary outcomes included bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, late-onset sepsis, length of stay, weight 28 days after birth, severity of PNAC, and the time to reversal of PNAC. RESULTS: Forty-four VLBW infants (35.5%) in the SMOFlipid group vs 41 (36.9%) in the Intralipid group achieved PNAC (P = 0.817). The subgroup analysis showed that the peak direct bilirubin level was lower (median [interquartile range] 55.6 [36.4] vs 118.4 [77.2] µmol/L; P < 0.001), and the time to reversal of PNAC was shorter (44 [49] vs 96 [61]; P < 0.001) in the SMOFlipid group than in the Intralipid group. CONCLUSION: SMOFlipid may represent a better alternative for VLBW infants who require prolonged parenteral nutrition.

Clinical effects of multi-oil versus pure soybean oil-based lipid emulsions for preterm infants: An observational study.

BACKGROUND AND OBJECTIVES: Conventional soybean oil-based intravenous lipid emulsions (SO-ILEs) have high polyunsaturated fatty acid (PUFA) contents and phytosterols that may have adverse effects in preterm infants. Recently, the multi-oil-based intravenous lipid emulsion (MO-ILE), SMOFlipid, has been widely utilized in the neonatal intensive care unit (NICU), but significant benefits over SO-ILEs in low gestational age neonates have yet to be demonstrated. This study was performed to compare the effects of the SO-ILE, Intralipid, and the MO-ILE, SMOFlipid, on neonatal health outcomes in preterm infants. METHODS AND STUDY DESIGN: We performed a retrospective review of preterm infants born at gestational week (GW) <32 receiving parenteral nutrition for longer durations (≥14 d) in the NICU between 2016 and 2021. The primary aim of this study was to investigate differences in morbidity between preterm infants receiving SMOFlipid and Intralipid. RESULTS: A total of 262 preterm infants were included in the analysis, with 126 receiving SMOFlipid and 136 receiving Intralipid. The SMOFlipid group had lower rates of ROP (23.8% vs 37.5%, respectively; p=0.017), although the rate of ROP was not different in multivariate regression analysis. The length of hospi-tal stay was significantly shorter in the SMOFlipid than SO-ILE group (median [IQR]=64.8 [37] vs 72.5 [49] days; p<0.001). CONCLUSIONS: The use of SMOFlipid as the lipid emulsion was associated with higher clinical efficacy than SO-ILE in preterm infants.

Meta-analysis of vitamin D and lung function in patients with asthma.

BACKGROUND: There is growing literature suggesting a link between vitamin D and asthma lung function, but the results from systematic reviews are conflicting. We conducted this meta-analysis to investigate the relation between serum vitamin D and lung function in asthma patients. METHODS: Major databases, including OVID, MEDLINE, Web of Science and PUBMED, were searched until 10th October 2018. All published observational studies related to vitamin D and asthma were extracted. All meta-analyses were performed using Review Manager 5.3.5. RESULTS: This quantitative synthesis found that asthma patients with low vitamin D levels had lower forced expiratory volume In 1 s (FEV1) (mean difference (MD) = - 0.1, 95% CI = - 0.11 to - 0.08,p < 0.01;I2 = 49%, p = 0.12) and FEV1% (MD = - 10.02, 95% CI = - 11 to - 9.04, p < 0.01; I2 = 0%, p = 0.82) than those with sufficient vitamin D levels. A positive relation was found between vitamin D and FEV1 (r = 0.12, 95% CI = 0.04 to 0.2, p = 0.003; I2 = 59%,p = 0.01), FEV1% (r = 0.19, 95% CI = 0.13 to 0.26, p < 0.001; I2 = 42%, p = 0.11), forced vital capacity (FVC) (r = 0.17, 95% CI = 0.00 to 0.34, p = 0.05; I2 = 60%, p = 0.04), FEV1/FVC (r = 0.4, 95% CI = 0.3 to 0.51, p < 0.001; I2 = 48%, p = 0.07), and the asthma control test (ACT) (r = 0.33, 95% CI = 0.2 to 0.47, p < 0.001; I2 = 0%, p = 0.7). Subgroup analysis indicated that the positive correlation between vitamin D and lung function remained significant in both children and adults. CONCLUSIONS: Our meta-analysis suggested that serum vitamin D levels may be positively correlated with lung function in asthma patients. Future comprehensive studies are required to confirm these relations and to elucidate potential mechanisms.

Evaluation of a novel thermosensitive heparin-poloxamer hydrogel for improving vascular anastomosis quality and safety in a rabbit model.

Despite progress in the design of advanced surgical techniques, stenosis recurs in a large percentage of vascular anastomosis. In this study, a novel heparin-poloxamer (HP) hydrogel was designed and its effects for improving the quality and safety of vascular anastomosis were studied. HP copolymer was synthesized and its structure was confirmed by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy ((1)H-NMR). Hydrogels containing HP were prepared and their important characteristics related to the application in vascular anastomosis including gelation temperature, rheological behaviour and micromorphology were measured. Vascular anastomosis were performed on the right common carotid arteries of rabbits, and the in vivo efficiency and safety of HP hydrogel to achieve vascular anastomosis was verified and compared with Poloxamer 407 hydrogel and the conventional hand-sewn method using Doppler ultrasound, CT angiograms, scanning electron microscopy (SEM) and histological technique. Our results showed that HP copolymer displayed special gel-sol-gel phase transition behavior with increasing temperature from 5 to 60 °C. HP hydrogel prepared from 18 wt% HP solution had a porous sponge-like structure, with gelation temperature at approximately 38 °C and maximum elastic modulus at 10,000 Pa. In animal studies, imaging and histological examination of rabbit common jugular artery confirmed that HP hydrogel group had similar equivalent patency, flow and burst strength as Poloxamer 407 group. Moreover, HP hydrogel was superior to poloxamer 407 hydrogel and hand-sewn method for restoring the functions and epithelial structure of the broken vessel junctions after operation. By combining the advantages of heparin and poloxamer 407, HP hydrogel holds high promise for improving vascular anastomosis quality and safety.

Construction and application of biotin-poloxamer conjugate micelles for chemotherapeutics.

Biotin was conjugated on poloxamer to prepare biotin-poloxamer (BP) conjugate micelles for chemotherapeutics. Epirubicin (EPI) was encapsulated in BP micelles. The EPI-loaded BP micelles were characterized in terms of size, ζ-potential, morphology, drug loading, drug encapsulation and drug release. Marrow leukemic HL-60 cells were used for evaluating the in vitro cytotoxicity of EPI-loaded BP micelles. Nude mice were axillainoculated subcutaneously HL-60 cells to establish tumour model for investigating the inhibition effects of EPI-loaded BP micelles. From the results, the sizes of these nanoparticles were about 100 nm. Fluorescence microscope observation supported the enhanced cellular uptake of the micelles. The order of the inhibition on tumour volume growth was: EPI-loaded BP micelles >EPI-loaded MATP micelles >EPI-loaded poloxamer micelles >EPI. BP micelles showed significant antitumour activity and low toxicity, compared with the non-targeted micelles. With the advantage of EPR effect and tumour-targeting potential, BP conjugate micelles might be developed as a new system for chemotherapeutics.

Preparation and antitumor activity of bFGF-mediated active targeting doxorubicin microbubbles.

Characterization and antitumor activity of basic fibroblast growth factor-mediated active targeting doxorubicin microbubbles (bFGF-DOX-MB) were investigated. Pluronic F68 with chemical conjugation of doxorubicin (DOX-P) and peptide KRTGQYKLC-conjugated DSPE-PEG2000 were prepared. bFGF-DOX-MB had a normal distribution of particle size, with average particle size of 2.7 µm. Using A549 mouse model, bFGF-DOX-MB combined ultrasound showed the best inhibition effect on tumor volume growth among all the test groups. Similar conclusion was obtained from experimental measurements of tumor weight change and blood cell count. From the results, chemotherapeutic drug inhibition on tumor growth could be enhanced by local ultrasound combined with active targeting bFGF-DOX-MB, which might provide a potential application for ultrasound-mediated chemotherapy.

Epirubicin loaded with propylene glycol liposomes significantly overcomes multidrug resistance in breast cancer.

Multidrug resistance (MDR) is one of the major reasons for the failure of cancer chemotherapy. A newly reported liposome carrier, propylene glycol liposomes (EPI-PG-liposomes) were made to load epirubicin (EPI) which enhanced EPI absorption in MDR tumor cells to overcome the drug resistance. MDA-MB 435 and their mutant resistant (MDA-MB 435/ADR) cells were used to examine the cellular uptake and P-gp function in vitro for EPI-PG-liposomes by fluorescence microscopy and FCM, respectively. Mammary tumor model was also established to investigate the tumor growth inhibition and pharmacodynamics of EPI-PG-liposomes in vivo. Morphology evaluation showed that EPI-PG-liposomes had a homogeneous spherical shape with an average diameter of 182 nm. Based on cell viability assay, fluorescent microscopy examination, and EPI uptake assay, EPI-PG-liposomes exhibited an effective growth inhibition not only in MDA-MB-435 cells, but also in MDA-MB 435/ADR cells. EPI-PG-liposomes have high permeability not only on tumor cell membrane, but also on cell nucleus membrane. P-gp function assay showed that the anticancer action of EPI-PG-liposomes was not related to P-gp efflux pump, suggesting that PG-liposomes would not affect the normal physiological functions of membrane proteins. EPI-PG-liposomes also showed a better antitumor efficacy compared to EPI solution alone. With high entrapment efficiency, spherical morphology and effective inhibition on MDR cancer cells, EPI-PG-liposomes may represent a better chemotherapeutic vectors for cancer targeted therapy.

Physical characterization and cellular uptake of propylene glycol liposomes in vitro.

In order to facilitate the intracellular delivery of therapeutic agents, a new type of liposomes-propylene glycol liposomes (PGL) were prepared, and their cell translocation capability in vitro was examined. PGL was composed of hydrogenated egg yolk lecithin, cholesterol, Tween 80 and propylene glycol. With curcumin as a model drug, characterization of loaded PGL were measured including surface morphology, particle size, elasticity, encapsulation efficiency of curcumin and physical stability. Using curcumin-loaded conventional liposomes as the control, the cell uptake capacity of loaded PGL was evaluated by detection the concentration of curcumin in cytoplasm. Compared with conventional liposomes, PGL exhibited such advantages as high encapsulation efficiency (92.74% ± 3.44%), small particle size (182.4 ± 89.2 nm), high deformability (Elasticity index = 48.6) and high stability both at normal temperature (about 25°C) and low temperature at 4°C. From cell experiment in vitro, PGL exhibited the highest uptake of curcumin compared with that of conventional liposomes and free curcumin solution. Little toxic effect on cellular viability was observed by methyl tetrazolium assay. In conclusion, PGL might be developed as a promising intracellular delivery carrier for therapeutic agents.

Using acoustic cavitation to enhance chemotherapy of DOX liposomes: experiment in vitro and in vivo.

Experiments in vitro and in vivo were designed to investigate tumor growth inhibition of chemotherapeutics-loaded liposomes enhanced by acoustic cavitation. Doxorubicin-loaded liposomes (DOX liposomes) were used in experiments to investigate acoustic cavitation mediated effects on cell viability and chemotherapeutic function. The influence of lingering sensitive period after acoustic cavitation on tumor inhibition was also investigated. Animal experiment was carried out to verify the practicability of this technique in vivo. From experiment results, blank phospholipid-based microbubbles (PBM) combined with ultrasound (US) at intensity below 0.3 W/cm² could produce acoustic cavitation which maintained cell viability at high level. Compared with DOX solution, DOX liposomes combined with acoustic cavitation exerted effective tumor inhibition in vitro and in vivo. The lingering sensitive period after acoustic cavitation could also enhance the susceptibility of tumor to chemotherapeutic drugs. DOX liposomes could also exert certain tumor inhibition under preliminary acoustic cavitation. Acoustic cavitation could enhance the absorption efficiency of DOX liposomes, which could be used to reduce DOX adverse effect on normal organs in clinical chemotherapy.

Experiment on the feasibility of using modified gelatin nanoparticles as insulin pulmonary administration system for diabetes therapy.

Polymeric nanoparticles are widely used as targeted carriers for biomacromolecules. In this paper, modified gelatin nanoparticles were prepared and their feasibility as insulin pulmonary administration system was investigated. D: ,L: -glyceraldehyde and poloxamer 188 were used for gelatin nanoparticle preparation. Novel water-in-water emulsion technique was used to prepare insulin-loaded nanoparticles. Morphological examination of insulin-loaded nanoparticles was carried out using scanning electron microscopy (SEM). Intratracheal instillation of insulin-loaded nanoparticles was performed to evaluate animal hypoglycemic effect. With fluorescence labeling of insulin, alveolar deposition and absorption of insulin-loaded nanoparticles were investigated. Histological changes in the lung were also observed to evaluate the safety. From the micromorphology observation, insulin-loaded nanoparticles under gelatin-poloxamer 188 ratio at 1:1 showed smooth and uniform surface, with average particle size 250 nm and Zeta potential -21.1 mV. From animal experiment, insulin-loaded nanoparticles under gelatin-poloxamer 188 ratio at 1:1 promoted insulin pulmonary absorption effectively and showed good relative pharmacological bioavailability. Proved by alveolar deposition result, FITC-insulin-loaded nanoparticle group was characterized by an acute and rapid hypoglycemic effect. In addition, nanoparticles could guarantee the safety of lung by reducing insulin deposition in lung. A transient weak inflammatory response was observed at 1 day after administration. With good physical characterization, high bioavailability, fast and stable hypoglycemic effect, insulin-loaded nanoparticles might be developed as a novel insulin pulmonary system for diabetes therapy.

Characterization and anti-tumor activity of chemical conjugation of doxorubicin in polymeric micelles (DOX-P) in vitro.

Characterization and anti-tumor activity of chemical conjugation of doxorubicin (DOX) in polymeric micelles were investigated. Polymeric micelles with chemical conjugation of doxorubicin (DOX-P) were prepared. Succinic anhydride activated pluronic F68 was first synthesized and the primary amine group in doxorubicin was conjugated to the terminal carboxyl of pluronic F68 via a amide. The resulting polymeric micelles in aqueous solution were characterized by measurement of size, ξ-potential, drug loading and critical micelle concentration. From characterization results, DOX-P micelles had superiorities over physically-loaded DOX micelles in loading efficiency, diameter and CMC value. From drug release experiment in vitro, DOX-P micelles reached a sustained release profile for DOX. The cytotoxic activity of the micelles against A549/DOX cells was greater than free DOX. Fluorescence microscope observation and flow cytometry analysis supported the enhanced cellular uptake of the micelles. From A549/DOX cells experiments, DOX-P micelles could enhance DOX anti-tumor activity and circumvent the multi-drug resistance (MDR) of A549/DOX cells. With low CMC value, high loading efficiency, nanometer diameter, good penetration ability and controlled release behaviour, DOX-P micelles might be developed as a new cancer targeted delivery system.

An in vivo experiment to improve pulmonary absorption of insulin using microbubbles.

BACKGROUND: Gas-filled phospholipid-based ultrasonic microbubbles (PUMs) are widely used in diagnostic imaging. The micro- or nanoparticle size and the physiochemical nature of shell provide the potential for a new way to improve pulmonary absorption for peptides and proteins. METHODS: Male Sprague-Dawley rats were fasted for 12 h. Then insulin solution and insulin-PUM mixture solution were administered by intratracheal instillation. The hypoglycemic effect was observed to evaluate insulin absorption after lung administration. Fluorescein isothiocyanate-dextran (molecular mass, 4 kDa) was used as the index of evaluating drug alveolar deposition and absorption by visualization techniques. RESULTS: Administration of insulin solution containing PUMs significantly reduced the blood glucose levels of Sprague-Dawley rats, compared with administration of insulin-only solution. The minimum reductions of the blood glucose concentration produced by insulin solution containing PUMs and by an insulin-only solution reached 60.81% and 34.60% of the initial glucose levels, respectively, and their bioavailabilities relative to subcutaneous injection were 48.58% and 29.09%, respectively. Histopathological study of the lung showed no changes in the morphology of the pulmonary alveoli after administration to these drugs. Only a slight inflammatory cell infiltration in the alveoli could be found in some rats. CONCLUSION: These results suggested that PUMs might be used as an effective way to improve pulmonary absorption for peptides and proteins.