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Nanoparticle Applications

Nanoparticles in Biology and Medicine

A brief history of firsts in nanotechnology: Nanotechnology started in 1959 when Feynman gave an after-dinner talk describing molecular machines built with atomic precision. In 1974, Taniguchi used the term "nano-technology" in a paper on ion-sputter machining. The molecular nanotechnology concept was coined by Drexler at MIT in 1977. The first technical paper on molecular engineering to manufacture with atomic precision was published in 1981, when the scanning tunneling microscope (STM) was invented. The Buckyball was discovered in 1985, and the first book on nanotechnology was published in 1986. During the same year, atomic force microscopy (AFM) was invented, and the first nanotechnology organization was formed. The first protein was engineered in 1987, and many firsts followed in nanotechnology, including the publication of the first textbook about the field in 1992, as well as the first nanomedicine book published in 1999. And it all starts with particles.

Let us find out what a particle is. A particle is a small, localized object that behaves as a whole unit and can be described using physical properties such as volume, size and mass. A nano-particle is "a particle having one or more dimensions of the order of 100 nm or less." Usually, fine particles range in their size between 2,500 and 100 nanometers. However, ultrafine particles, or nanoparticles, range in sizes between 100 and 1 nanometers.

During the 1970-80’s, when the first thorough fundamental studies were running with "nanoparticles" in the United States (by Granqvist and Buhrman) and Japan, (within an ERATO Project), they were called "ultrafine particles" (UFP). During the 1990s, before the National Nanotechnology Initiative was launched in the United States, the new name, "nanoparticle" had become fashionable. Nanoclusters have at least one dimension between 1 and 10 nanometers and a narrow size distribution. Nanopowders are agglomerates of ultrafine particles, nanoparticles, or nanoclusters. Nanometer-sized single crystals or single-domain ultrafine particles, are often referred to as nanocrystals. The field of nanotechnology is rapidly developing, and new types of nanomaterials are being developed constantly. It is expected that nanomaterials will be developed at several levels, as part of material devices and systems. Many nanomaterials are now commercially available. The cells of living organisms are typically 10 μm in size. Parts of the cells are even much smaller, in the sub-micron size range.

Figure 1: This figure illustrates the size of a nanoparticle. If a nanoparticle was the size of a football - this image shows how atoms, cells and organisms would compare at a more familiar scale to humans.

Proteins that make up the cells nanomachinery are just around 5 nanometers (nm) in size. These are the sizes of the smallest man-made nanoparticles. Their size allows them to be used as probes to study the cells’ biological processes. Typically, for biological applications, nanomaterials are selected for their optical and magnetic properties. However, nanomaterials are also applied for novel electronic, optoelectronis, and memory devices. Figure 1 illustrates the size of nanoparticles.

The fact that nanoparticles exist in the same size domain as proteins allows them to be used to label or tag proteins, either in vivo or in vitro. To allow the interaction of nanoparticles with the biological target, a molecular coating or layer acting as an interface will need to be attached to the particle. Examples of biological coatings include antibodies, biopolymers such as collagen, or monolayers of small biocompatible molecules. Since the use of optical detection techniques are widely used in biological research, nanoparticles should either fluoresce or change their optical properties in response to a biological function. Figure 2 illustrates the sizes and shapes of a few nanoparticles. A list of applications involving nanoparticles follows below.

Sizes and shape of different nanoparticles

Figure 2: Sizes and shape of different nanoparticles. This cartoon shows the morphology of nanoparticles that can be used for neuroimaging. Source: Moresco & Masserine 2012.

Some applications of nano-materials in biology and medicine are:

Fluorescent biological labels for fluorescent signaling
Drug and gene delivery
Bio detection of pathogens
Detection of proteins – Antigen detection
Probing of DNA structure
Tissue engineering
Tumor destruction via heating (hyperthermia)
Separation and purification of biological molecules and cells
Linker activated nanoparticles
Biocompatible nanoparticles
MRI contrast enhancement
Molecular imaging such as computed tomography (CT), positron emission computed tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance (MRI),
Phagokinetic studies

Representation of multifunctional iron Figure 3: Representation of multifunctional iron oxide nanoparticles showing multiple modes of functionalization. Representation of multifunctional nanoparticles Figure 4: Representation of multifunctional nanoparticles.

Nanoparticles that usually form the core of nano-biomaterials can be composed of inorganic, polymeric materials or can be in the form of nano-vesicles surrounded by a membrane or a layer. The shapes of these particles can come in different morphologies. Furthermore, nanoparticles can be functionalized in multiple ways. Figures 3 and 4 show the graphical representation of different ways to functionalize nanoparticles. For example, as depicted in figure 3, the particles can be conjugated to different types of molecules, such as antibodies, green fluorescent protein (GFP), avidin, or streptavidin, as well as to DNA/RNA oligomers and gold particles or, as shown in Figure 4, contrast agents useful for CT/MRI imaging, radiotracers useful for PET/SPECT imaging, functionalized with drugs for targeted drug delivery or specific ligands, as well as special surfaces such as hydrophilic surfactants to enhance biocompatibility.

It is thought that nanoparticles will play an increasing role in nanomedicine in the future. Nanomedicine applies nanotechnology with the goal to improve the quality of human lives. Useful medical applications of nanoparticles include improved drug delivery, such as protein, peptide, and oligonucleotide delivery in biological systems, nanoparticles to specific targets in tumors and cancers, and nanoparticles for tissue visualization to enhance surgical techniques or to visualize tumors. It is hoped that it will become possible in the near future to design nanorobots or nanomachines that allow for the repair of damage parts of the cell.

More recently, many companies have begun to use nanotechnologies. The majority of the companies are small recent spinouts of various research institutions. Most of the companies are developing applications for the pharmaceutical industry, mainly to enhance or enable drug delivery. Other companies exploit quantum size effects in semiconductor nanocrystals to tag biomolecules or use gold nanoparticles for the labeling of various cellular parts. Cytodiagnostics, one such company, provides gold, silver, and magnetic nanoparticles with sizes ranging from 5 nm to 400 nm. These particles can be conjugated to biomolecules such as antibodies, BSA, KLH, and many others.

Biosynthesis Inc. in Lewisville, Texas offers custom conjugation of antibodies or other proteins to this type of nanoparticles. To be able to perform custom conjugations, approximately 1-2 mg of purified and lyophilized antibody (or any other protein) is required. 

Services include: 1. antibody or protein sourcing, if needed; 2. conjugation of a customer protein to selected gold nanoparticles; and 3. Purification of the conjugate.

Furthermore, oligonucleotides and other molecules can be conjugated to gold nanoparticles as well. Biosynthesis provides custom conjugation of single-stranded or double-stranded oligonucleotides to gold nanoparticles with sizes ranging from 5 nm to 200 nm. Final conjugate yield depends on both sizes of the oligo and nanoparticle. For a 20 mer oligo, the loading would be 0.2-1 OD/mg nanoparticle. The smaller the particle size, the higher yield.

Services include: 1. synthesis of oligonucleotides for conjugation. The customers usually supplies the nucleotide sequence, and decides which terminal (5' or 3') will be attached to the gold surface, and Biosynthesis Inc. does the rest; 2. Conjugation of the oligonucleotide to a gold nanoparticle size of customer’s choice; 3. Purification of the conjugate.

The following table shows a list of nanomedical technologies.

Table-1: Nanomedicine Technologies (Source: Freitas 2005)
Raw nanomaterials Cell simulations and cell diagnostics Biological research

Nanoparticle coatings
Nanocrystalline materials

Cell chips
Cell simulators

Nanobiology
Nanoscience in life sciences

Artificial binding sites DNA manipulation, sequencing, diagnostics Drug delivery

Artificial antibodies
Artificial enzymes
Artificial receptors
Molecular imprinted polymers

Genetic testing
DNA microarrays
Ultrafast DNA sequencing
DNA manipulation and control

Drug discovery Biopharmaceuticals
Drug encapsulation
Drug delivery
Smart drugs

Nanostructured materials Tools and diagnostics Biotechnology, biorobotics, and nanorobots

Cyclic peptides
Dendrimers
Detoxification agents
Fullerenes
Functional drug carriers
MRI scanning
Nanobarcodes
Nanoemulsions
Nanofibers
Nanoparticles
Nanoshells
Carbon nanotubes
Noncarbon nanotubes
Quantum dots

Bacterial detection systems
Biochips
Biomolecular imaging
Biosensors and biodetection
Diagnostic and defense applications
Endoscopic robots and microscopes
Fullerene-based sensors
Cellular imaging
Lab on a chip
Monitoring
Nanosensors
Point of care diagnostics
Protein microarrays
Scanning probe microscopy

Biological viral therapy
Virus-based hybrids
Stem cells and cloning
Tissue engineering
Artificial organs
Nanobiotechnology
Biorobotics and biobots

DNA-based devices and nanorobots
Diamond-based nanorobots
Cell repair devices

Cytodiagnostics, another company, offers a unique proprietary protocol that produces particles with uniform shapes and a narrow size distribution. The gold nanoparticle surface can be modified to allow for the conjugation to molecules such as biotin and other molecules of choice. Furthermore, particles can be functionalized with carboxyl, amine, and methyl groups, among others.

nanoparticles
Figure 5: Sizes of gold nanoparticles are illustrated.
Source: http://www.cytodiagnostics.com/gold_nanoparticle_products.php
nanoparticles

Silver Nanoparticles are also available with core sizes of 40 nm - 100nm

Figure 6: Sizes of silver nanoparticles are illustrated.
Source: http://www.cytodiagnostics.com/store/pc/Silver-Nanoparticles-c150.htm

High-quality monodisperse silver nanoparticles with a narrow size distribution (CV <15%) are available as well. Nanosilver products are ideal for a wide array of applications such as “Conjugate Development,”, “Sensor Development,”, “Molecular Imaging’,’Surface Enhance Raman Spectroscopy (SERS),”, and“Bactericidal applications.”

Adsorption spectrum Figure 6: Adsorption spectrum of silver nanoparticles in different wavelengths.
Source: http://www.cytodiagnostics.com/store/pc/Silver-Nanoparticles-c150.htm

Superparamagnetic iron nanoparticles, both in the metallic, and oxide forms, can be used for bioconjugation as well and are widely used in the life sciences. Typical applications include but are not limited to the separation and purification of biomolecules, such as proteins and DNA, from complex mixtures, as well as in immunoprecipitation protocols. By using only a magnet for fast pull-down and isolation of magnetic particles, cumbersome and long purification protocols using columns or centrifugation are not needed. Other applications may include medical diagnostics, catalysis, probing agents to indirectly study the structure of mixed self-assembled monolayers (SAMs), solid phase extraction, anode materials for Li-ion batteries, and electromagnetic interference (EMI) shielding materials.

Source: http://www.cytodiagnostics.com/magnetic_nanoparticles.php
Superparamagnetic iron nanoparticles

The company Nanoprobes offers 1.4 nm Nanogold® particles. These are gold compounds that are not just adsorbed to proteins, like colloidal gold, but covalently reacts at specific sites under mild buffer conditions with molecules that are selected for conjugation. A well-defined product can be synthesized that can be purified chromatographically.

 Source: http://www.nanoprobes.com/products/LabRgts.html#feat

Features of Nanogold®
  • Unparalleled penetration of conjugates up to 40 µm.
  • Higher density of immunolabeling than with larger gold probes.
  • Can be conjugated to any molecule with a suitable reactive group. Available with different reactivities.
  • Extremely uniform 1.4 nm gold particle
  • Label at specific sites, which do not obstruct native reactivity.
  • Close to stoichiometric labeling.
  • Reacts under mild, neutral conditions
  • Conjugates are easily isolated by gel filtration.
  • Conjugates are stable to a wide range of pH and ionic strengths.
  • High Representation of multifunctional ironstability: conjugates show unchanged reactivity after storage for a year.
Nanogold
References F Re, R Moresco and M Masserini; Nanoparticles for neuroimaging. Journal of Physics D: Applied Physics Volume 45 Number J. Phys. D: Appl. Phys. 45
Robert A. Freitas Jr., What is nanomedicine? Nanomedicine: Nanotechnology, Biology, and Medicine 1 (2005) 2– 9 http://www.foresight.org/Nanomedicine/