TABLE OF CONTENTSNANOTECHNOLOGYINSIGHTS
TABLE OF CONTENTS                    INTRODUCTION                    In recent years there has been ever increasing activi...
TABLE OF CONTENTSCONTENTSFundamental Concepts•	 Frequently Asked Questions- Nanotechnology and Engineered   Nanomaterials•...
TABLE OF CONTENTS                    Fundamental Concepts                     •	 Frequently Asked Questions- Nanotechnolog...
Frequently                        Nanotechnology and                                                                      ...
Table ofTABLE OF CONTENTS                        Contents                        What is nanotechnology?                  ...
Q    What is nanotechnology? A   Nanotechnology is the science and technology of precisely manipulating the struc-        ...
Even though ISO does not distinguish between engineered nanoparticles and                            naturally occurring n...
Fullerenes, graphene and carbon nanotubesA Fullerene is any molecule in the form of a hollow sphere, ellipsoid or tubular ...
small size they show different properties to bulk material. Hence the ‘tunability’,                        for example, se...
Table 1. Nanomaterial types and dimension characteristics.      Type of Nanomaterial     Number of dimensions and size    ...
Table 1. Nanomaterial types and dimension characteristics.                          Type of Nanomaterial     Number of dim...
Table 2. Selection of nanomaterials and usage or application area.    Market           Industry        Type of            ...
Table 3. Nanomaterial characteristics, their impact and importance.                     Nanomaterial Characteristic    Imp...
Q   What analytical techniques are used to characterize nanomaterials?     A   As shown in Figure 6 there are seven key ch...
TABLE OF CONTENTS                    Figure 7. High-level overview of the engineered nanomaterial manufacturing process an...
Table 4. Nanomaterial characteristics and applicable analytical technologies.                                             ...
Nanomaterial CharacteristicsSize                 Particle Size         Surface             Surface              Shape   Ag...
regulations and working with the EPA to establish nanomaterial guidelines for healthand safety for the workers and for the...
Q     What solutions are provided by PerkinElmer for nanomaterials                               characterization?TABLE OF...
PerkinElmer is an active member of the ISO group establishing nanomaterial testing     protocols and participates in NNI m...
9.   Gion, A., (2010) Bucky Balls, March 2010: http://www.3rd1000.com/bucky/bucky.htm                         10. Evident ...
25. Nanocomp Technologies, Concord, NH; USA, (2010), http://www.nanocomptech.    com/html/nanocomp-what-we-do.html26. Fede...
44. Heithmar, E.M., and Siska, E.M., (2010), Single particle-inductively coupled plasma                             mass s...
TABLE OF CONTENTSLooking for other ways to learn more about Nanotechnology?There are many different resources available th...
White                                                                                                         Nanopharmace...
Engineered nanoparticles are of great scientific interest.                What material parameters are important?    They ...
For	Nanoparticle	Composition	you	might	choose	one	of	the	        Who is involved in Nanopharmaceuticals?                  ...
Table 1. Nanomaterial characteristics and applicable analytical technologies.                                             ...
Nanomaterial CharacteristicsSize                   Particle Size         Surface             Surface   Shape          Aggl...
What are nanomaterials used for in                               Selecta’s unique tSVP™ platform includes a self-assemblin...
Below is a diagram from Cerulean pharma inc. that des-            who had previously relapsed and progressed on multiple  ...
Nanotechnology Insights e-Zine
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In recent years there has been ever increasing activity and interest within the scientific and engineering fields about engineered nanoparticles (ENP). PerkinElmer's analytical instruments enable engineers and scientists to measure, characterize, and better understand nanomaterials for industrial and academic nanotechnology research. In this Nanotechnology Insights e-Zine you will find a wide range of solutions and scientific papers about nanomaterial applications (from synthesizing to end use) that illustrate PerkinElmer's support and contribution to customers working in this revolutionary science.

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  1. 1. TABLE OF CONTENTSNANOTECHNOLOGYINSIGHTS
  2. 2. TABLE OF CONTENTS INTRODUCTION In recent years there has been ever increasing activity and interest within the scientific and engineering fields about engineered nanoparticles (ENP). PerkinElmer’s analytical instruments enable engineers and scientists to measure, characterize, and better understand nanomaterials for industrial and academic nanotechnology research. In this Nanotechnology Insights e-Zine you will find a wide range of solutions and scientific papers about nanomaterial applications (from synthesizing to end use) that illustrate PerkinElmer’s support and contribution to customers working in this revolutionary science. Read, Learn, and Share! Want more information? Click here to speak to one of our experts and they can help answer your questions
  3. 3. TABLE OF CONTENTSCONTENTSFundamental Concepts• Frequently Asked Questions- Nanotechnology and Engineered Nanomaterials• Nanopharmaceuticals and PerkinElmerThermal Analysis• Improved HyperDSC Method to Determine Specific Heat Capacity of Nanocom- posites and Probe for High-Temperature Devitrification• A Study of Aged Carbon Nanotubes by Thermogravimetirc AnalysisMolecular Spectroscopy• Simple Method of Measuring the Band Gap Energy Value of TIO2 in the Pow- der Form using a UV/Vis/NIR SpectrometerAtomic Spectroscopy• Analysis of NIST Gold Nanoparticles Reference Materials Using the NexION 300 ICP-MS in Single Particle Mode• Colorado School of Mines Uses a NexION 300Q ICP-MS to Obtain a Better Understanding of the Impact of Engineered NanomaterialsHyphenated Techniques• An Introduction to Flow Field Flow Fractionation and Coupling to ICP-MS• Coupling Flow Field Flow Fractionation to ICP-MS for the Detection and Characterization of Silver Nanoparticles• Characterizing Interaction of Nanoparticles with Organic Pollutants Using coupling Thermal Analysis with Spectroscopic Techniques ?
  4. 4. TABLE OF CONTENTS Fundamental Concepts • Frequently Asked Questions- Nanotechnology and Engineered Nanomaterials • Nanopharmaceuticals and PerkinElmer
  5. 5. Frequently Nanotechnology and TABLE OF CONTENTS asked questions Engineered Nanomaterials A Primer authors: Andrew W. Salamon, Patrick Courtney and Ian ShuttlerIntroductionIn recent years there has been ever increasing activity and excitement within the scientificand engineering communities, driven heavily by government investment, about engineerednanotechnology applications. The U.S. National Science Foundation has estimated thatthe global nanotechnology market could be worth U.S.$1 trillion by 2015.1 In parallel,much has been written and presented about the excitement and possible dangers of thesematerials. The tone of these media articles range from how these wonder materials aregoing to revolutionize all aspects of our lives to how they might kill us! The purpose ofthis primer is to provide some basic information about engineered nanomaterials so thatyou will be better informed, understand the new ‘jargon’ and appreciate some of thepotential new applications of these materials. In addition, understanding the wide rangeand types of measurements needed to characterize these nanomaterials along with whatsolutions PerkinElmer has to support customers working in this field are outlined. ?
  6. 6. Table ofTABLE OF CONTENTS Contents What is nanotechnology? 3 What is the market and potential of nanotechnology? 4 What are engineered nanomaterials? 4 Fullerenes, graphene and carbon nanotubes 5 Quantum dots 5 Nanoparticles 6 Nanofibers and Nanowires 6 Where are nanomaterials being used today and in the future? 7 How are nanomaterials characterized? 7 What analytical techniques are used to characterize nanomaterials? 12 What are the environmental implications of nanotechnology? 13 What solutions are provided by PerkinElmer for nanomaterials characterization? 15 Where can I find more information? 16 References 16 Useful books and websites for more information 19 2
  7. 7. Q What is nanotechnology? A Nanotechnology is the science and technology of precisely manipulating the struc- TABLE OF CONTENTS ture of matter at the molecular level. The term nanotechnology embraces many different fields and specialties, including engineering, chemistry, electronics, and medicine, among others, but all are concerned with bringing existing technologies down to a very small scale, measured in nanometers.2 Processes and functionality take place at the nanoscale, exhibiting properties not available in the bulk mate- rial. But what is a nanometer? Figure 1 compares the nano-region to things we know, such as a pin, insect and cells and provides a visual perspective.Figure 1. Size relationships from large to small to nano. A nanometer is a thousandth of a micron and a micron is a thousandth of a millimeter, so a nanometer is a millionth of a millimeter or 10-9 meters. To be classified as a nanomaterial (NM), the material must be less than 100 nm in size in at least one direction. According to the International Standards Organization® (ISO) a nano-object is a material with at least one, two or three external dimensions in the nanoscale range of 1 to 100 nm and a nanoparticle is a nano-object with all three external dimensions in the 1 to 100 nm range and showing a property not evident in the bulk material. Hence, a nanofiber, 400 nm long and 12 nm in diameter, and a 20 nm diameter nanoparticle, are both classified as nanomaterials.3 3 ?
  8. 8. Even though ISO does not distinguish between engineered nanoparticles and naturally occurring nanoparticles, you should be aware that there are naturally occurring nanoparticles in the aquatic environment such as biodegraded organicTABLE OF CONTENTS matter and colloidal inorganic species and in soils; clays, organic matter and various metal oxides.4 Many important functions of living organisms take place at the nano- scale. The human body uses natural nanoscale materials such as proteins and other molecules, to control the body’s many systems and processes. A typical protein such as hemoglobin, which carries oxygen through the bloodstream, is 5 nm in diameter.5 However, this primer concentrates on Engineered Nanomaterials (ENMs). Q What is the market and potential of nanotechnology? A According to the U.S. National Nanotechnology Initiative (NNI), Federal Government funding in the United States, for nanotechnology, has increased from approximately $464 million in 2001 to nearly $1.9 billion for the 2010 fiscal year. Private industry is investing at least as much as the government, according to estimates. The United States is not the only country to recognize the tremendous economic potential of nanotech- nology. While it is difficult to measure accurately, estimates from 2005 showed the European Union (EU) and Japan are investing approximately $1.5 billion and $1.8 billion, respectively, in nanotechnology. Behind them were Korea, China and Taiwan with $300 million, $250 million and $110 million respectively, invested in nanotechnology research and development.6 Last year the Russian government announced that it was investing $11 billion in an ambitious plan to develop and commercialize nanotechnologies.7 It is not only gov- ernments that are investing heavily in this area, venture capital firms invested $702M in nanotechnology start-ups in 2007 across 61 investments. The Japanese Mitsubishi Institute projected nanotechnology to be worth U.S.$150 billion on the global market by 2010 and Lux Research® estimated a U.S.$2.6 trillion global market by 2014.1 The U.S. NNI continues to be well funded with a 2010 budget of $1.6B, with total spending since 2001 of nearly $14B. However, to put some of these numbers into perspective, allocation of NNI funds for environmental, health and safety research since 2005 totals $480M.8 In spite of this it is clear that significant investments are being made in all aspects of nanotechnology and that there is considerable potential. Q What are engineered nanomaterials? A There are many new material terminologies associated with this field. This section gives a short overview of some of the different types of nanomaterials. 4
  9. 9. Fullerenes, graphene and carbon nanotubesA Fullerene is any molecule in the form of a hollow sphere, ellipsoid or tubular TABLE OF CONTENTSstructure composed entirely of carbon. They are commonly referred to as“Buckyballs” – named after Buckminster Fuller who designed geodesic physicalstructures and buildings based on this geometry. A Buckyball is a carbon basedhollow geometric sphere, first found in soot developed from a laboratory experiment.It resembles a hollow spherical geodesic dome and is comprised of 60 carbonatoms (C60). Discovered in 1985, it is the roundest and most symmetrical largemolecule known to man.9 Fullerenes or Buckyballsare used in nanotechnology. Graphene is a one atomthick planar sheet of carbon atoms densely packedin a honeycomb crystal lattice. Graphene is the basicstructural building block of carbon nanotubes andfullerenes. Carbon nanotubes (CNT) also known as‘buckytubes’ have a cylindrical nanostructure in theform of a tube and an engineered CNT typically has ananoscale thick wall, geometrically shaped similar toa Buckyball, with a nanoscale diameter, and a length Figure 2. C60 buckyball.that may exceed 100 nm. Carbon nanotubes are manufactured as single wall carbon nanotubes (SWCNT) or multiwall car- bon nanotubes (MWCNT). An example is shown in Figure 3. They are synthesized in a variety of ways, including arc discharge, laser ablation and chemical vapor deposition. With respect to tensile strength, carbon nanotubes are the strongest andFigure 3. Multiwalled carbon stiffest materials yet discovered, more than 5 timesnanotube. stronger than Kevlar®. Since CNTs have a very low density, their specific strength is 300 times greaterthan stainless steel, though under compression CNTs appear to be a lot weaker.Quantum dotsQuantum dots, also known as nanocrystals, are another form of nanomaterial andare a specific type of semiconductor. They are 2-10 nanometers (10-50 atoms) indiameter, and because of their electrical characteristics, they are [electrically] tun-able.10 The electrical conductivity of semiconductors can change due to externalstimulus such as voltage or exposure to light, etc. As quantum dots have such a 5 ?
  10. 10. small size they show different properties to bulk material. Hence the ‘tunability’, for example, sensitivity to different wavelengths of light, can be adjusted by the number of atoms or size of the quantum dot. Quantum dots are typically madeTABLE OF CONTENTS from CdSe, ZnS or CdTe compounds, though from a EU Restriction of Hazardous Substances (RoHS) perspective, cadmium-free quantum dots are required.11 For an excellent explanation of quantum dots and their operation in a cadmium selenide semiconductor see the website associated with reference.10 Nanoparticles Nanoparticles (NP) are synthesized or machined. They range in size from 2 nm to 100 nm. Nanoparticle materials vary depending on their application. Because Nanoparticles are invisible to the naked eye, they are usually supplied suspended in a liquid. This is done for safety and handling reasons. Figure 4 shows gold nanoparticles suspended in liquid. The color is due to the refraction of light the surface area of the particular nanoparticle reflects. Different sized nanoparticles exhibit different colors based on its surface area.12 Figure 4. Suspension of gold Figure 5. SEM image of aligned nanoparticles. nanofibers. Photo courtesy of Univ. of Wisconsin – Madison, Department of Chemistry. Nanofibers and Nanowires Nanofibers are slightly larger in diameter than the typical nanomaterial definition, though still invisible to the naked-eye. Their size ranges between 50 nm - 300 nm in diameter and are generally produced by electro spinning in the case of inor- ganic nanofibers or catalytic synthesis for carbon nanotubes. Figure 5 shows an SEM image of aligned nanofibers. Nanofibers can be electrostatically aligned and biochemically aligned.13,14 Further information about nanofibers fabrication can be found in reference.15 Similar to nanofibers are nanowires, though nanowires are considerably smaller in diameter, of the order of 4 nm and conduct electricity. In Table 1, the different size characteristics of the various nanomaterials are summarized. 6
  11. 11. Table 1. Nanomaterial types and dimension characteristics. Type of Nanomaterial Number of dimensions and size TABLE OF CONTENTS Nanoparticle Three dimensions in the 1 to 100 nanometers (nm) range Nanotubes/nanowires Two dimensions in the 1 to 100 nm range Nanofibers Length ranges between 50 nm and 300 nm with diameter <50 nm Nanofilms One dimension in the 1 to 100 nm range Nanoplates Two dimensions in the 1 to 100 nm rangeQ Where are nanomaterials being used today and in the future?A Some of the current applications of many of these nano-related materials and technology are outlined in Table 2 (Page 8). While this table is not intended to be exhaustive, it does show how wide ranging the applications are. It is clear that the nanomaterial science revolution has the potential and magnitude to be an enormous leap forward in technology. However, it should be noted that there are increasing concerns about the impact of these materials in the environment and their possible impact on human health. Currently the Woodrow Wilson Center for Scholars through their Project on Emerging Nanotechnologies (PEN) lists in their database, 1015 commercially available nanotechnology containing consumer products in over 20 countries16 up to 2009. This website and searchable database is recommended for those wishing to learn more. A more comprehensive listing of current and possible future applications of nanomaterials is available on www.PerkinElmer.com/nanoQ How are nanomaterials characterized?A It is important to understand that the excitement regarding the synthesis and application of nanomaterials is based on the fact that, because of their very small size, the characteristics and behavior are quite different to bulk materials with the same composition. Consequently, the range of parameters that has to be assessed to characterize these materials is large. Fundamentally there are seven key characteristics that contribute to the uniqueness of nanomaterials and these are summarized in Table 3. In addition to the key seven characteristics, there are two additional qualities that are unique to nanomaterials and important in characterizing them. These are agglomeration, which is the tendency of the particles to clump together and form larger combined particles, and the particle size distribution. 7 ?
  12. 12. Table 1. Nanomaterial types and dimension characteristics. Type of Nanomaterial Number of dimensions and sizeTABLE OF CONTENTS Nanoparticle Three dimensions in the 1 to 100 nanometers (nm) range Nanotubes/nanowires Two dimensions in the 1 to 100 nm range Nanofibers Length ranges between 50 nm and 300 nm with diameter <50 nm Nanofilms One dimension in the 1 to 100 nm range Nanoplates Two dimensions in the 1 to 100 nm range Q Where are nanomaterials being used today and in the future? A Some of the current applications of many of these nano-related materials and technology are outlined in Table 2 (Page 8). While this table is not intended to be exhaustive, it does show how wide ranging the applications are. It is clear that the nanomaterial science revolution has the potential and magnitude to be an enormous leap forward in technology. However, it should be noted that there are increasing concerns about the impact of these materials in the environment and their possible impact on human health. Currently the Woodrow Wilson Center for Scholars through their Project on Emerging Nanotechnologies (PEN) lists in their database, 1015 commercially available nanotechnology containing consumer products in over 20 countries16 up to 2009. This website and searchable database is recommended for those wishing to learn more. A more comprehensive listing of current and possible future applications of nanomaterials is available on www.PerkinElmer.com/nano Q How are nanomaterials characterized? A It is important to understand that the excitement regarding the synthesis and application of nanomaterials is based on the fact that, because of their very small size, the characteristics and behavior are quite different to bulk materials with the same composition. Consequently, the range of parameters that has to be assessed to characterize these materials is large. Fundamentally there are seven key characteristics that contribute to the uniqueness of nanomaterials and these are summarized in Table 3. In addition to the key seven characteristics, there are two additional qualities that are unique to nanomaterials and important in characterizing them. These are agglomeration, which is the tendency of the particles to clump together and form larger combined particles, and the particle size distribution. 7
  13. 13. Table 2. Selection of nanomaterials and usage or application area. Market Industry Type of Use/Application Area TABLE OF CONTENTS Segment Nanomaterial Environmental Water Nano zero valent Being tested for the remediation of ground and surface waters iron (nZVI) exposed to chlorinated hydrocarbons17 Gold nanoparticles Various gold nanomaterials are used to enhance imaging properties of a variety of MRI and CT-based contrast agents18 UV absorbing Improved and sustainable water based surface coatings to nanomaterials protect and preserve wood, concrete and metal surfaces used in construction19 Safety and Food Clay Nanomaterials are being used in food packaging. The Security penetration of light, moisture, or gases can alter the sensory characteristics of food products, as well as increase spoilage. Nanomaterials enhance packaging barrier properties20 Energy Pd and V doped Enhance hydrogen fuel cells by increasing storage capacities carbon nanotubes and showing faster hydrogen absorption kinetics21 Medical Various materials Nanomaterials coated with pharmaceutical compounds are being considered as novel inhalation delivery systems for medications difficult to administer by other means22 Textiles/ Silver nanoparticles Integrated with sports clothing to prevent microbial growth, Apparel and odor23,24 Cosmetics/ Nano titanium Used in some cosmetics. The applications include: eye liners, Personal dioxide and nano moisturizers, lipsticks, make-up foundations, soaps, sunscreen, Care Products zinc oxide mascara, and nail polish16 Industrial Defense CNTs Body armor – multilayer-epoxy composites manufactured with CN sheets, the size of a piece of plywood 4’ x 8’ foot, provide a shield that can stop a 9 mm bullet and weighs no more than a pack of playing cards25 Aerospace Clay nanoparticles Incorporated with thermoplastics to create improved fire retardant aircraft interiors26 Automotive 10 nm Cerium oxide Forms part of the Envirox™ diesel fuel catalyst which improves nanoparticles combustion due to the increased surface area of the cerium oxide nanoparticles27 Recreation/ Unknown Holmenkol® AG supply a chemical nanotechnology coating Manu- system under the brand name ‘Nanowax®’ to replace conven- facturing tional ski and snowboard waxes28 Sports CNTs/Yarn High end golf club shafts are made with nano-composites to make equipment the shaft stronger and more flexible. Racing bicycle components298 ?
  14. 14. Table 3. Nanomaterial characteristics, their impact and importance. Nanomaterial Characteristic Impact and ImportanceTABLE OF CONTENTS Size Key defining criteria for a nanomaterial3 (see Table 1). Shape Carbon nanosheets with a flat geodesic (hexagonal) structure show improved performance in epoxy composites versus carbon fibers.30 Surface Charge Surface charge is as important as size or shape. Can impact adhesion to surfaces and agglomeration characteristics. Nanoparticles are often coated or ‘capped’ with agents such as polymers (PEG) or surfactants to manage the surface charge issues. Surface Area This is a critical parameter as the surface area to weight ratio for nanomaterials is huge. For example, one gram of an 8 nm diameter nanoparticle has a surface area of 32 m2. Nanoparticles may have occlusions and cavities on the surface. Surface Porosity Many nanomaterials are created with zeolite-type porous surfaces. These engineered surfaces are designed for maximum absorption of a specific coating or to accommodate other molecules with a specific size Composition The chemical composition of nanomaterials is critical to ensure the correct stoichiometry has been achieved. The purity of nanomaterials, impact of different catalysts used in the synthesis and presence of possible contaminants needs to be assessed along with possible coatings that may have been applied. Structure Knowledge of the structure at the nano level is important. Many nanomaterials are hetero- geneous and information concerning crystal structure and grain boundaries is required. Figure 6. Key parameters to characterize nanomaterials. 9
  15. 15. Q What analytical techniques are used to characterize nanomaterials? A As shown in Figure 6 there are seven key characteristics along with agglomeration TABLE OF CONTENTS and particle size distribution that need to be measured to fully describe a nano- material. Consequently, at the nanoscale, analytical measurement challenges are considerable and the ability to use, for example, one technique such as inductively coupled plasma-mass spectrometry (ICP-MS) to measure the elemental concentration of gold in a suspension of gold nanoparticles as the only metric to assess the material, does not provide all the information needed. To completely characterize the material it is necessary to know a multitude of chemical and physical parameters including; the size of the particles, their shape, surface characteristics, presence of any surface coating and presence of impurities. This small subset illustrates the magnitude of the measurement challenge facing the nanomaterials industry. Table 4 lists the key characteristics and many of the current analytical technologies that can be applied. In addition to looking at a variety of analytical techniques and their application to nanomaterials it is also important to understand where measurements need to be made, what type of measurements are required and why. To understand this, an overview of the nanomaterial manufacturing process and value chain is necessary. This includes consideration of aspects such as source and quality of raw materials, control of the synthesis/manufacturing process, validation of the final product and subsequent use or incorporation into another product, e.g., a cosmetic preparation. Along this manufacturing chain are a variety of points at which material and hazardous waste may need to be disposed of and there is potential for environmental exposure. Figure 7 provides a high level view of this process in a very fast changing technology area and outlines which characteristics may need to be assessed at the various measurement points. To understand which analytical technologies may be required to provide this information, Figure 7 and Table 4 can be compared. This chain has been developed from recent market research and customer feedback. Key nanomaterial characteristics require new measurement technologies. An analyti- cal technique that is becoming more prevalent in the nanomaterial field is that of Field Flow Fractionation (FFF) coupled with Light Scattering (LS) and possibly ICP-MS for elemental nanoparticle characterization. Field Flow Fractionation is a separation technique similar to chromatography whereby colloids, macromolecules and nanoparticles are separated by size and should allow a separation of natural and engineered nanomaterials. Further details can be found in a recent review article on the coupling of FFF with ICP-MS31 and the websites under references.32,3310 ?
  16. 16. TABLE OF CONTENTS Figure 7. High-level overview of the engineered nanomaterial manufacturing process and key characteristics. Electron microscopy is also widely used to characterize nanoparticles. The surface area, porosity, particle shape, and agglomeration can be examined with Scanning Electron Microscopes (SEM), Atomic Force Microscopes (AFM), Tunneling Electron Microscopes (TEM), and Confocal Microscopes. In the production and characterization of carbon nanotubes (CNTs) the use of Thermogravimetric Analysis (TGA) has found considerable application and can be used to show batch to batch reproducibility, detect changes in the process and validate purification protocols.34 During both the production and formulation process, many nanoparticles are coated or ‘capped’ with a variety of molecules. For assessing the coating, the hyphenated technique of TGA coupled with GC/MS is finding use.35 A critical application in this area is determining the amount of anti-cancer drug that is coated on nanoparticles. This is needed to characterize the dosage being consumed by the patient. Q What are the environmental implications of nanotechnology? A Process waste has always been a manufacturing issue. It is slightly different today when nanoparticles are considered. Nano-waste is different than bulk material waste. It’s been seen in laboratory experiments that nanomaterials can enter the human body by dermal exposure, inhalation, and ingestion.36 While there are no specific nanomaterials regulations, yet, there is increasing review and concern both within the industry and in the environmental field as to the fate and behavior of these materials in the environment. Many nanomaterial manufacturers are following bulk material 11
  17. 17. Table 4. Nanomaterial characteristics and applicable analytical technologies. Nanomateria TABLE OF CONTENTS Concentration Particle Size Particle Size SuAnalytical Technique Distribution ChInductively Coupled Plasma – Mass Spectrometry ICP-MSField-flow Fractionation + ICP-MS FFF-ICP-MSLiquid Chromatography – Mass Spectrometry LC-MSOptical Spectroscopy – UV/Vis UV/VisFluorescence Spectroscopy FLTurbidityScanning Electron Microscopy SEMTransmission Electron Microscopy (+EDX) TEMAtomic Force Microscopy AFMConfocal MicroscopyField Flow Fractionation FFFDynamic Light Scattering DLSStatic Light Scattering SLSMolecular Gas Adsorption (BET) BETDialysisElectrophoresis and Capillary ElectrophoresisUltrafiltrationCentrifugationFiltrationNanoparticle Tracking Analysis NTASize Exclusion Chromatography SECSelected Area Electron Diffraction SAEDZeta Potential by DLSX-ray Diffraction XRDThermogravimetric Analysis TGAQuartz MicrobalancesDifferential Scanning Calorimetry DSCDynamic Mechanical Analysis DMAFourier Transform Infrared Spectroscopy FT-IRFT-IR ImagingRaman SpectroscopyTGA coupled with Gas Chromatography – Mass Spectrometry TGA-GC/MSLaser Induced Plasma Spectroscopy LIPSHydrodynamic Chromatography HDCLaser Induced Breakdown Detection LIBDX-ray Photoelectron Spectroscopy XPSElectron Energy Loss Spectroscopy EELS (+EDX) Commonly used in the Microscopy characterization of techniques nanomaterials ?
  18. 18. Nanomaterial CharacteristicsSize Particle Size Surface Surface Shape Agglomeration Structure Composition TABLE OF CONTENTS Distribution Charge Area Not widely Available from applicable PerkinElmer 13
  19. 19. regulations and working with the EPA to establish nanomaterial guidelines for healthand safety for the workers and for the end users. The EPA has declared that nano-carbon is a new material and use and requires that it be substantiated as safe.37 TABLE OF CONTENTSSo airborne nanoparticles, nanoparticles in water, and skin exposure to nanomaterialsare being addressed by all parties concerned, but there is much research to be doneand a key aspect of this work is the need for methods and analytical techniques thatcan separate, identify and quantitate ENPs in amongst naturally occurring nanoparticles.As consumers, we should to be aware of nanoparticles in the products we use andthe food we eat, but currently there are no labeling regulations. There is legislationbeing implemented in Europe that requires cosmetic manufacturers to list anynanoparticles used in their products.38,39 This is the first European industry to haverequired labeling. To date labeling is not required for any other industries anywherein the world.Within the United States, the EPA and other government agencies are proactive inregards to nanotechnology. The Federal Government has established the NationalNanomaterial Initiative (NNI) where government agencies and private industry meetto discuss and understand nanomaterial implications of the environment and humanhealth. PerkinElmer participates in NNI meetings and is working with the EPA andother agencies to better understand nanomaterials. Figure 8 depicts the life cycleof nanomaterials in the environment and identifies what government agencies areaddressing these segments of the life cycle. The source and emission in Figure 8corresponds to the manufacturing waste in figure 7. The waste interaction withthe environment could occur from material taken to a dump, incinerated or washeddown the drain. Environmental Health and Safety (EHS) applies to nanomaterialworkers as human exposure could occur during the manufacturing process. Figure 8. Nanomaterial life cycle in the environment. Source: DOE Molecular Foundry – Lawrence Berkeley National Laboratory. 13 ?
  20. 20. Q What solutions are provided by PerkinElmer for nanomaterials characterization?TABLE OF CONTENTS A Although nanomaterials are small and cannot be seen with the naked eye, it seems likely that their impact on the world will be huge. PerkinElmer is involved in the nanomaterial revolution by participating and working with government agencies, research universities, nanomaterial manufacturers, and end-user industries. While PerkinElmer does not supply all the possible measurement technologies required as listed in Table 4, in certain important areas we have a rich solution offering to enable customers to make critical measure- ments. As customers discover what measurement parameters and performance criteria are important, we believe that our offerings will deliver more value and come to be recognized as important solutions to challenging problems. PerkinElmer has the following solutions available for customers who require nanomaterial characterization: Table 5. PerkinElmer analytical solutions. Analytical Technology Application UV/Vis The LAMBDA™ 850/950 are being used to assess nanomaterial surface coating on glass for the solar energy industry. The LAMBDA 1050 equipped with a 150 mm integrating sphere has been used to measure the band gap (an important semiconductor characteristic) of TiO2 nanomaterials.40 Fluorescence The LS-55 is being used to measure the fluorescence shift in quantum dots. In addition, quantum dots are being considered as reference materials to calibrate fluorescence spectrometers.41 FT-IR Photocatylitic degradation of dyes and other photosensitive materials. Use of FT-IR imaging to examine gold nanostructures embedded in 50 nm thin polymethylmethacrylate film to develop novel materials.40 Raman Surface characterization of films and other substrate materials that are coated with nanomaterials. TGA Pyris™ 1 TGA finds application in characterizing CNTs during the manufacturing process and for incoming inspection. DSC DSC 8500 is being used to characterize amorphous pharmaceuticals that employ nanomaterials such as determining the glass transition temperature (Tg) to assess the nano-crystalline structure.40 StepScan™ and HyperDSC® have been used to study the rigid amorphous fraction in polymethylmethacrylate silicon oxide nano-composites.42 DSC-Raman Morphology characterization of SWCNTs in composites. DMA To assess the strength of different composite mixtures of CNT/epoxy. TGA-GC/MS Being used by an EPA lab to measure the degree of coating on ENPs under different conditions. AA Mainly used to measure bulk concentrations in fabricated materials such as Ag nanoparticle impregnated fabrics [Ag in textile/Germany]. ICP Assessment of gold and copper concentration in digests of elemental nanomaterial suspensions.43 ICP-MS Rapidly becoming the elemental measurement technique of choice for ENPs, especially Au, Ag, Pt, Ce, W, Ti, etc. in the environment and increasingly being coupled with Field Flow Fractionation. In a recent review article on this hyphenated technique, of the 28 papers referenced, 18 used PerkinElmer® ICP-MS systems.31 Researchers are now looking to perform single particle analysis with ICP-MS as this gives additional size and distribution information.44 14
  21. 21. PerkinElmer is an active member of the ISO group establishing nanomaterial testing protocols and participates in NNI meetings and a variety of international nanomaterial scientific meetings. TABLE OF CONTENTSQ Where can I find more information?A To learn more about PerkinElmer analytical solutions for nanomaterial applications, please visit http://www.perkinelmer.com/nano. This will continue to develop in the future to provide access to key scientific publications, background information, application notes and links to useful websites. This ‘Primer’ is intended to provide you with useful background information; it cannot answer every question, but it should stimulate material characterization discussions that hopefully will lead to an analytical solution. Have questions, need more information? Please contact Andrew Salamon, Patrick Courtney or your local PerkinElmer sales representative. We are happy to answer your nano-related questions.References1. Burnett, K., and Tyshenko, M.G., (2010), A comparison of human capital levels and the future prospect of the nanotechnology industry in early sector investors and recent emerging markets, Intl. J. of Nanotechnology, 7, 2/3, 187-208. http:// www.inderscience.com/browse/index.php?journalID=54&year=2010&vol=7&issue=2/32. American Heritage Dictionary, March 2010. http://dictionary.reference.com/ browse/Nanotechnology3. International Standards Organization, 2008, ISO/TS 27687:2008 and 2010, ISO/ CD TS 80004-1:20104. Klaine, S.J., Alvareez, J.J., Batley, G.E., et al., (2008), Critical Review, Nanomaterials in the environment: behaviour, fate, bioavailability and effects, Environ. Toxicol. Chem, 27, 1825-18515. National Nanomaterial Initiative, March 2010: http://www.nano.gov/Nanotechnology_ BigThingsfromaTinyWorldspread.pdf6. National Nanomaterial Initiative, March 2010: http://www.nano.gov/html/facts/faqs.html7. Nature, (2009), 461, 1036-1037, doi: 10.1038/4611036a8. National Nanomaterials Initiative, 2010, Supplement to the President’s FY2011 budget http://www.nano.gov/NNI_2011_budget_supplement.pdf 15 ?
  22. 22. 9. Gion, A., (2010) Bucky Balls, March 2010: http://www.3rd1000.com/bucky/bucky.htm 10. Evident Technologies, (March 2010): http://www.evidenttech.com/quantum-dots- explained/how-quantum-dots-work.htmlTABLE OF CONTENTS 11. Nanoco Group PLC website, (2010), http://www.nanocotechnologies.com/content/ AboutUs/AboutQuantumDots.aspx 12. Nanocomposix Corp., (March 2010): http://www.nanocomposix.com/product-gold/ nanoxact-gold.html 13. Li, D., Wang, Y., Xia, Y., (2004), Electrospinning Nanofibers as Uniaxially Aligned Arrays and Layer-by-Layer Stacked Films, Adv. Matls., 16, 4, 361-366, DOI 10.1002/adma.200306226, http://www3.interscience.wiley.com/journal/107630203/ abstract 14. Patel, S., Li, S., (2007), Bioactive Aligned Nanofibers for Nerve Regeneration, Nanotech Conference, Santa Clara, CA, USA. http://www.nsti.org/BioNano2007/ showabstract.html?absno=1301 15. Hegde, R.R., Dahiya, A., Kamath, M.G., (2005), Nanofiber nonwovens, http://web. utk.edu/~mse/Textiles/Nanofiber Nonwovens.htm 16. Woodrow Wilson Center for Scholars, Project on Emerging Technologies (2010), http://www.wilsoncenter.org/index.cfm?topic_id=166192&fuseaction=topics.home 17. Nanoiron Future Technology, Rajhard, Czech Republic, http://www.nanoiron.cz/en/ home-page 18. Moriggi, L., Cannizzo, C., Dumes, E, et al., (2009), Gold Nanoparticles Functionalized with Gadolinium Chelates as High-Relaxivity MRI Contrast Agents, J. Am. Chem. Soc., 131 (31), pp 10828–10829, DOI: 10.1021/ja904094t, 19. Nanovations Pty, Ltd., New South Wales, Australia, (2010), http://www.nanovations.com.au/index.htm 20. Nanocor, USA, www.nanocor.com 21. A to Z of Nanotechnology website, (2010), http://www.azonano.com/details.asp? ArticleID=1339 22. Yang, W., Peters, J.I., Williams III, R.O., (2010), Inhaled nanoparticles – a current review., Int. J. of Pharmaceutics, 356, 1-2, 239-247, doi:10.1016/j.ijpharm.2008. 02.011 23. 3XDRY® Essex Fishing Shirt, (2010). http://www.simmsfishing.com/site/3xdry_essex_ shirt.html# 24. PuckSkin Hockey Apparel, BC, Canada, (2010), http://www.puckskin.com/home.htm 16
  23. 23. 25. Nanocomp Technologies, Concord, NH; USA, (2010), http://www.nanocomptech. com/html/nanocomp-what-we-do.html26. Federal Aviation Administration, Fire Safety Division, Washington DC, USA, (2010), TABLE OF CONTENTS http://www.fire.tc.faa.gov/research/targtare.stm27. Energenics web page, suppliers of Envirox™ http://www.energenics.org/envirox.html28. Holmenkol AG, Germany, (2010), http://www.nanowax.de/index.php?id=10&L=129. Easton Sports Inc., CA, USA, http://eastonbike.com/30. Goa, F., University of Nottingham Trent, UK, January 26, 2010, Lecture Presentation31. Dubascoux, S., Le Hecho, I., Hassellöv, M., et al, (2010), Field-flow fractionation and inductively coupled plasma mass spectrometer coupling: History, development and applications. J. Anal. Atom. Spectrom, DOI: 10.1039/b927500b, web prepublication 23-March-201032. Postnova Corp., Germany, (2010), http://www.postnova.com/33. Wyatt Technology Corporation,USA, (2010), http://www.wyatt.com/34. Mansfield,E., Kar, A, Hooker, S.A., (2010), Applications of TGA in quality control of SWCNTs, Anal. Bioanal. Chem., 396(3), 1071-1077.35. Sahle-Demesie, E., EPA, USA, (March 2010), Personal communication with A. Salamon, PerkinElmer36. National Nanotechnology Initiative - Human Health Workshop (2009), Washington DC., USA, November 17 – 18.37. Environmental Protection Agency, Washington DC, USA, (2010), Control of nanoscale materials under the Toxic Substances Control Act, http://www.epa.gov/oppt/nano/38. European Union Cosmetics directive, 76/768/EEC, 25 March 200939. Bowman, D.M., van Calster, G., Friedrichs, S., (2010), Nanomaterials and regulation of cosmetics, Nature Nanotechnology 5, 92 doi:10.1038/nnano.2010.1240. Courtney, P., (2009), Functional measurements in nanomaterisals using optical and thermal techniques, PerkinElmer poster presented at the 3rd Nanomaterials Conference, Bonn, Germany, 16 – 18 June. http://www.nanotechia.org/events/ nanomaterials-200941. Upstone, S., Seer Green, UK, (2008), PerkinElmer Presentation, Colloquium on Optical Spectroscopy (COSP), Berlin, Germany42. Schick, C., (2009), Study Rigid Amorphous Fraction in Polymer Nano-Composites by Step Scan and Hyper DSC, PerkinElmer Application Note #008648_0143. Sarojam, P., (2010), Elemental characterization of gold and copper nanoparticles with ICP-OES, PerkinElmer Application Note (in preparation) 17 ?
  24. 24. 44. Heithmar, E.M., and Siska, E.M., (2010), Single particle-inductively coupled plasma mass spectrometry of metal-containing nanomaterial in surface waters around Las Vegas, Nevada, USA, Poster presentation at the 2010 Winter Conference onTABLE OF CONTENTS Plasma Spectrochemistry, Fort Myers, Florida, USA, January 4-9. Useful books and websites for more information Nanochemistry – A Chemical Approach to Nanomaterials, 2nd Edition, (2009), Ozin, G.A., Arsenault, A.C., Cademartiri, L.,RSC Publishing, Cambridge, UK, ISBN: 978-1- 84755-895-4 Introduction to Nanoscience, (2010), Lindsay, S.M., Oxford University Press, Oxford, UK, ISBN: 978-019-954420-2 PerkinElmer Nano Applications Library, http://www.perkinelmer.com/nano U.S. National Nanomaterials Initiative (NNI), http://www.nano.gov/ University of California Center for Environmental Implications of Nanomaterials, USA, http://cein.cnsi.ucla.edu/pages/ Duke University Center for the Environmental Implications of Nanotechnology, USA, http://www.ceint.duke.edu/ U.S. Department of Defense, Nano-Funding, http://nanosra.nrl.navy.mil/funding.php Current Government Nanomaterial Solicitations, http://www.nano.gov/html/funding/ currentsol.html Nanotechnology Nanomaterial Suppliers, http://www.nanowerk.com/nanotechnology/ nanomaterial/suppliers_plist.php?subcat1=np Overview of ground water treatment and chemistry with nano zerovalent iron, http://cgr.ebs.ogi.edu/iron/ UK-based nanotechnology forum intended for anyone who wants to learn more about this technology, products etc., http://www.nanoandme.org/home/ Nanotechnology Now information forum, http://www.nanotech-now.com/nano_intro.htm A to Z Nanotechnology, a free-to-access nanotechnology website, http://www.azonano. com/default.asp Nanotechnologies Industry Association, Brussles, Belgium, (2010), http://www.nanotechia. org/content/aboutus/ The Nanotube Site. Very comprehensive listing of information and publications on carbon nanotubes. (2010). http://www.pa.msu.edu/cmp/csc/nanotube.html 18
  25. 25. TABLE OF CONTENTSLooking for other ways to learn more about Nanotechnology?There are many different resources available that allow scientists toexplore the depths of the Nanotechnology world.Please see below for some recommended online resources: LinkedIN Groups: • Nanotechnology in Drug Delivery • Nanotechnology Zone • Nanotechnology : Materials and Fabrication Websites • Nano.gov • http://sis.nlm.nih.gov • www.perkinelmer.com/nano ?
  26. 26. White NanopharmaceuticalsTABLE OF CONTENTS paper Nanomaterials Author Andrew W. Salamon Sr. Staff Scientist PerkinElmer, Inc. Shelton, CT USA This poster compares the nano-region to things we know, such as a pin, insect and cells to provide a visual perspective. PerkinElmer, Inc. Nanotechnology is the science and technology of precisely manipulating the structure of matter at the molecular level. 940 Winter Street For Nanomaterial Applications, please visit www.perkinelmer.com/nano Waltham, MA 02451 Copyright ©2010, PerkinElmer, Inc. All rights reserved. PerkinElmer is a registered trademark of PerkinElmer, Inc. All other trademarks are the property of their respective owners. 009227_01 Nanopharmaceuticals “Nanotechnology is widely anticipated as one of the key Introduction and PerkinElmer technologies of the 21st century.”1 PerkinElmer supplies nanomaterial characterization instruments for industrial and academic nanotechnology research. Industrial nanotechnology applications are far-reaching, spanning all science and engineering disciplines. One of the most promising nanotechnology fields is Nanopharmaceuticals. Because nanomaterials may enter the body through dermal exposure, inhalation, ingestion, or ocular contact, they lend themselves to innovative drug delivery systems. Pharmaceutical research, toxicology studies, formulation, and manufacture of pharmaceutical products require material characterization to ensure consistent drug safety and effectiveness. PerkinElmer has been providing analytical instruments to the pharmaceutical industry for more than 60 years. As such, nanopharmaceutical material applications are no exception for PerkinElmer. What are Nanomaterials? Nanomaterials are materials that range in size from approximately 1 nm to 100 nm. There are more rigorous definitions that are specific to certain applications such as cosmetics. In Europe’s efforts to label cosmetics that contain nanoparticles, this definition evolved: “nanomaterial means an insoluble or biopersistant and intentionally manufactured material with one or more external dimensions, or an internal structure, on the scale from 1 to 100 nm.”2
  27. 27. Engineered nanoparticles are of great scientific interest. What material parameters are important? They effectively bridge a gap between bulk materials and To completely characterize nanomaterial it is necessary to atomic and molecular structures. Nanoparticle mechanical know a multitude of chemical and physical pararmeters TABLE OF CONTENTS properties are different than bulk material. Surface area including: the size of the particle, their shape, surface is disproportionate to weight, for instance, an 8 nm gold characteristics, the presence of surface coatings, and the material has a surface area of 32 square meters per gram. presence of impurities. Materials of nanoscale proportions exhibit unique characteristics. Examples are gold nanopartilces and silver Consequently, at the nanoscale, analytical measurement nanoparticles smaller than 12 nm that exhibit an affinity for challenges are considerable and the ability to use, for magnetism. In bulk form gold and silver are non-magnetic. example, one technique such as inductively coupled plasma and mass spectrometry (ICP-MS) to measure the elemental There is a diverse field of applications over a broad range of concentration of gold in a suspension as the only metric, industries: does not provide enough information. • Energy, energy-conservation, pharmaceuticals, chemicals, catalysts How are engineered nanomaterials measured? • High performance-composite engineered materials – Seven of the nine nanomaterial characteristics: military to leisure time applications Particle Size, Size Distribution, Surface Charge, • Coatings, electronics, sensors and displays Surface Area, Shape, Agglomeration, and Structure, • And more are characterized by one of the following analytical techniques: What materials are used to make Engineered • Scanning Electron Microscopy (SEM) Nanomaterials? • Transmission Electron Microscopy (TEM) There are several categories of nanomaterials, naturally • Atomic Force Microscopy (AFM) occurring nanomaterials are found in nature, engineered • Confocal Microscopy (CFM) nanomaterials are synthesized for a specific purpose or • Dynamic Light Scattering (DLS) function, manufactured nanomaterials are produced for • Field Flow Fractionation (FFF) commercial purposes, and incidental nanomaterials are generated as an unintentional by-product of a process.3 • Molecular Gas Adsorption (BET) • Electrophoresis Particle Size Some engineered nanomaterials are: • Gold, Silver, Copper, Selenium, Iron, Titanium, Zinc, and Note Aluminum Ultraviolet/Visible Spectroscopy and Fluorescence • Zinc oxide, Titanium oxide Spectroscopy are used for particle size identification as long • Carbon – Carbon Nanotubes, Buckyballs, and Graphene. as the material is known and it is reflective. Fluorescence • Clay Spectroscopy is also used for agglomeration studies. • Organic materials/biodegradable Nanoparticle Concentration and Composition are two nano- particle characteristics that that are not covered by the analytical techniques described in the paragraph above. There are many analytical techniques that do cover concen- tration and composition. The correct analytical technique is determined by the material, coatings, and nano application. For Nanoparticle Concentration you might choose one or several of the following analytical techniques: • Inductively Coupled Plasma and Mass Spectroscopy (ICP-MS) • Liquid Chromatography and Mass Spectroscopy (LC-MS) • Ultraviolet/Visible Spectroscopy (UV/Vis) • Fluorescence Spectroscopy (FL) Key parameters to characterize nanomaterials. Figure adopted from Hassellöv, M., and Kaegi, R., Analysis and characterisation of manufactured nanoparticles in aquatic environments, Chapter 6 in Environmental & Human Health Impacts of Nanotechnology, Eds., Lead, J.R. & Smith, E., 2009 Blackwell Publishing Ltd.2 ?
  28. 28. For Nanoparticle Composition you might choose one of the Who is involved in Nanopharmaceuticals? following analytical techniques: all major pharmaceutical companies are involved in • Inductively Coupled Plasma and Mass Spectroscopy (ICP-MS) Nanopharmaceuticals.TABLE OF CONTENTS • Liquid Chromatography and Mass Spectroscopy (LC-MS) • GlaxoSmithKline (GSK) • Ultraviolet/Visible Spectroscopy (UV/Vis) • Merck • Fluorescence Spectroscopy (FL) • Johnson & Johnson • Thermogravimetry (TGA) • Novartis • Differential Scanning Calorimetry (DSC) • Pfizer • Dynamic Mechanical Analysis (DMA) Small “start-up” nanopharmaceutical companies play an • Fourier Transform Infrared Spectroscopy (FT-IR) important role in research and development. Some not-so- well-known, small, new, nanopharmaceutical-focused • Raman Spectroscopy companies are: • Thermogravimetry, Gas Chromatography, and Mass • Cerulean Pharma Inc. Spectroscopy (TGA-GC/MS) • Bind Biosciences • Thermogravimetry and Mass Spectroscopy (TGA-MS) • Selecta Biosciences For composition, you may be concerned with purity or the coatings on nanomaterials besides the substrate material of all U.S. universities that conduct pharmaceutical or medi- the nanoparticle. All of the italicized analytical techniques cal research are involved in nanopharmaceuticals. Some of are nano-characterization instruments that PerkinElmer the most well known academic nano-research institutions offers. Please remember that there is not just one analytical are: technique that can characterize a nanomaterial. All analytical techniques are also listed in Table 1. • UCLA • Rice University What pharmaceutical applications are likely to • Georgia Tech utilize nanomaterials? • MIT Nanopharmaceutical markets include products for humans, pets, and Farm animals. From the list below you can see • Yale University that nanotechnology innovation will affect most people: • Many more… • Medicines for most diseases and illnesses – tablet or academic authors of nanopharmaceutical scientific liquid form research papers span the globe. They originate from: • Vaccines for most diseases and illnesses • Chemotherapeutic agents • Iran • Anti-cancer drugs • Israel • Personal care products: shampoos and body washes, etc. • Poland • Medical devices and diagnostics, Molecular diagnostics, • Italy Diagnostic tests • Germany • Dental health products • Over-the-counter medicines • Russia • Nutritional products • China • Managing-obesity products • Australia • Medical and Surgical devices • Japan • Ocular health products and instruments • UK • Cardiology and Pulmonary medicine • Many more… • Osteoporosis • Injury healing • Generic pharmaceuticals • Smoking cessation 3
  29. 29. Table 1. Nanomaterial characteristics and applicable analytical technologies. Na TABLE OF CONTENTS Concentration Particle Size Particle Size Analytical Technique Distribution Inductively Coupled Plasma – Mass Spectrometry ICP-MS Field-flow Fractionation + ICP-MS FFF-ICP-MS Liquid Chromatography – Mass Spectrometry LC-MS Optical Spectroscopy – UV/Vis UV/Vis Fluorescence Spectroscopy FL Turbidity Scanning Electron Microscopy SEM Transmission Electron Microscopy (+EDX) TEM Atomic Force Microscopy AFM Confocal Microscopy Field Flow Fractionation FFF Dynamic Light Scattering DLS Static Light Scattering SLS Molecular Gas Adsorption (BET) BET Dialysis Electrophoresis and Capillary Electrophoresis Ultrafiltration Centrifugation Filtration Nanoparticle Tracking Analysis NTA Size Exclusion Chromatography SEC Selected Area Electron Diffraction SAED Zeta Potential by DLS X-ray Diffraction XRD Thermogravimetric Analysis TGA Quartz Microbalances Differential Scanning Calorimetry DSC Dynamic Mechanical Analysis DMA Fourier Transform Infrared Spectroscopy FT-IR FT-IR Imaging Raman Spectroscopy TGA coupled with Gas Chromatography – Mass Spectrometry TGA-GC/MS Laser Induced Plasma Spectroscopy LIPS Hydrodynamic Chromatography HDC Laser Induced Breakdown Detection LIBD X-ray Photoelectron Spectroscopy XPS Electron Energy Loss Spectroscopy EELS (+EDX) Commonly used in the Microscopy characterization of nanomaterials techniques4 ?
  30. 30. Nanomaterial CharacteristicsSize Particle Size Surface Surface Shape Agglomeration Structure Composition TABLE OF CONTENTS Distribution Charge Area Not widely Available from applicable PerkinElmer 5
  31. 31. What are nanomaterials used for in Selecta’s unique tSVP™ platform includes a self-assembling pharmaceuticals? nanoparticle platform that is synthetic, modular, and engi- Nanomaterials are used primarily for drug delivery systems, neered for highly-effective targeting to immune cells. The TABLE OF CONTENTS but also are used for product packaging, colorants; bone, tSVP™ vaccines incorporate only the essential elements skin, and muscular growth; and medical imaging. required for a specific, robust immune response, based on precise engineering that is only possible with Selecta’s Drug delivery systems can be simple such as gold nano- proprietary, nanoparticle self-assembly process. particles coated with a vitamin or nutrient. Or it could be as complex as a nanoparticle that is coated with functional Below is a diagram of a product from Bind Biosciences groups that target specific tumor cells or organs and then inc. that describes another type of complex nano- are able to release the drug in some manner; time-released, pharmaceutical delivery system.6 released by heat, released by light, or released by magnetism. There are even nano-delivery systems that seek and destroy Targeted Nanoparticle Platform cells by entering the targeted cells and explode. Thus BIND’s targeted nanoparticles consist of the following exploding within the cell and completely destroying the cell. components that facilitate optimization and control: Some time-released nanopharmaceuticals are encapsulated in lipids for use in salves and ointments. Titanium Oxide nanoparticles are used for white colorant in some salves and ointments and also in Dental Health products. Below is a diagram of a product from Selecta Biosciences Company. this complex nanopharmaceutical delivery system is designed to combat an influenza virus.5 tSVp™ – a new class of synthetic vaccines for Optimal immune response Selecta’s targeted Synthetic Vaccine Particle (tSVP™) product platform enables, for the first time, the highly-precise and modular development of therapeutic and prophylactic targeting ligand provides recognition, enabling targeted vaccines with optimal efficacy, duration of coverage and nanoparticles to identify and bind to their intended target safety, to greatly improve the lives of patients. site. They are designed to recognize specific proteins or receptors that are found on the surface of cells involved in Selecta’s tSVP™ platform creates fully-integrated synthetic disease or the surrounding extracellular matrix. nanoparticle vaccines engineered to mimic the properties of natural pathogens to elicit a maximal immune response. Surface functionalization shields targeted nanoparticles The tSVP™ vaccines are rationally designed to optimize the from immune surveillance, while providing attachment for presentation of antigens to the nexus of the immune system the targeting ligand through proprietary linkage strategies. and ensure a focused and undistracted response. Selecta’s We have developed proprietary methods for precisely tSVP™ platform accomplishes this by delivering antigens controlling the surface characteristics necessary to ensure and adjuvants, within the same biodegradable nanoparticle, the drug is delivered efficiently and consistently. directly to antigen-presenting cells. This approach maximizes polymer matrix encapsulates payload molecules in a matrix the immune response while minimizing undesirable off- of clinically validated biodegradable and biocompatible target effects. polymers that can be designed to provide the desired drug release profile. therapeutic payloads can be incorporated into our targeted nanoparticles, including small molecules, peptides, proteins and nucleic acids, such as siRNA. 6 ?
  32. 32. Below is a diagram from Cerulean pharma inc. that des- who had previously relapsed and progressed on multiple cribes a complex nanopharmaceutical delivery system. lines of prior therapy. Notably, these advanced cancer patients had highly aggressive tumor types, such as non-TABLE OF CONTENTS CRLX101 small cell lung and pancreatic cancer, with typical survival of less than six to eight months. These observations corre- CRLX101 is comprised of the high potency anti-tumor agent late with CRLX101’s pharmacokinetics profile including an camptothecin coupled to a cyclodextrin based polymer that extended half-life of more than 30 hours and a low volume self-assembles into nanoparticles of consistent size and of distribution of 2.1 liters per square meter, an indication other physical attributes. of low systemic exposure of free drug. These data are also Below is a schematic representation of CRLX101. consistent with animal pharmacokinetic data demonstrating a high and prolonged localized drug exposure in the tumor. camptothecin (CPT) Cerulean Senior Director of Research Scott Eliasof, Ph.D., polyethylene glycol (PEG) presented recent results on the Company’s pre-clinical lead b-cyclodextrin candidate, CRLX288, a docetaxel nanopharmaceutical. His (CCD) presentation focused on animal studies showing a significant improvement in the therapeutic index of CRLX288 compared to the parent drug docetaxel. Specifically, Dr. Eliasof reported that CRLX288 achieved complete regression and inhibition CRLX101 provides clinical validation of the CDP technology of tumor growth in 100 percent of the animals studied for improving the tolerability of the parent drug camptothecin. greater than 100 days post-treatment, at dose levels that Results from the Phase 1 clinical study of CRLX101 have were well tolerated, in both typical size xenograft tumors shown that it has a favorable safety profile in patients with of 100 mm3 as well as in xenograft tumors as large as advanced cancer. Combining camptothecin’s potency and 800 mm3. CRLX288’s superior efficacy over the parent drug Cerulean’s nanopharmaceutical design features, we believe docetaxel in animal studies was consistent with other pre- CRLX101 has the potential to kill tumor cells while minimizing clinical findings showing 20 times more drug accumulating the side effects typically associated with chemotherapy in the tumor as compared to treatment with free docetaxel treatment. [bulk material]. It is easily noted that all three nanopharmaceutical delivery Together, the Phase 1 findings for CRLX101 and the systems are very different and all require material character- pre-clinical data on CRLX288 demonstrate that Cerulean’s ization by some analytical technique. This ensures patient nanopharmaceutical platform has the potential to markedly safety and product effectiveness for each. enhance efficacy and tolerability of therapeutic agents in humans. Such biological outcome is targeted to be achieved Amazing results with drug-containing nanoparticles that are designed to remain intact in circulation, accumulate in tumor tissues, When nanopharmaceutical drug delivery systems as sophisti- enter cancer cells, and provide a long and sustained drug cated as the three above are used in certain cancer cases the effect with slow and controlled drug release. results have been better than traditional bulk chemotherapy with little or no side effects. Please note that CLRX101 delivers the drug, camptothecin. Camptothecin is very potent and when delivered in bulk Below are excerpts from Cerulean Pharma Inc. clinical and form not only killed the tumors but in some cases killed pre-clinical Nanopharmaceutical data for their product patients. When the same dosage of camptothecin is deliv- CRLX101 and progress with pre-clinical lead CRLX288. ered in nanoscale increments the drug is still as effective as Cerulean Chief Medical Officer John Ryan, Ph.D., M.D., in bulk delivery, but there are no side effects. This maybe a reported results from the dose-finding, safety and tolerability result of attacking the tumor on a cell by cell basis. In fact, Phase 1 clinical study of CRLX101. Specifically, Dr. Ryan in laboratory tests a double dose of camptothecin bulk form discussed data establishing the maximum tolerated dose and was delivered on the nano scale and there were still no side the recommended dose and schedule for a planned Phase 2 effects.9 study. He reviewed observations of progression-free disease of greater than six months in five advanced cancer patients 7

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