Nanoscale Phenomena

For me, nanomaterials is most exciting material type under research today – mainly because there is a whole area of interesting physics phenomena that occur for materials at the nanoscale. Optical, electrical, physical and chemical properties can differ for bulk and nano-sized materials due to spatial confinement. At the nanoscale electromagnetic forces dominate over gravitational forces, quantum mechanics must be used to describe energy and motion, the molecular motion becomes relevant and there is a greater surface to volume ratio.

So, what is so special about nanotechnology? Firstly, what makes nanomaterials so useful is simply the size of the material. As I previously discussed in my Using Nanotechnology to Destroy Cancer post, nanomaterials are incomprehensibly small in size. Considering the fact that DNA is typically 2 nanometers in size and through using nanoparticles – we can readily interact with such biomaterials. This, of course, is why nanomedicine has such huge potential in medicine. Instead of using conventional medicine, we could potentially use nanomedicine which is much more targeted toward the tissue which requires the medication. There also exists many uses of nanotechnology as nanosensors in medicine but outside of the body particularly for diagnostics. Typically, in these applications, some sort of bodily fluid (blood/saliva/urine) which would exhibit certain biomarkers in the case of disease would be mixed with specific nanosensors which are highly sensitive to the specific biomarkers. This enables highly accurate diagnosis without the need for risky biopsies. A great paper which discusses these diagnostic devices is High-sensitivity nanosensors for biomarker detection by Swierczewska et. al.. Asides from in the medical field, the small size of nanoparticles is highly useful for applications like nano-based batteries and artificial photosynthesis.

Modified from Source

Next, let us discuss the surface to volume ratio. So, let us say that we have a cube with side length of 4cm, the total area of the 6 faces of the cube is 96cm². Now if we divide this same cube into 8 cubes – keeping the same volume – each cube would have a side length of 2cm. Doing the same math, we get a surface area of 24cm² per cube, or for the total surface area of the 8 cubes, we get 192cm². Therefore, with the exact same volume of cube material,  dividing this cube into many small cubes increases the total surface area. Now imagine that instead of splitting this cube into 8 cubes, we split into nano sized cubes. The surface area would be increased very significantly. More surface area = more atoms at the surface and less nonreactive inner atoms = improved reactivity at the nanoscale -> nanomaterials make great catalysts. Also, with this increase in surface area – we have more room on the surface to add functionality, for example, targeting moieties. This high surface to volume ratio also makes nanomaterials ideal for catalysis.

Surface to volume ratio with cube example. Source


Nanomaterials used in Nanomedicine

∑Materials which have at least one dimension less than 100nm are classified as nanomaterials. These materials can be may shapes and sizes like spheres, rods, wires, cubes, plates, stars, cages, pyramids among some funny named shapes like nanohedgehogs, nanocandles and nanocakes! See the paper Morphology-Controlled Growth of ZnO Nanostructures Using Microwave Irradiation: from Basic to Complex Structures for some really inventive names for various shaped nanomaterials!

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Nanocube Source
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Nanotriangles Source
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Nanostar Source


Aside – scientists are pretty terrible at naming things, for example, the “creative” names given to optical telescopes – the Extremely Large Telescope , Large Binocular TelescopeOverwhelmingly Large TelescopeVery Large Optical Telescope.

These nanoparticle shapes come in different sizes and different materials too. Broadly we can categorize nanomaterials into two groups – organic or inorganic (but it is possible to have a hybrid inorganic-organic nanoparticle too). Organic nanoparticles aren’t nanoparticles from your local farmers market – they are nanoparticles which contain carbon (and often hydrogen too which forms hydrocarbons) whereas most inorganic nanoparticles don’t contain carbon atoms. Organic nanomaterials include carbon (except fullerenes) , polymeric and lipid-based nanocarriers. Inorganic nanoparticles include metallic/plasmonic, magnetic, upconversion, semiconductor and silica based nanoparticles.

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Example of Organic Nanomaterials – Carbon Nanotubes Source
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Example of Inorganic nanomaterial – Cadmium Selenium Quantum Dots, Metallic nanoparticles which fluoresce in different colors dependent on the size of the particle – Source

Organic Nanomaterials

The main groups of organic nanocarriers are liposomes, micelles, protein/peptide based and dendrimers. Protein/peptide based nanocarriers are amorphous (non-crystalline) materials generally conjugated to the therapeutic agent and is often further functionalised with other molecules. Micelles and liposomes are formed by amphiphilic (both hydrophilic and hydrophobic parts), micelles form monolayers whereas liposomes form bilayers.  Lastly, dendrimer nanocarriers are tree-like structures which have a starting atom core (eg. nitrogen) and other elements are added through a series of chemical reactions resulting in a spherical branching structure. This final structure is not unlike blood hemoglobin and albumin macromolecules.

These vesicular nanocarriers can be used to trap both hydrophobic and hydrophilic drugs and even small nanoparticles inside the aqueous/lipid core. This provides protection for drugs and facilitates significant drug loading – minimising toxicity and increasing blood circulation time (increasing possibility that the drug will reach the therapeutic target from avoiding opsonisation).

Inorganic Nanomaterials

inorganic nanomaterials are stable, robust, resistant, highly functional. and are quite easily cleared from the body. Furthermore, inorganic material exhibit truly exciting mechanical, optical, physical and electrical phenomena at the nanoscale which can be tailored through changes in material, phase, shape, size and surface characteristics. Oftentimes, it is necessary to add a biocompatible surface to inorganic nanoparticles to avoid toxicity,  especially for heavy metals.

Semiconductor Nanomaterials

Quantum dots are the most well-known semiconductor nanoemitter. These are typically very small in size ~5nm, which is smaller or equal to the exciton Bohr radius giving quantum confinement. Electrons are subatomic particles with a negative elementary electric charge, electron holes is an empty position in an atom or lattice that an electron could occupy. An exciton is a  bound state where an electron and electron hole are electrostatically attracted to each other through Coulombic forces. An exciton bohr radius is the separation distance between the hole and electron. Due to 3 dimensional confinement effects, quantised energy levels are produced in the filled low energy valence band and in the empty conduction band of the quantum dots which is very unlike bulk semiconductors. The energy gap between the conduction and valance band varies with the size of the quantum dot which explains the tunable emissions (colour) when excited. Additionally, alloyed quantum dots can be further tuned because the bandgap is approximately equal to the weighted average of the composite semiconductor material. Quantum dots excited in the near-infrared are expected to be revolutionary in biomedical imaging. There has been concerns about the stability and toxicity, as many quantum dots lose luminescence intensity when exposed to light/air/oxygen/water and they are generally composed of heavy metal materials.

Upconversion Nanomaterials

Upconversion nanomaterials consist of two parts, first – the host dielectric lattice (e.g., NaYF4) with one or more guest trivalent lanthanide (atomic numbers 57–71) ions (e.g., Er3+, Yb3+). Upconversion is an anti-stokes process, two or more lower energy photons are absorbed (either simultaneously or stepwise) via long-lived real electronic states of the lanthanide dopant and a higher energy photon is emitted. The lanthanide element has a specific electronic configuration with energy levels which is usually independent of the host material type, the nanoparticle shape and its size.

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Electrons are arranged in shells around an atom’s nucleus, where the closest electrons to the nucleus have the lowest energy. Each shell can hold a certain number of electrons (principal quantum number) – the first shell (1) can hold 2 electrons, the second (2) 8 and the third (3) 18. Within these shells are subshells (defined by the  azimuthal quantum number) and are labelled s,p,d or f which can hold 2,6,10 or 14 electrons respectively.

In the case of upconversion, the 5s and 5p shells are full whereas the 4f-4f shells are not. But, because 5s and 5p are full – they shield the 4f-4f shells which allows sharp line-like luminescence, i.e. the luminescence peak is not broad. This luminescence is also resistant to photobleaching, high photostability and are nonblinking, which of course is beneficial over fluorescent molecules which experience high levels of degradation. Through careful design, upconversion nanomaterials can display a variety of emission and excitation wavelengths from UV to NIR.

These upconversion nanoparticles can be incorporated with photosensitizers to produce reactive oxygen species which generally require activation by UV light. This therapy procedure is called Photodynamic therapy and can be used for treating a wide range of medical conditions including malignant cancers and acne. Upconverison nanomaterials also have applications in multimodal imaging through the use of specific dopants – high atomic number dopants for computed tomography (CT) imaging, radioisotopes for  single-photon emission tomography (SPECT) imaging or positron emission tomography
(PET) imaging.

Magnetic Nanomaterials

At the nanoscale, certain magnetic materials below a specific size exhibit a special form of magnetism called superparamagnetism. Superparamagnetic nanoparticles behave as single domain paramagnets when under an external magnetic field but once the field is removed – there is no residual magnetisation. Typically, these materials are Iron oxide nanoparticles. Additionally, these nanomaterials tend to be non-toxic and can be readily coated with molecules for further functionalization. These nanoparticles are commonly used as MRI contrast agents in magnetic resonance imaging (MRI). Furthermore, magnetic nanoparticles can be used in nanotherapy either through magnetic-field-directed drug delivery or through magnetic hyperthermia which involves localized heating of diseased tissues and therefore, cell death.

Silica Nanoparticles

Silica is a highly biocompatible biomaterial which is often used in nanomedicine.

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Mesoporous Silica Nanoparticles Source

Mesoporous silica nanoparticles are silica nanoparticles which have been template-patterned to have pores throughout the particle. This is done through the use of surfactants like Cetrimonium bromide (CTAB), which is extracted after synthesis leaving holes where the CTAB once was. In these pores, water insoluble materials can be added, such as drugs for chemotherapy, dyes for imaging or even small nanoparticles. These pore sizes can be controlled to encapsulate various sizes of biomolecules. Silica is often used to coat nanoparticles to achieve biocompatibility and to simplify further functionalisation.



Plasmonic Nanomaterials

Now, saving the best for last – plasmonic nanoparticles.

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Localised surface plasmon of Plasmonic nanoparticles Source

Plasmonic nanoparticles consist of noble metals like gold, silver, copper and aluminium. At the nanoscale, these materials can support Localized surface plasmons, which is a collective oscillation of the free surface electrons at the interface between the nanomaterial and the surrounding dielectric medium when resonance occurs between the natural resonant frequency of the surface electrons and the frequency of the incident light photons. The LSPR can be tuned with the material, size and shape of the nanoparticle.

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Plasmonic nanoparticles plasmon resonance varying with change of shape of gold nanoparticles. Aspect ratio = the ratio of the width of a nanorod to its length. Source

Plasmonic nanoparticles can scatter and absorb light, for example, for smaller nanoparticles absorption tends to dominate (more light is absorbed – which is generally converted to heat energy) and for larger nanoparticles scattering tends to dominate (which is exploited in bioimaging). For this reason, smaller nanoparticles are often used in photothermal therapy. In Photothermal therapy, plasmonic nanoparticles accumulate in diseased tissues then are irradiated with resonant light, the nanoparticles absorb this light energy and convert it to heat energy, resulting in localised heating of the damaged tissue. This localised heating causes cell death, thus this therapy can be used for cancerous tumors. This heating can be visualised using thermographical measurements or using a dark field microspectroscope, plasmon scattering can be used in medical imaging. Please give Biomedical applications of plasmon resonant metal nanoparticles, Liao et. al. a read for additional information.

Using Nanotechnology to Destroy Cancer

The  American Cancer Society reports trends in cancer death rates among men and women between the years 1930 and 2010 (see slideshow below). Of course, there are fluctuations throughout these years – but it could be concluded that rates of cancer death nowadays are not all that different from 50 years ago. It is clear from this that diagnostic and therapeutic methods haven’t advanced very much in decades, despite the huge advancement in the knowledge of cancer mechanisms and biology.

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The million-dollar question. Why haven’t we cured cancer yet? The biggest reason would probably be that cancer is complex. It exists in many types (100+ that affect humans) each with many variants and severities. Additionally, two people with the exact same type, variant, and severity given precisely the same therapy would likely result in their bodies reacting in very different ways. For this reason, a single bullet approach is just not going to work.

So, How?

Diagnosing, treating and monitoring cancer will have to be personalisable.  One way of advancing toward personalisable medicine is through the incorporation of nanotechnology. Nanotechnology works within the dimensions and tolerances of less than 100 nanometers. The size of this nanomaterial is difficult to conceptualize – the size of a single nanoparticle is to a football as a football is to the earth. Working at this scale has many benefits – to start with, nanomaterials are still small relative to the biological materials that they interact with. For example, the average animal eukaryotic (complex) cell is 25 µm. That’s roughly 1000 times bigger than a typical 25nm nanoparticle used in nanomedicine. See the infographic below for more size comparisons.

Size comparisons in the nanoscopic range. Source

Thanks to nanoparticles being comparable in size to this biological matter of interest, we can readily interact with cells, bacteria, viruses etc. This is something that traditional cancer therapy falls short of, hence we get untargeted chemotherapy where patients suffer damage to both diseased and healthy tissues resulting in nausea, hair loss, and other unwanted side effects.

Nanomedicine therapeutic methods vary widely, but usually, we want certain cells to uptake nanoparticles. But what does uptake mean? Nanomedicines for disease diagnostics or therapy often must be internalised inside a cell to perform the activity – be that delivering standard hydrophobic anticancer drugs, allowing targeted imaging of 

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Cell structure Source

tissues or to facilitating therapy like photothermal therapy. In the human body, we have trillions of cells, which have different functions. Inside of these cells is many components which are separated from the cell exterior by a membrane which is semi-permeable. Certain types of nanoparticles can penetrate this membrane better than others – depending on certain factors like the surface charge of the particle, its composition/surface composition, its shape and its size. 

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Particles entering a cell Source

The illustration above shows how particles can penetrate cells. Nanoparticles penetrate into cells through three pathways: phagocytosis, pinocytosis or endocytosis. For further reading on these processes and cellular uptake, I highly recommend the paper Cellular Uptake, Intracellular Trafficking, and Cytotoxicity of Nanomaterials – Zhao et. al..

So now we know that nanoparticles can penetrate inside of cells to carry out their specific function – but how do we know if they are uptaking in the targeted diseased cells such as cancer cells? Usually, nanoparticles for nanomedicine are functionalised with a targeting moiety – i.e. a special molecule(s) is added to the nanoparticle which has an affinity to a certain cell. Active targeting of specific cells uses targeting moieties which is typically a ligand on the nanoparticle which can connect with a receptor on the cell membrane. When the nanoparticle connects to this receptor site, the cell signals to open a pathway in the membrane – allowing the nanoparticle to enter the cell. So of course, the targeting moiety must be specially selected so that the nanoparticle specifically binds to the targeted cell which has this specific receptor. Thanks to the nanoparticles high surface to volume ratio, it is possible to attach multiple targeting moieties. So nanoparticles can be designed to be even more selective – targeting multiple receptors at once which correspond to a specific cell. For further reading into targeting moieties, Yu et. al. wrote a fantastic paper on this called Targeting Strategies for Multifunctional Nanoparticles in Cancer Imaging and Therapy.

Now it’s time for some controversy. Many nanomedicine journal papers consider the Enhanced Permeability and Retention (EPR) effect to be the ultimate evidence to support nanomedicines place in the future of medicine. The EPR effect suggests that more nanoparticles would accumulate in cancerous tumours as opposed to healthy tissues. The concept stems from the way that cancer tumours form. For cancer tumours to grow as aggressively as they do, the tumour cells must sufficiently stimulate blood vessel production (angiogenesis). Vascular endothelial growth factor (VEGF) is the signal protein which is produced to stimulate the generation of new blood vessels and branching of pre-existing vessels. When this signal protein is overexpressed, cancer cells can continue to grow and metastasize with the formation of the newly formed blood vessels (neovasculature). If the production of new blood vessels is not sufficient the nutrition and oxygen supply would be cut off and would halt tumour growth.

The EPR effect Source

 The neovasculature in cancer tumours is unlike other tumour blood vessels. The endothelium, the most interior layer of cells inside a blood vessel, is badly aligned, and the small pores of the endothelium are enlarged. The smooth muscle layer and innervation (nerve cell supply) is also lacking and the lumen (inside space of vessel) is wider than average blood vessels. Receptors to angiotensin II are impaired, angiotensin II is a peptide hormone that causes vasoconstriction and thus an increase in blood pressure. Tumour tissues also tend to have ineffective lymphatic drainage, which is essentially the bodies waste and debris clearing mechanism. Combined, these abnormalities are thought to lead to unusual molecular and fluid transport dynamics which help nanoparticles spread inside the cancer tissue – while leaving healthy tissues untouched.

Seems too good to be true? Probably. So far, this effect has mostly failed clinically and has only been seen in mice apart from a few exceptional tumours such as head and neck cancers. So, it is necessary for those of us who design nanomedicine to not rely on this form of targeting and to incorporate other targeting moieties and stimuli responsive nanomedicine. To read more about the controversy surrounding the EPR effect, this review paper by Deinheir is quite good To exploit the tumour microenvironment: Since the EPR effect fails in the clinic, what is the future of nanomedicine?.

So, now we know how nanoparticles can be used in nanomedicine to target specific cells and enter inside them. Next time, I will discuss Nanomaterials used in Nanomedicine.

How does nanomedicine actively destroy cancer?