Micro-syringe chip-guided intratumoral administration of lipid nanoparticles for targeted anticancer therapy.

BACKGROUND: Nano-sized drug delivery system has been widely studied as a potential technique to promote tumor-specific delivery of anticancer drugs due to its passive targeting property, but resulting in very restricted improvements in its systemic administration so far. There is a requirement for a different approach that dramatically increases the targeting efficiency of therapeutic agents at targeted tumor tissues. METHODS: To improve the tumor-specific accumulation of anticancer drugs and minimize their undesirable toxicity to normal tissues, a tumor-implantable micro-syringe chip (MSC) with a drug reservoir is fabricated. As a clinically established delivery system, six liposome nanoparticles (LNPs) with different compositions and surface chemistry are prepared and their physicochemical properties and cellular uptake are examined in vitro. Subsequently, MSC-guided intratumoral administration is studied to identify the most appropriate for the higher tumor targeting efficacy with a uniform intratumoral distribution. For efficient cancer treatment, pro-apoptotic anticancer prodrugs (SMAC-P-FRRG-DOX) are encapsulated to the optimal LNPs (SMAC-P-FRRG-DOX encapsulating LNPs; ApoLNPs), then the ApoLNPs are loaded into the 1 µL-volume drug reservoir of MSC to be delivered intratumorally for 9 h. The tumor accumulation and therapeutic effect of ApoLNPs administered via MSC guidance are evaluated and compared to those of intravenous and intratumoral administration of ApoLNP in 4T1 tumor-bearing mice. RESULTS: MSC is precisely fabricated to have a 0.5 × 4.5 mm needle and 1 µL-volume drug reservoir to achieve the uniform intratumoral distribution of LNPs in targeted tumor tissues. Six liposome nanoparticles with different compositions of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (PC), 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (PS), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)2000] (PEG2000-DSPE) are prepared with average sizes of 100-120 nm and loaded into the 1 µL-volume drug reservoir in MSC. Importantly negatively charged 10 mol% of PS-containing LNPs are very slowly infused into the tumor tissue through the micro-syringe of the MSC over 6 h. The intratumoral targeting efficiency of MSC guidance is 93.5%, effectively assisting the homogeneous diffusion of LNPs throughout the tumor tissue at 3.8- and 2.7-fold higher concentrations compared to the intravenous and intratumoral administrations of LNPs, respectively. Among the six LNP candidates 10 mol% of PS-containing LNPs are finally selected for preparing pro-apoptotic SMAC-P-FRRG-DOX anticancer prodrug-encapsulated LNPs (ApoLNPs) due to their moderate endocytosis rate high tumor accumulation and homogenous intratumoral distribution. The ApoLNPs show a high therapeutic effect specifically to cathepsin B-overexpressing cancer cells with 6.6 µM of IC50 value while its IC50 against normal cells is 230.7 µM. The MSC-guided administration of ApoLNPs efficiently inhibits tumor growth wherein the size of the tumor is 4.7- and 2.2-fold smaller than those treated with saline and intratumoral ApoLNP without MSC, respectively. Moreover, the ApoLNPs remarkably reduce the inhibitor of apoptosis proteins (IAPs) level in tumor tissues confirming their efficacy even in cancers with high drug resistance. CONCLUSION: The MSC-guided administration of LNPs greatly enhances the therapeutic efficiency of anticancer drugs via the slow diffusion mechanism through micro-syringe to tumor tissues for 6 h, whereas they bypass most hurdles of systemic delivery including hepatic metabolism, rapid renal clearance, and interaction with blood components or other normal tissues, resulting in the minimum toxicity to normal tissues. The negatively charged ApoLNPs with cancer cell-specific pro-apoptotic prodrug (SMAC-P-FRRG-DOX) show the highest tumor-targeting efficacy when they are treated with the MSC guidance, compared to their intravenous or intratumoral administration in 4T1 tumor-bearing mice. The MSC-guided administration of anticancer drug-encapsulated LNPs is expected to be a potent platform system that facilitates overcoming the limitations of systemic drug administration with low delivery efficiency and serious side effects.

Understanding the Flame Retardant Mechanism of Intumescent Flame Retardant on Improving the Fire Safety of Rigid Polyurethane Foam.

Combinations of multiple inorganic fillers have emerged as viable synergistic agents for boosting the flame retardancy of intumescent flame retardant (IFR) polymer materials. However, few studies on the effect of multiple inorganic fillers on the flame retardant behavior of rigid polyurethane (RPU) foam have been carried out. In this paper, a flame retardant combination of aluminum hydroxide (ATH) and traditional flame retardants ammonium polyphosphate (APP), pentaerythritol (PER), melamine cyanurate (MC), calcium carbonate (CC), and expandable graphite (EG) was incorporated into RPU foam to investigate the synergistic effects of the combination of multiple IFR materials on the thermal stability and fire resistance of RPU foam. Scanning electron microscopy (SEM) and thermogravimetric analysis (TGA) revealed that 8 parts per hundred polyols by weight (php) filler concentrations were compatible with RPU foam and yielded an increased amount of char residue compared to the rest of the RPU samples. The flame retardancy of multiple fillers on intumescent flame retardant RPU foam was also investigated using cone calorimeter (CCTs) and limiting oxygen index (LOI) tests, which showed that RPU/IFR1 (APP/PER/MC/EG/CC/ATH) had the best flame retardant performance, with a low peak heat release rate (PHRR) of 82.12 kW/m2, total heat release rate (THR) of 15.15 MJ/m2, and high LOI value of 36%. Furthermore, char residue analysis revealed that the use of multiple fillers contributed to the generation of more intact and homogeneous char after combustion, which led to reduced decomposition of the RPU foam and hindered heat transfer between the gas and condensed phases.

Effect of Enhanced Recovery After Surgery program on hospital stay and 90-day readmission after pancreaticoduodenectomy: a single, tertiary center experience in Korea.

PURPOSE: Despite increasing number of reports on Enhanced Recovery After Surgery program (ERAS) and readmission after pancreaticoduodenectomy (PD) from Western countries, there are very few reports on this topic from Asian countries. This study aimed to evaluate the effects of ERAS on hospital stay and readmission and to identify reasons and risk factors for readmission after PD. METHODS: This retrospective cohort study included 670 patients who underwent open PD from January 2003 to December 2017. The patients were classified into ERAS (n = 352) and non-ERAS (n = 318) groups. Patients' characteristics, perioperative outcomes, and readmission rates were compared. RESULTS: There were no significant differences in the postoperative complication rates between the groups. The mean postoperative hospital stay was significantly shorter in the ERAS group (24.5 vs. 18.0 days, P < 0.001), but the 90-day readmission rate was similar in the 2 groups (9.1% vs. 8.5%, P = 0.785). Complications associated with pancreatic fistula (42.4%) were the most common cause for readmission. In the multivariate analysis, diabetes mellitus (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.05-3.24; P = 0.034), preoperative non-jaundice (OR, 0.45; 95% CI, 0.25-0.82; P = 0.009) and severe postoperative complications (OR, 4.12; 95% CI, 2.34-7.26; P < 0.001) were identified as risk factors for readmission. CONCLUSION: The results confirmed that the ERAS program for PD was beneficial in reducing postoperative stay without increasing readmission risks. To decrease readmission rates, prudent discharge planning and medical support should be considered in patients who experience severe complications.

Sequence and expression analysis of extracellular signal-regulated kinase 1 from flounder (Paralichthys olivaceous).

Extracellular signal-regulated kinases (ERKs) are a subgroup of mitogen-activated protein kinases (MAPK) that function as important intermediates in signal transduction pathways initiated by several types of cell surface receptors. We cloned a transcript of ERK1 from a cDNA library of flounder leukocytes stimulated with bacterial lipopolysaccharide and hemagglutinin lectin. Flounder ERK1 consists of 1502 nucleotides and encodes a polypeptide of 393 amino acids. Flounder ERK1 showed 90 and 89% amino acid sequence identity to ERK1 of carp and zebrafish, respectively, and over 85% to that of mammals. Multiple bands were detected by Southern blot analysis of flounder genomic DNA after digestion with various restriction enzymes, implying the presence of additional MAPK genes in flounder. Real-time PCR revealed the ubiquitous expression of flounder MAPK in all tissues with high levels of transcription in brain, gill, and fin, but not in muscle or skin. Flounder MAPK was successfully expressed in mammalian COS1 cells and phosphorylated myelin basic protein (MBP) substrate when the cells were stimulated with PMA or EGF, indicating that flounder MAPK is functional in animal cells.