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Beverly Hills, CA, United States

Chao P.,Rutgers University | Chao P.,Hurel Corporation | Deshmukh M.,Rutgers University | Kutscher H.L.,Rutgers University | And 7 more authors.
Anti-Cancer Drugs

Large (>6μm) rigid microparticles (MPs) become passively entrapped within the lungs after intravenous (i.v.) injection making them an attractive and highly efficient alternative to inhalation for pulmonary delivery. In this study, PEGylated 6 μm polystyrene MPs with multiple copies of the norvaline (Nva) α-amino acid prodrug of camptothecin (CPT) were prepared. Surface morphology was characterized using a scanning electron microscope. CPT was released from the CPT-Nva-MPs over 24 h in rat plasma at 37°C. In-vivo CPT plasma concentrations were low (approximately 1 ng/ml or less) and constant over a period of 4 days after a single i.v. injection of CPT-Nva-MPs as compared with high but short-lived systemic exposures after an i.v. injection of free CPT. This suggests that sustained local CPT concentrations were achieved in the lung after administration of the MP delivery system. Anticancer efficacy was evaluated in an orthotopic lung cancer animal model and compared with a bolus injection of CPT. Animals receiving free CPT (2 mg/kg) and CPT-Nva-MPs (0.22 mg/kg CPT and 100 mg/kg MPs) were found to have statistically significant smaller areas of lung cancer (P<0.05 and 0.01, respectively) than untreated animals. In addition, 40% of the animals receiving CPT-Nva-MPs were found to be free of cancer. The CPT dose using targeted MPs was 10 times lower than after i.v. injection of free CPT, but was more effective in reducing the amount of cancerous areas. In conclusion, CPT-Nva-MPs were able to achieve effective local lung and low systemic CPT concentrations at a dose that was 10 times lower than systemically administered CPT resulting in a significant improvement in anticancer efficacy in an orthotopic rat model of lung cancer. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Deshmukh M.,Rutgers University | Chao P.,Rutgers University | Chao P.,Hurel Corporation | Kutscher H.L.,Rutgers University | And 2 more authors.
Journal of Medicinal Chemistry

The objective of the present study was to identify a camptothecin (CPT) prodrug with optimal release and cytotoxicity properties for immobilization on a passively targeted microparticle delivery system. A series of α-amino acid ester prodrugs of CPT were synthesized, characterized, and evaluated. Four CPT prodrugs were synthesized with increasing aliphatic chain length (glycine (Gly) (2a), alanine (Ala) (2b), aminobutyric acid (Abu) (2c), and norvaline (Nva) (2d)). Prodrug reconversion was studied at pH 6.6, 7.0, and 7.4 corresponding to tumor, lung, and extracellular/physiological pH, respectively. Cytotoxicity was evaluated in A549 human lung carcinoma cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The hydrolytic reconversion rate to parent CPT increased with decreasing side chain length as well as increasing pH. The Hill slope of 2d was significantly less than CPT and the other prodrugs tested, indicating a higher cell death rate at lower concentrations. These results suggest that 2d is the best candidate for a passively targeted sustained release lung delivery system. ©2010 American Chemical Society. Source

Hurel Corporation | Date: 2010-01-05

Flow cytometers and flow-based analyzers providing cell and particle analysis, detection, and counting for scientific, laboratory, and general research uses; Plates, glass slides and chips having multi-well arrays that can be used in chemical analysis, biological analysis and patterning for scientific, laboratory and medical research use; Reaction systems for catalyst research.

Hurel Corporation | Date: 2015-02-26

Tissue cultures, buffering solutions, and associated analytic methods suitable for measuring the uptake of proteins and other chemical entities into cells, and the efflux of proteins and other chemical entities out of cells, including without limitation with respect to hepatobiliary cells.

Hurel Corporation | Date: 2015-09-02

An in vitro methods of characterizing biliary excretion of a chemical entity using a single hepatocyte culture. Comprising providing cell culture comprising hepatocytes forming at least one bile canaliculus; contacting the cell culture with a first chemical entity for a time sufficient to allow uptake of the chemical entity by hepatocytes in the culture; disrupting the at least one bile canaliculus without lysing the hepatocytes and detecting the amount (if any) of the first chemical entity and/or a metabolite thereof released by the at least one bile canaliculus; and lysing the hepatocytes and detecting the amount of the first chemical entity and/or a metabolite thereof released by the hepatocytes.

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