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TherapeUTex Preclinical Core Lab Overview

The primary goal of the TherapeUTex Preclinical Core Lab is to characterize properties and efficacy of new therapeutic compounds in animal models by focusing on drug delivery and pharmacokinetic/pharmacodynamic (PK/PD) studies. Efforts include drug formulation and optimization of delivery method as well as development of various disease related animal models with expertise in infectious diseases and cancer/angiogenesis, evaluation of optimal drug concentrations, toxicity, efficacy, and target validation using a variety of approaches.

Drug Formulation and Delivery
When considering the development of any drug formulation or delivery device/method, it is essential to understand its dissolution, physical and/or chemical properties as required by the USP.

1. Hanson SR8-Plus Dissolution Bath, including DS-8 AutoPlus DissoScan, MF-8 AutoPlus MultiFill Collector and 8453 UV/Vis-System: Used to optimize formulation design by analyzing dissolution rates. Type I baskets and Type II paddles enable a flexible testing station while a flow through sampling attachment allows the operator to have a high throughput (efficiency) capability where compounds are easily identifiable with a chromophore (detectable color). Samples can also be taken at various time points and analyzed with other equipment such as HPLC.

2. Waters HPLC system including 1525 Micro Binary HPLC pump, 2707 Autosampler, 2489 UV/Visible Detector and Empower 2 software: For the characterization of drug chemical properties as well as analysis of compounds found in blood and tissue samples.

3. Malvern STP2000 Spraytec including the STP2300 Inhalation Cell and STP2520 Wet Sample Dispersion Unit: Laser Diffraction provides real-time measurements of particle sizes in sprays, nebulized aerosols, liquids, and powders (1-900 µm). The operation of the Spraytec is consistent with the ISO 13320-1 directive which sets out the general principles and requirements for droplet sizing using the technique of laser diffraction, an optional software enhancement to allow for 21CFR Part 11 compliance for FDA-regulation.

4. Malvern Zen1600 Zetasizer: The Zetasizer measures particle sizes (<1 µm) in liquid form using Brownian Motion. Like the Spraytec system, the Zetasizer uses the technique of laser diffraction.

5. MSP Corporation Next Generation Pharmaceutical Impactor: Separates aerosol and powder particles by size via a system of sieves and HCP5 high capacity vacuum pump and regulator for further analysis. Prior to the administration of pulmonary therapeutics, it is necessary to evaluate their performance in vitro. The NGI allows us to predetermine aerosol properties for different formulations. With this information it is possible to correlate lung deposition, local therapy and systemic delivery with the physical characteristics of the aerosol deposition as required by the USP.

6. TA Instruments AR-G2 Rheometer: Measures the viscosity, flow, transient (Creep and Stress Relaxation), and oscillation of fluid drug formulations.

7. Texture Tech TA.XTplus Texture Analyzer: Measures extrusion, shearing, tension, bending, puncture, and compression capacity of drug formulations and devices alike.

8. Thermo Multiskan FC Plate Reader: For the analysis of protein, antibody, etc. levels in a 96-well plate format.

9. Spex SamplePrep 6870 CryoMill: Used for the rapid reduction in size of soft to medium-hard and fibrous materials. The unit is used in conjunction with liquid nitrogen in order to effectively mill low Tg polymers and thermally labile material. Particle size reduction is an essential formulation step for the preparation of many pharmaceutical dosage forms (oral, topical, inhalation etc). This type of mill has a variety of interchangeable accessories to allow a wide range of particle sizes to be produced (from approx 10 µm to 400 µm – depending on material). Small to large quantities of material can also be processed very rapidly from 10 g to 500 g batch sizes.

Animal Modeling
The TherapeUTex Preclinical Core Lab can help transition your compound studies to the next level of animal testing. With faculty and staff expertise in infectious diseases including lung inflammation and cancer/angiogenesis, we can help from experimental design and implementation of efficacy and pharmacokinetic/pharmacodynamic studies, animal colony management and genotyping, surgical technique and training, to data analysis.

1. Thermo Forma Chromatograpy Refrigerator, Forma Enzyme/Lab Freezer, and Forma Ultra Low Freezer: 4°C refrigerator and -20°C freezer for short-term storage of samples and reagents. -80°C freezer for long-term storage of tissue and blood samples.

2. Eppendorf Refrigerated Clinical Benchtop Centrifuge and 5415R Refrigerated MicroCentrifuge. For sample prep and storage.

3. Bio-Rad C1000 Thermal Cycler 48/48: When using genetically modified mouse models, it is necessary to identify the presence or absence of genes of interest by amplifying the gene using Polymerase Chain Reaction (PCR). Further, a PCR machine can be used to check for gene expression as a part of target validation for compounds under study.

4. Leica-Meyer Instruments M205 FA Stereomicroscope System: Whole live animal or tissue imaging of fluorescently tagged cells or compounds to identify tissue or drug distribution in the animal. Color images of small animals, organs and/or tissues can also be acquired with this equipment. The RGD filter and camera allow documentation of images for data collection and publication.

Histology and Pharmacokinetic/Pharmacodynamic (PK/PD) Studies
Once tissue and blood samples have been collected, several different forms of target validation by analysis of drug accumulation, metabolism, and elimination can be evaluated.

1. Leica TP1020 Automatic Tissue Processor: For processing fixed tissues by dehydration and paraffin infusion.

2. Leica EG1150H Paraffin-embedding station and EG1150C Cold Plate: For paraffin embedding fixed and processed tissue for histological analysis and long-term storage.

3. Leica RM2255 Fully Motorized Rotary Microtome: For sectioning nearly single cell layers of paraffin-embedded tissue for histological and ImmunoHistoChemistry (IHC) analysis.

4. Leica CM1950 Cryostat: For sectioning nearly single cell layers of frozen tissue for ImmunoHistoChemistry analysis.

5. Leica-Meyer Instruments DMI1600B Inverted Fluorescent Microscope: For analysis of Histological samples as well as fluorescent evaluation of IHC. This same microscope can be used for live cell imaging. Expression or localization of fluorescently labeled proteins can be measured in living cells and studied in a time-dependent fashion. Can also be used to study the timeframe of cellular uptake of fluorescently labeled peptides or proteins.

6. Waters HPLC system including 1525 Micro Binary HPLC pump, 2707 Autosampler, 2489 UV/Visible Detector and Empower 2 software: see above for detail.

Last Reviewed: August 18, 2009

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