Synthesis, characterization, and biological verification of asialoglycoprotein receptor-targeted lipopolysaccharide-encapsulated PLGA nanoparticles for the establishment of a liver fibrosis animal model.

Liver fibrosis is generally preceded by various liver injuries and often leads to chronic liver diseases and even cirrhosis. Therefore, a liver fibrosis animal model is the cornerstone for the development of therapeutic strategies for hepatic diseases. Although administration of hepatotoxic substances and/or bile duct ligation have been widely performed to construct the in vivo model over the last decades, they are seriously hindered by time-consuming protocols, high mortality, and instability, indicating that an effective and safe approach for the induction of liver fibrosis is still urgently needed nowadays. In this study, we have developed asialoglycoprotein receptor (ASGPR)-targeted lipopolysaccharide (LPS)-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles named ALPNPs for establishing an animal model of liver fibrosis. The ALPNPs are characterized as having a spherical nanostructure with size of 182.9 ± 8.89 nm and surface charge of -8.3 ± 1.48 mV. An anti-ASGPR antibody bound to the surface of the nanoparticles with a crosslinking efficiency of 95.03% allows ALPNPs to have hepatocyte-binding specificity. In comparison to free LPSs, the ALPNPs can induce higher aspartate aminotransferase and total bilirubin concentrations in plasma, reduce the blood flow rate in the portal system and the kidneys, and increase vascular resistance in the liver, kidneys, and collateral shunting vasculature. Based on histological and RNA-seq analyses, the ALPNPs can provide similar capability on inducing hepatic inflammation and fibrosis compared to free LPS but possess higher liver targetability than the naked drug. In addition, the ALPNPs are less toxic in organs other than the liver in comparison to free LPS, demonstrating that the ALPNPs do not elicit off-target effects in vivo. Given the aforementioned efficacies with other merits such as biocompatibility and drug release controllability provided by PLGA, we anticipate that the developed ALPNPs are highly applicable in establishing animal models of liver fibrosis in pre-clinical studies.

Reactivity of a Fe(III)-Bound Methoxide Supported with a Tris(thiolato)phosphine Ligand: Activation of C-Cl Bond in CH2Cl2 by Nucleophilic Attack of a Fe(III)-OCH3 Moiety.

Two mononuclear nonheme Fe(III) complexes, [PPh4][Fe(III)(PS3″)(OCH3)] (1) and [PPh4][Fe(III)(PS3″)(Cl)] (2), supported by a tris(benzenethiolato)phosphine derivative PS3″ (PS3″ = P(C6H3-3-Me3Si-2-S)3(3-)) have been synthesized and characterized. The structures resolved from X-ray crystallography show that Fe(III) centers in both complexes adopt distorted trigonal-bipyramidal geometry with a methoxide or a chloride binding in the axial position. The magnetic data for both are consistent with intermediate-spin Fe(III) centers with a C3 symmetry (S = 3/2 ground state). The bound methoxide in 1 is labile and can be replaced by a CH3CN molecule. The forming Fe(III)-CH3CN species can be further reduced by cobaltcene quantitatively to a stable Fe(II)-CH3CN complex, [Fe(PS3″)(CH3CN)](-). One-electron oxidation of 2 by ferrocenium gave a Fe(IV) analogue, [Fe(IV)(PS3″)(Cl)]. Importantly, the Fe(III)-OCH3 moiety in complex 1 acts as a strong nucleophile that activates the C-Cl bond in CH2Cl2, leading to the formation of complex 2 quantitatively. Complex 1 also reacts with other electrophiles, benzyl chloride and benzyl bromide, to generate Fe(III)-X species (X = Cl or Br). The reactions were investigated and monitored by UV-vis-NIR, NMR, and ESI-MS spectroscopies.

Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib monotherapy.

PURPOSE: To explore predictive factors for time to treatment failure (TTF) in chemotherapy-naive non-small-cell lung cancer (NSCLC) patients receiving gefitinib treatment. PATIENTS AND METHODS: We designed a phase II study to test gefitinib antitumor efficacy in advanced-stage, chemotherapy-naive NSCLC patients. Patients were treated with gefitinib 250 mg/d. Tumor assessments were performed every 2 months. Responding or stable patients were treated until progression or unacceptable toxicity. All scans were reviewed independently. EGFR exons 18-21 sequence, K-ras exon 2 sequence, and MET gene copy numbers were examined in available samples. Clinical or molecular predictors of TTF were examined by multivariate analysis. RESULTS: One hundred six patients were enrolled. Ninety patients had tumor samples for biomarker tests. Overall response rate was 50.9% (95% CI, 41.4% to 60.4%). Median TTF was 5.5 months, and median overall survival (OS) was 22.4 months. The response rate and median TTF of the patients with exon 19 deletion (n = 20) were 95.0% and 8.9 months, for exon 21 L858R mutation (n = 23) were 73.9% and 9.1 month, and for other types of EGFR mutations (N = 12) were 16.7% and 2.3 months, respectively. In multivariate analysis, the presence of EGFR deletion exon 19 or L858R EGFR mutations in adenocarcinoma patients predicted longer TTF. High copy number of MET seemed to correlate with shorter TTF in patients with gefitinib-sensitive activating EGFR mutations. CONCLUSION: In this prospective study, EGFR exon 19 deletion or L858R mutations in adenocarcinoma were the best predictors for longer TTF in stage IIIB/IV chemotherapy-naive NSCLC patients receiving first-line gefitinib monotherapy.

Infantile myofibromatosis presenting with scalp dermoid cyst.

Infantile myofibromatosis is a disorder of infancy and early childhood, typically presenting as a solitary lesion or multiple widespread nodular tumors localized to skin, subcutaneous tissue, muscle, bone, viscera, or central nervous system. We present a case of infantile myofibromatosis, multicentric type, in a 4-month-old male infant who initially presented with an occipital scalp mass and other skin-colored nodular mass lesions over his face, trunk, and four limbs. He received tissue biopsy to establish a definite diagnosis. Craniotomy was also arranged for tumor removal due to dural involvement with internal extension and compression of adjacent sigmoid sinus. The patient eventually died of cardiopulmonary failure secondary to primary pulmonary hypertension at age 11 months. Before his death, he had suffered from abdominal distention and frequent vomiting, followed by aggravated respiratory distress and cyanosis. Aggressive surveillance for cardiopulmonary or gastrointestinal involvement is recommended in such cases because prognosis varies according to the involvement of vital organs.

Gefitinib reverses chemotherapy resistance in gefitinib-insensitive multidrug resistant cancer cells expressing ATP-binding cassette family protein.

Gefitinib inhibits the ATP-binding site of the tyrosine kinase associated with the epidermal growth factor receptor. It is conceivable that gefitinib may inhibit functions of ATP-binding cassette (ABC) transporters by binding at their ATP-binding sites. The aim of this study is to systematically explore the combined effect of gefitinib and chemotherapeutic agents in gefitinib-insensitive multidrug resistant (MDR) cells that overexpress ABC transporters. MCF7 breast carcinoma cells and CL1 lung adenocarcinoma cells were both insensitive to gefitinib. MDR cancer cells were developed by stepwise escalating concentrations of each chemotherapeutic agent in culture media. Cells that overexpress P-glycoprotein (MCF7/Adr and CL1/Pac), breast cancer-resistant protein (MCF7/TPT and CL1/Tpt), and MDR-associated protein 1 (MCF7/Vp) were used in this study. All resistant mutants were insensitive to gefitinib. Gefitinib (0.3-3 micromol/L) added to culture media had no effect on IC50 values of paclitaxel, topotecan, doxorubicin, or etoposide in wild-type MCF7 or CL1 cells. In contrast, these concentrations of gefitinib caused a dose-dependent reversal of resistance to paclitaxel in CL1/Pac cells, to doxorubicin in MCF7/ADR cells, and to topotecan in CL1/Tpt and MCF7/TPT cells. Gefitinib had no influence on sensitivity to etoposide in MDR-associated protein1 overexpressing MCF7/VP cells. Topotecan efflux was inhibited and accumulation was partially restored in CL1/Tpt and MCF7/TPT cells when cells were incubated simultaneously with gefitinib. Our results suggest that the interaction of gefitinib and chemotherapeutic agents does occur in cells expressing one of these two proteins.