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Advantages of the Alexa Fluor dyes in Molecular Imaging New Secondary Detection Tools for Flow Cytometry and IHC, Small Animal In Vivo Imaging Reagents Dana Brozban Technical Sales Specialist Imaging and Microscopy [email protected] Today’s Presentation • Focus on Key Molecular Probes Products and Applications • Alexa Fluor® Dyes • Zenon ® Technology for secondary detection • Small Animal In Vivo Imaging (SAIVI™ Reagents) Invitrogen Proprietary and Confidential 2 Desirable Characteristics of Fluorophores: 1) Emission at wavelengths that minimize problems with autofluorescence 2) Minimal spectral overlap with other fluors (Minimal Compensation) 3) Bright (high QY and Extinction Coefficient) 4) Minimal photo bleaching for sorting and microscopy 5) Minimal non-specific cell binding Invitrogen Proprietary and Confidential 3 What Does a Fluorescent Dye Look Like? • Rigid conjugated -electron system is generally required for fluorescence Phenolphthalein Flexible, non-fluorescent Invitrogen Proprietary and Confidential Fluorescein Rigid, fluorescent 4 Efficiency or Total Fluorescence e = Absorbance x Path Length [M] e = Extinction Coefficient, Path Length is typically 1 cm for most cuvettes, [M] = the molar concentration •More highly conjugated (ring structures) compounds give higher extinction coefficient as they absorb more light. - Benzene has an extinction coefficient of ~1000 - Ethidium Bromide has an extinction coefficient of ~ 6000 Quantum Yield = Number of Photons Emitted by the Fluorochrome divided by the number of photons absorbed. Another way to look at the “quality” of a fluorochrome is to use: e x Q Yield = Efficiency or Total Fluorescence. Invitrogen Proprietary and Confidential 5 Protecting the fluorescence signal Q: What are the problem faced with standard fluorescent dyes? Invitrogen Proprietary and Confidential 6 Protecting the fluorescence signal Problem Low signal intensity Photobleaching Sensitivity to environmental conditions Solution The Alexa Fluor® dyes: brighter, more photostable, pH insensitive Invitrogen Proprietary and Confidential 7 Immuno Histochemistry Workflow Workflow Problems Culture Cells Fix cells Permeabilise Blocking Buffer Primary Antibody Secondary Antibody Nuclear Stain Low Signal Intensity Photobleaching Non-specific Binding Mount Microscopy Invitrogen Proprietary and Confidential Filter Quality 8 Multiplexing Alexa Fluor® Dyes across the spectrum Colour Selection Invitrogen Proprietary and Confidential ♦ Brightness ♦ Photostability 9 Multiplexing-The Four Main Colours Emission wavelengths: 350 700 Blue 400 Green 450 DAPI/UV Alexa Fluor® 350 Coumarin, AMCA 568 488 350 647 Orange 500 Far Red 550 600 FITC TRITC Alexa Fluor® 488 Fluorescein (FITC) Cy2 Alexa Fluor® 555 Rhodamine, TAMRA, TRITC Cy3 650 FAR RED Alexa Fluor® 647 Cy5, APC Alexa Fluor® 594 Texas Red, Cy3.5 Colour Selection Invitrogen Proprietary and Confidential ♦ Brightness ♦ Photostability 10 Alexa Fluor ® 488 and fluorescein — Alexa Fluor® 488 --- fluorescein Invitrogen Proprietary and Confidential 11 Alexa Fluor ® 488 vs Fluorescein Bleaching 2x Real Time Invitrogen Proprietary and Confidential 12 Alexa Fluor ® Dyes: pH Insensitive Alexa Fluor488 Oregon Green Invitrogen Proprietary and Confidential FITC 13 Alexa Fluor ® Dyes – Photo Stability Laser-scanning cytometry EL4 cells biotin-anti-CD44 + streptavidin conjugates Photobleaching dye solutions in capillary tubes Invitrogen Proprietary and Confidential 14 Better Performance Invitrogen Proprietary and Confidential 15 Alexa Fluor ® 647 vs. Cy5 Compare Alexa Fluor conjugates to any other fluorescent conjugates Invitrogen Proprietary and Confidential 16 Alexa Fluor® 405 / Pacific Blue® Alexa Fluor® 405 Excitation: 405 nm Emission max.: 421 nm Molecular Weight: 1028 Da Extinction Coefficient: 34,000 M-1cm-1 Pacific Blue® Excitation: 405 nm Emission max.: 455 nm Molecular Weight: 339 Da Extinction Coefficient: 46,000 M-1cm-1 •Great match for the 407 nm line of the krypton laser and the 405 and 408 violet diode lasers. Invitrogen Proprietary and Confidential 17 Alexa Fluor® 405 / Pacific Blue® anti-human CD8 AF 405 MFI = 88 Pacific Blue MFI = 145 •Alexa Fluor 405 Brightness- on the order of magnitude of FITC •Alexa Fluor 405 is purported to be less prone to problems with non- specific binding. •Photo-stability: 24 hour exposure, no reduction in signal anti-human CD45 Pacific Blue MFI = 419 AF 405 MFI = 199 •Pacific Blue is brighter than Alexa Fluor 405. • Pacific Blue has no compensation issues with UV excitable dyes • Studies have shown a decrease in signal of Pacific Blue following fixation. 1 Flow cytometry data generated at the J. David Gladstone Institute core flow cytometry laboratory, San Francisco, CA, headed by Marty Bigos, assistant Valerie Stepps Invitrogen Proprietary and Confidential •Therefore if you need to fix, consider using Alexa Fluor 405 18 Alexa Fluor ® 488 succinimidyl ester SO 3 H N 2 SO 3 O + NH 2 CO 2 O N O O Amine reactive Invitrogen Proprietary and Confidential O 19 Single Conjugates Single Alexa 405 Alexa 405 Alexa 405 Alexa 488 Alexa 488 Alexa 488 Alexa 647 Alexa 647 Alexa 647 Single Conjugates are made by attaching small fluorescent molecules (fluorophores) to the antibody at optimal F to P ratio’s. Invitrogen Proprietary and Confidential 20 Types of Fluors Tandem – Fluorescence Resonance Energy Transfer (FRET) Dyes • Emission of one dye overlaps the excitation of a second. • When close, energy is transferred to the second. • The second emits a longer wavelength of light than the first. Alexa 610 PE Alexa 610 Invitrogen Proprietary and Confidential Alexa 610 Alexa 750 APC Alexa 750 Alexa 750 21 Tandem Conjugates - Energy Transfer Dyes Fluorescence Resonance Energy Transfer (FRET) Donor R-PE APC Invitrogen Proprietary and Confidential Acceptor Alexa Fluor® dye 22 Tandem Conjugates - Energy Transfer Dyes PE-AF 610 PE-AF 647 R-PE APC PE-AF 680 APC-AF 680 APC-AF 700 APC-AF 750 Invitrogen Proprietary and Confidential 23 R-Phycoerythrin (PE-Alexa Fluor 610) • Large multi-subunit, globular (~240 kDa) protein derived from algae. • >20 chromophores per molecule • High quantum yield (bright) • Excitation 488 nm and 532 nm • Emission Maximum 575 nm Invitrogen Proprietary and Confidential 24 Alexa Fluor® 610 Carboxylic Acid, Succinimidyl Ester Alexa Fluor 610 Characteristics R-Phycoerythrin Alexa Fluor 610 Formula Weight………… 1171.66 Absorbance Maximum… 612 nm Extinction Coefficient….. 145,000 M-1cm-1 Emission Maximum……. 628 nm Invitrogen Proprietary and Confidential 25 PE-Alexa Fluor 610 The Visible Spectrum Ultraviolet Infrared Light Light 400 500 600 Wavelength (nm) R-Phycoerythrin, Chains: A, B, K, and L PE-Alexa Fluor 610 an alternative to PE-Texas Red •Energy transfer dye excited at 488, with maximal emission at 628 nm. •Higher quantum yield than PE-Texas Red with lower compensation in PE channel •Ideally suited for multicolor applications with the superior alternative for PE-Cy5 : PE-Alexa Fluor 647 Invitrogen Proprietary and Confidential 27 APC-Alexa Fluor 750 The Visible Spectrum Ultraviolet Infrared Light Light 400 500 600 Wavelength (nm) Allophycocyanin, Chains A and B APC-Alexa Fluor 750 Analysis APC-Cy7 anti-human CD4 Spectra MFI = 193 Compensation = 28% APC Channel 1 2 750 anti-human CD4 APC-Alexa%Fluor Compensation • Instrument: Tritech1 modified BD FACScan™ 2 • Human peripheral blood lymphocytes • APC-Cy7 and APC-AF750 detected through 765/20 filter, split from APC with 675 SP Light Stability 45 40 40 35 30 25 20 28 T = 0 hrs. 21 47% MFI = 551 T = 6.5 hrs. 16 Incr. Compensation = 16% 15 20% Incr. 10 5 0 CD4 APC-Cy7 CD4 APC-A750 APC Channel Tritech, Edgewater, MD BD, Becton Dickinson Biosciences Immunocytometry Systems, San Jose, CA Invitrogen Proprietary and Confidential 29 APC-Alexa Fluor 750 vs. APC-Cy7 • APC-Alexa Fluor 750 is perfectly interchangeable with APC-Cy7. • APC-Alexa Fluor 750 is brighter than APC-Cy7 by as much as 2-fold. • APC-Alexa Fluor 750 exhibits roughly half the compensation of APC-Cy7. • APC-Alexa Fluor 750 is significantly more photostable than APC-Cy7. Invitrogen Proprietary and Confidential 30 Antibodies and ImmunoFluorescence Invitrogen Proprietary and Confidential 31 Fluorescence reagents-Labeling Direct-Labeled Primary Antibody • Lowest Background • Potentially low signal due to abundance of target or dye • Dye could affect antigen recognition site Zenon Technology • Brighter Signal • Dye does NOT affect antigen recognition site Indirect-Labeled Secondary Antibody • Higher Background • Brighter Signal Tyramide Signal Amplification (TSATM) • Higher Background • Brightest Signal Invitrogen Proprietary and Confidential 32 Fluorescence reagents-Direct • Simple and easy to follow protocols • Reactive dye is pre-measured – no need to weigh out small quantities of dye • Procedure (including purification) takes ~2 hours, with little hands on time • Three kit sizes Alexa Fluor® Protein Labeling Kit (1 mg) + Alexa Fluor® Monoclonal Labeling Kit (100 ug) New - Alexa Fluor® Microscale Protein Labeling Kit (20-100 ug) Invitrogen Proprietary and Confidential 33 Fluorescence reagents-Zenon® Labeling ~ 1 μg primary antibody Add Zenon® reagent at desired molar ratio Incubate 5 minutes Block with nonspecific IgG & Use directly Invitrogen Proprietary and Confidential 34 Zenon labeling technology- Stability Kinetically trapped complex formation: key to making the system work. Fast complex formation Mouse anti-biotin IgG1 Slow complex dissociation Blocked mouse anti-biotin IgG1 + Alexa Fluor 488 Zenon Capture by BSA-biotin in microtiteer plate + Alexa Fluor 488 Zenon Capture by BSA-biotin in microtiteer plate Control IgG1 Invitrogen Proprietary and Confidential 35 WHY use ZENON? • Simple No need to use secondary antibodies anymore • Speed Zenon labeling complexes are ready to use for cell staining within 5 minutes… • Quantitative Labeling 100% of the primary antibody sample is labeled. • No Preparation Removal of exogenous proteins such as serum albumin from primary antibody samples is unnecessary. • Compatibility Multiple Zenon One–labeled mouse antibodies can be used in the same immunolabeling protocol. • Economy A standard Zenon labeling requires only 1 µg of primary antibody (versus 100 µg for chemical labeling). Save time and money. Invitrogen Proprietary and Confidential 36 Example 1: Triple Immunofluorescence Staining of Muntjak Cells with Zenon • anti-nuclear mouse mAb + Alexa Fluor 350 Zenon labeling reagent • F-actin + Alexa Fluor 488 phalloidin • anti-tubulin mouse mAb + Alexa Fluor 568 Zenon labeling reagent Invitrogen Proprietary and Confidential 37 Example 2: Switching Fluorescent Colors: Same Cell Type, Same Targets • F-actin + Alexa Fluor 350 phalloidin • anti-tubulin mouse mAb + Alexa Fluor 488 Zenon labeling reagent • anti-nuclear mouse mAb + Alexa Fluor 647 Zenon labeling reagent Invitrogen Proprietary and Confidential 38 Just in case you were wondering… Muntjak Invitrogen Proprietary and Confidential 39 Fluorescence reagents - Indirect Goat anti-Rabbit IgG Host animal in which antibody was raised Animal in which antigen was isolated Immunoglobin against which antibody was raised We Offer a Wide Selection of Secondary Antibodies Invitrogen Proprietary and Confidential 40 Tyramide Signal Amplification (TSA™) TSA™ can provide high resolution and high S/N Invitrogen Proprietary and Confidential 41 Chromosome FISH: Labeled Streptavidin vs TSA™ Streptavidin Alexa Fluor 546 Alexa Fluor 546 TSA Alexa Fluor 546 Dye FISH Signal: Streptavidin vs TSA RFU 1500 1000 500 0 AF546-SA AF546-TSA 10-fold increase in sensitivity w/ TSA™ Invitrogen Proprietary and Confidential 42 Why Use TSA? 3 color sequential TSA™ Invitrogen Proprietary and Confidential • Increased sensitivity – ~100-fold compared to avidin–biotinylated enzyme complex (ABC) • Generates multiple copies of Alexa Fluor dyes at target site • Gives high-resolution signal amplification • When normal amplification methods fail – Low abundance targets 43 Immuno Histochemistry Workflow Workflow Problems Culture Cells Fix cells Permeabilise Blocking Buffer Primary Antibody Secondary Antibody Nuclear Stain Low Signal Intensity Photobleaching Non-specific Binding Mount Microscopy Invitrogen Proprietary and Confidential Filter Quality 44 Protecting the fluorescence signal-Antifade Reagents Prolong® Gold •Optimized formulation-Superior antifade with little or no impact on initial fluorescence intensity •Ready to use - dropper bottle •Cures to a firm gel – no more nail polish NEW: SlowFade® Gold - antifade mounting media which doesn’t polymerize Invitrogen Proprietary and Confidential 45 Immuno Histochemistry Workflow Workflow Problems Culture Cells Fix cells Permeabilise Blocking Buffer Primary Antibody Secondary Antibody Nuclear Stain Low Signal Intensity Photobleaching Non-specific Binding Mount Microscopy Invitrogen Proprietary and Confidential Filter Quality 46 Increase S/N ratio – Reducing Non-specific background Non-specific binding - any signal not related to the target of interest, therefore increasing the background. Problem Non-specific binding of dye conjugates Standard blocking agents don’t work Solution •Image-iTTM FX Signal Enhancer – non-serum based blocking reagent Decrease background - Increase Specific Signal Invitrogen Proprietary and Confidential 47 Increase S/N Ratio - Image-iTTM FX signal enhancer BPAE Cells Stained with TMR Streptavidin Not blocked Blocked Image-iTTM FX signal enhancer decreases background fluorescence! Invitrogen Proprietary and Confidential 48 Alexa Fluor® Image-iT™ FX & Image-iT™ SFX Kits The Alexa Fluor® Image-iT™ FX Kits provide all of the dyes and reagents you need for optimal imaging of fixed cells and tissue sections for a more convenient price: – Alexa Fluor® Dye conjugates for superior photostability and brightness – ProLong Gold antifade reagent for reduced photobleaching independently of the color of your fluorochrome – Image-iT FX Signal Enhancer for improved signal-to-noise ratio - CultureWell chambered coverslips to make sample processing more convenient. NEW : Alexa Fluor® Image-iT™ SFX Kits = Start-Up Kits: 1. Alexa Fluor® Dye conjugates in small packaging combined with…. 2. Image-iT™ FX Signal Enhancer for superior, photostable, bright and highly specific staining ! NEW Easier to Use Kits Invitrogen Proprietary and Confidential 49 Small Animal In Vivo Imaging (SAIVI™) DRIVERS for INVITROGEN • Bring our expertise in molecular biology to develop solutions in molecular imaging • Develop tools to enable the acceleration of drug discovery • Continue to support our customers in the development of useful tools as they use more in-vivo assays The VISION for INVITROGEN • • Leverage our Molecular Probes Labeling & Detection technology in the Optical imaging space with injectable NIR reagents and Qdot technology – L&D – Cell Biology – In vivo Imaging Leverage our other appropriate technologies (gene regulation and delivery) into the in vivo imaging space COMPELLING REASONS for Optical • • • • • Low cost: Compared to all Ease of use: Compared to all High sensitivity: – superior to anatomical MR & CT – competitive with functional PET Optical can enable benchtop imaging for the PI Quantitative Optical can displace some PET COMPELLING REASONS for NIR Injectables VisEn Bioluminescence GFP NIR Injectables No Background Hi Sensitivity Hi Light Output Good Sensitivity Hi Light Output Good Sensitivity Ease of Use Huge Target Flexibility Depth Penetration Low Light Output Labor/Cost/Time Limited Depth Labor/Cost/Time Autofluorescence* Autofluorescence* NIR injectables can simplify and improve optical SAIVI Invitrogen Proprietary and Confidential 50 Dye Technologies Alexa Fluor Dyes Alexa Fluor 647 Cy5, (APC) allophycocyanin Total fluorescence significantly higher than Cy5 conjugates, unlike Cy5, 647 has little change in fluorescence when conjugated to most proteins, nucleic acids, thus greater total fluorescence at the same degree of labeling. Alexa Fluor 660 Cy5.5, APC Good spectral separation from orange fluoreophores. Efficiently excited by 633 nm and 647 nm laser lines Alexa Fluor 680 NA Highly recommended for use int the LI-COR Odyssey instrument for their “in-cell” westerns Alexa Fluor 750 Cy7 Longest-wavelength Alexa Fluor commercially available Fluorescent Nanocrystals. Invitrogen Proprietary and Confidential 51 SAIVI TM Imaging Reagents CORE TECHNOLOGY CUSTOMER TOOLS CONTRAST AGENTS TARGETED PROBES Dyes Dye Labeling Kits • • • To enable intravital imaging and blood flow imaging Broad Applications (2006) • • Multiple NIR wavelengths: – AF: 647, 680, 750 – Multiplexing – Spectral separation Multiple chemistries: – Better specificity – Brighter Patented Bodipy dye portfolio Quantum Dots • Expanded in-vivo utility • • 3 degrees of flexibility Multiple NIR wavelengths: – AF: 647, 680, 750 – NIR Nanocrystals – Multiplexing – Spectral separation Scale (0.1mg, 1.0 mg) Degree of Labeling Control for brightness vs specificity vs pharmacokinetics Quantum Dots • Available Now Invitrogen Proprietary and Confidential Conjugation Kits Available Now Alexa Fluor NIR Dyes • • Labelled colloidal agents Labelled proteins To enable Customer Research in: • • • • Cell Tracking (Now) • Quantum Dot Qtracker® non-targeted solution for tail vein injection Apoptosis: Angiogenesis: Cancer: Inflammation: Qtracker® cell labeling kits Confidential Custom Services (Now) • Aimed at Pharma/Biotech Available Now Unparalleled flexibility 52 Alexa Fluor NIR Dye (SAIVI) Protein Labeling Kits • Simple and easy to follow protocols • Reactive dye is pre-measured – no need to weigh out small quantities of dye • Procedure (including purification) takes ~2 hours, with little hands on time • Two kit sizes Alexa Fluor® Protein Labeling Kit (1 mg) Invitrogen Proprietary and Confidential Alexa Fluor® Monoclonal Labeling Kit (100 ug) 53 SAIVI TM Labeling Kits: Three degrees of flexibility IgG IgG IgG Effect of Modulating Agent on Degree of Labeling DOL 6 NIR dye DOL 3 NIR dye DOL 1 NIR dye Wavelength A simple and quick protocol for variation and control of the degree of labeling (DOL) allows for optimization of brightness and specificity in in vivo applications. Normalized Degree of Labeling 1.2 1 0.8 0.6 0.4 0.2 0 0 ul 750 nm 30ul 10 ul Microliters of Added Modulating Agent 680 nm 647 nm 0.1 mg Scale 1.0 mg Control of Degree of Labeling (DOL) of a typical IgG anitbody with Alexa Fluor 680 NIR dye using a SAIVI™ Alexa Fluor 680 0.1 mg Antibody/Protein Labeling Kit. Alteration of DOL was achieved without a significant change in protein volume or concentration. Final yield of purified protein remains constant across the DOL range. Three degrees of flexibility provide unprecedented convenience. Invitrogen Proprietary and Confidential 54 In-vivo imaging across the entire continuum Molecular Targeting Non-targeted Intravascular Cell Surface Interstitial Quantum Dots Intracellular Metabolic Quantum Dots Alexa Fluors Alexa Fluors Cellular Tracking Passive Proliferation Uptake Metabolism Reporter Systems Quantum Dots Alexa Fluors Post-mortem analysis Physiology Molecular Quantum Dots Alexa Fluors Invitrogen Proprietary and Confidential 55 Alexa Fluor Dyes Simply The Best • Brightness • Photostability • Color Selection • pH Insensitivity • Water Solubility • Ease of Use • Wide Selection Invitrogen Proprietary and Confidential •Broad Selection 56 Immuno Histochemistry Workflow Workflow Problems Culture Cells Fix cells Permeabilise Blocking Buffer Primary Antibody Secondary Antibody Nuclear Stain Low Signal Intensity Photobleaching Non-specific Binding Mount Microscopy Invitrogen Proprietary and Confidential Filter Quality 57 Semrock BrightLine® filters • 2 to 4 times the brightness • Twice the contrast • Extremely low crosstalk • Unparalleled performance – brightest & most discriminating filters for the fastest measurements • Unique spectral capabilities – unlock new capabilities that you once only dreamed about! • Proven reliability for permanent performance – work in hot, humid or corrosive environments • Highest batch-to-batch reproducibility – ensure the repeatable manufacturing of your product Invitrogen Proprietary and Confidential 58 Independent images taken by experts in the field • Differences in film density and resulting overall film quality are readily apparent Semrock Filters Ion-Beam Sputtered Hard Coating E-beam Evaporated Soft Coating Major Competitor Identical conditions Invitrogen Proprietary and Confidential 59 BrightLine® spectra versus leading competitor Exciter / emitter pairs for FITC Competitor’s multiband set Photographs of a Molecular Probes FluoCells #2 slide taken on an Olympus BX41 microscope using a Spot Insight Color camera by Diagnostic Instruments Inc. with competing DAPI/FITC/Texas Red multiband filters sets BrightLineTM multiband set TM Multiband – visibly superior … BrightLine Invitrogen Proprietary and Confidential 60 … and, quantitatively superior! Competitor BrightLineTM Color images were captured by a Spot Insight color CCD camera by Diagnostic Instruments Inc. Analysis based on monochrome images captured by a QImaging Retiga cooled 12-bit CCD camera Invitrogen Proprietary and Confidential 61 Compared to the competitors’ best filter set … Competitor Semrock BrightLine® Competitor Semrock BrightLine® Comparisons done under identical imaging conditions using an Olympus BX61WI microscope outfitted DSU spinning-disk confocal unit and a Hamamatsu ORCA-ER monochrome CCD camera. RMK sample courtesy of Mike Davidson, Molecular Expressions™. Invitrogen Proprietary and Confidential 62 Semrock for the ultimate in… The Semrock BrightLine® family When you want the best images ! Invitrogen Proprietary and Confidential Brightness, Performance, Reliability ! 63 Invitrogen Proprietary and Confidential 64 www.invitrogen.com/iProtocol Invitrogen Proprietary and Confidential 65 www.invitrogen.com/iPath Invitrogen Proprietary and Confidential 66 www.invitrogen.com/Antibodies Invitrogen Proprietary and Confidential 67 Invitrogen Proprietary and Confidential 68 Invitrogen Proprietary and Confidential 69 Literature and brochures Easy downloads from the web, or available on request. Invitrogen Proprietary and Confidential 70 We wrote the book on fluorescence detection . . . You can have your own copy! www.probes.invitrogen.com Invitrogen Proprietary and Confidential 71 Questions… Invitrogen Proprietary and Confidential 72