Nanotechnology and nanomedicine
Nanotechnology is the manipulation of matter on a molecular scale. At that scale a material behaves differently from the same material in bulk. Particles made this way are found in consumer products, environmental applications and medicines, and in 2014 their regulation and long-term effects were still unsettled.
What nanotechnology is
Nanotechnology is generally defined as the manipulation of matter on a molecular scale, typically in the nanometre range. Nanomatter is typically smaller than a cell and bigger than a small molecule. In 2014 the EU defined nanomaterials as natural, incidental or manufactured material containing particles, unbound or as an aggregate or agglomerate, where 50% or more of the particles in the number size distribution have one or more external dimensions in the range 1 to 100 nm. Particles can be engineered as spheres, cylinders, rods or tubes, from metallic, polymeric or biological material such as DNA or amino acids, or from combinations of these. Nanotechnology is a sophisticated tool that can build, characterise and use nanoscale structures across a range of disciplines to create new applications.
Properties at the nanoscale
A gecko holds to a ceiling not by glue, suction or static electricity but by specific nanostructures on its feet. Roughly two million nanohairs grow from pads on its toes and end in still smaller gripping hairs. The nanohairs greatly increase the area in contact with a surface, which leads to high van der Waals forces between the animal and the ceiling. Pushing down generates shear forces that bend the hairs and increase the contact area further, and relaxing the feet lets them lift off. Nanostructured surfaces of this kind have inspired a reusable dry glue that uses nanotube bundles as synthetic hairs. Its adhesive capacity is nearly four times that of gecko feet, and it sticks even to Teflon.
Several properties allow nanoparticles to be used in practical applications. Their surface-to-volume ratio is large compared with the bulk material, so they interact strongly with their surroundings. Because of that contact area, chemical and biological degradation is much faster than in the bulk material, though much slower than for smaller molecular structures in solution. For inorganic nanoparticles, the melting point depends strongly on particle size. Nanoparticles can increase the solubility of hydrophobic compounds and act as delivery vectors in nanomedicine. Some show different colours depending on their size, because they are in the size range of the wavelength of visible light. Particles that interact with light energy are used in cancer therapy to create localised heat that destroys diseased tissue. These characteristics have driven the use of nanotechnology in the food industry, consumer products, the medical sector and environmental fields.
Uses in consumer products and the environment
Chocolate, non-dairy creamer and sunscreen are consumer products with a high content of nanoparticles. Nano-sized titanium dioxide and zinc oxide particles, typically under 100 nm, are frequently used in sunscreen as inorganic sun blockers at up to 10% by weight. They reduce the opaqueness usually found in sunscreens containing larger, micrometre-scale particles of the same materials. Nanoparticles also give properties to food. Because they absorb ultraviolet radiation, they can coat confectionery to prolong shelf life. They also whiten chocolate, non-dairy creamer and sauces, and improve the flowability of salt. Foods with the highest titanium dioxide nanoparticle contents include candies, sweets and chewing gum, where the particles act mainly as a whitener. In 2014 a typical adult in the United States might be exposed daily to up to 1 mg of titanium per kilogram of body weight, around 1012 particles.
Nanoparticles in the environment can come from natural sources such as forest fires or volcanic eruptions, from accidental release through vehicle exhaust or industrial processes, or from the intentional use of engineered products. Besides medicine, the industrial applications of engineered nanoparticles include ground water remediation and the nanobionic engineering of plants. Nanotechnology holds great potential for environmental applications such as wastewater treatment and the nanobionic engineering of plants. Current and potential applications in wastewater treatment include the absorption of heavy metals by oxidised carbon nanotubes, the reduction of contamination by metal oxide nanoparticles added to filter membranes, and titanium dioxide photocatalysis to remove trace amounts of microbial pathogens. Introducing single-walled carbon nanotubes into the chloroplasts of nano-engineered plants can raise photosynthetic activity to more than three times that of controls. The nanotubes absorb light across ultraviolet, visible and near-infrared wavelengths that chloroplast antenna pigments do not normally capture, and they can transfer electrons to the photosynthetic machinery of the chloroplasts. Nanobionic engineering of plant function can thereby contribute to developing biomimetic materials that make better use of available light.
First- and second-generation nanomedicines
Nanomedicine is the application of nanotechnology in medicine. Because of their unique and adaptable properties for targeted delivery of a therapeutic payload, nanoparticles are emerging as promising tools for innovative pharmaceutical treatment. By 2014 the first generation of nano-oncological therapeutics was already on the market. Its characteristic is passive targeting: having a greater molecular weight than small molecules, the particles tend to accumulate in tumour tissue with increased vascular permeability, which the literature calls the enhanced permeability and retention effect. Albumin-bound paclitaxel and liposomal doxorubicin, the pioneer drugs of this generation, were licensed by the European Medicines Agency (EMA) for metastatic breast cancer.
In a phase III trial in women with metastatic breast cancer, polyethylene-glycol-functionalised liposomal doxorubicin gave efficacy comparable to doxorubicin with significantly reduced cardiotoxicity (P < 0.001), myelosuppression, vomiting and hair loss. In another, albumin-bound paclitaxel showed significantly higher response rates than standard paclitaxel (P = 0.001), a longer time to tumour progression and a favourable safety profile.
In 2014 a second generation was in development, aiming at greater specificity and timely release of the therapeutic agent. Nanoparticles are typically taken into cells in endolysosomal vesicles depending on their size, shape, volume and particularly their surface characteristics. These properties may also be used to guide the particle to a location of interest in the body, lowering the concentration at which the agent has a therapeutic effect. To increase localisation, molecules such as antibodies can be put on the particle surface to target antigens overexpressed on cancer cells. A protective layer of macromolecules such as polyethylene glycol extends the particle's stability, and encapsulating the active compound increases its solubility in the body.
Besides chemotherapeutic drugs, DNA and small interfering RNA (siRNA) can also be used as active compounds. In a mouse model, nanoparticles containing CD98 siRNA decreased artificially induced colitis, showing the potential of siRNA-loaded polymeric nanoparticles to target intestinal inflammation. Active and passive accumulation in tumour tissue can also improve imaging when the particle carries a cargo, such as gadolinium, that magnetic resonance imaging detects easily. A particle carrying both an active compound and an imaging agent, called a nanotheranostic, offers imaging and therapy at once. These modifications are important tools for scientists developing nanotherapeutics.
Regulation of nanomedicines
The unique properties of nanomedicines pose additional problems for regulation and approval. In 2014 the EMA and the US Food and Drug Administration (FDA) regulated them under the same procedures used for small-molecule pharmaceuticals or for medical devices. Because the EMA regulates the approval of pharmaceutical products and of medical devices differently, a nanotheranostic raises the question of how its assessment fits into those procedures. Licensing regulations specific to nanomaterials were lacking. A lack of definitions for nanomaterials and limited standard nomenclature and reference material added to the difficulty. Both agencies had issued draft guidance papers, which were expected to be precursors of requirements specific to nanomedicines.
Developing generic equivalents of nanomedical products, called nanosimilars, is even more ambitious than developing biosimilars. The copy has to express the same complex physicochemical properties as the patented product, such as in vitro leakage rate and liposomal size distribution, and establishing these requires sophisticated analytical methods. In 2014, three years after the last patent on the liposomal doxorubicin Doxil expired, only one generic, Lipodox, had been approved, by the FDA but not by the EMA.
Non-biological complex drugs are nanotechnologies that cannot be comprehensively characterised by physicochemical analysis. In 2020 the FDA had a working group on them. They include swelling cross-linked polymers; liposomes, dendrimers and polymeric micelles; iron carbohydrate complexes; glatiramoids; and ocular emulsions. Their classification varies worldwide, and some are considered biological. Albumin-bound nanoparticles and low-molecular-weight heparins are among the products whose classification varies.
Effects on health and the environment
In 2014 the long-term effects of nanoparticles had not been fully investigated despite their common occurrence in everyday life, and guidelines on how to evaluate and quantify them were lacking. To establish such guidelines, stakeholders including the OECD and the EU were attempting to define the impact of nanomaterials on human health and the environment. The long-term effects of nanoparticles on the environment and on human health needed further clarification.
Dietary nanoparticles may harm human health. In a pilot study in patients with Crohn's disease, reducing dietary titanium dioxide microparticles, including nanoparticles under 0.1 μm, increased disease remission. Patients with lower numbers of lumen microparticles had a significant reduction (P = 0.002) in the disease activity index compared with controls. Once ingested, some of the degradation-resistant titanium dioxide microparticles were absorbed across the gastrointestinal mucosa and some accumulated in macrophages, potentially causing local inflammation that leads to Crohn's disease. These findings would suggest an association between dietary uptake of nanoparticles and inflammatory bowel diseases.
Released particles may enter the marine environment through the sewer system and accumulate in consumers throughout the food chain. In one study, polystyrene nanoparticles affected both the fat metabolism and the ingestion behaviour of crucian carp, possibly through a disturbance in fat metabolism connected to apolipoproteins accumulating on the nanoparticle corona. Certain nanoparticles can also harm plants. Accumulated titanium dioxide nanoparticles have been associated with reduced hydraulic conductivity in maize root cell walls, and so with reduced transpiration and leaf growth.
Exposure of humans, animals and plants to nanoparticles can be beneficial but also potentially detrimental. Extrapolation from controlled experiments in an artificial setting should be conservative, so it is important to determine the quantity of exposure and the long-term effects of engineered nanoparticles in ecosystems. In 2014 regulation and specific guidance on nanoparticle testing were needed.