* This is the Veterinary Version. *
Nanotechnology is a new enabling technology with the potential to revolutionize animal health. A nanomaterial has been defined as a material engineered to be <100 nm in one or more dimensions. A nanometer is one one-billionth of a meter; to put the nanoscale into perspective, a human hair is ~80,000 nm in diameter. Chemicals at the nanoscale display physical and chemical behaviors that can differ markedly from those of the bulk chemical (eg, in optical properties, conductivity, or electromagnetism). These behaviors are attributed to a combination of the small size, chemical composition, physicochemical properties, and surface structures of nanomaterials. Of major importance to the development of nanotechnologies for animal health will be a thoughtful, thorough, and balanced assessment of the benefits and risks involved. Risks can originate from any novel hazards of nanomaterials, the distribution profiles of nanomaterials in animals, the exposure of people to nanomaterials, and the toxicity and fate of nanomaterials in the environment. Additional challenges relate to the detection and analysis of nanomaterials.
This discussion focuses on the application of nanotechnology in the delivery of veterinary drugs and vaccines, a field predicted to expand. Many of the benefits of nanotechnology in drug delivery are the result of improved apparent solubility or stability or both; an increased concentration of drug at the site of action (increased efficacy); a decreased concentration of drug at locations in the body remote from the site of action (reduced systemic toxicity); and modified pharmacokinetics, including controlled release.
There are numerous "drivers" of nanotechnology-based drug delivery. Pharmaceutical considerations are one such driver (see drug nanocrystals, below); another is the need for veterinary nanomedicines that overcome problems refractory to conventional therapy. One objective of "smart" drug delivery is to target specific sites. This strategy allows the use of smaller quantities of drug than would otherwise be possible. The passive targeting of intravenously administered drug, for example, depends on the enhanced permeability and retention (EPR) effect, a phenomenon whereby nanoparticles extravasate at sites of increased vascular permeability, such as tumors, infections, and areas of inflammation, and then accumulate at these sites. Surface modification of nanoparticles is used to prolong the circulation time and enhance the EPR effect. For example, coating nanoparticles with the hydrophilic substance polyethylene glycol lessens opsonization through a steric effect, thereby reducing the subsequent uptake of nanoparticles by the reticuloendothelial system. Conversely, uncoated nanoparticles are rapidly phagocytosed, a process used to advantage to treat intracellular parasites and infections located in phagocytic cells. In a separate process known as active drug targeting, nanoparticles with targeting moieties (eg, antibodies, ligands) attached to their surfaces are able to bind to specific tissues or cell types. Similarly, magnetic nanoparticles under the influence of an alternating magnetic field transport drugs to their sites of action. Individualized and targeted drug therapy across animal species is an extension of the "smart" drug delivery concept. With this approach, miniature sensing and delivery devices, some with embedded PK/PD algorithms or using nanodelivery platforms that provide local feedback on delivery mechanisms, are envisioned. Also envisioned are nanoscale devices with the capability to detect and treat an infection, nutrient deficiency, or other health problem before symptoms are evident. In the case of antibiotics, the envisioned system would use less drug, thereby relieving concerns surrounding the potential development of antibiotic-resistant strains of bacteria and thus increasing food safety for consumers. Exciting advancements in the field of vaccine delivery are also being made (see vaccine delivery and vaccine adjuvants, below).
The ratio of surface area to volume of a drug nanocrystal is orders of magnitude greater than that of its microscale or macroscale drug counterpart. Poorly water soluble drugs with a bioavailability that is dissolution-rate limited demonstrate markedly improved bioavailability when administered in a nanoform. Another advantage is that drug nanocrystals demonstrate reduced variability in bioavailability for the fed and fasted states. Nanosized drug crystals are produced either by top-down technology, in which micronized particles are subjected to milling or grinding, or by bottom-up technology involving nanoprecipitation.
Drugs and proteins conjugated to polymers such as polyethylene glycol degrade more slowly than do drugs or proteins alone. As a consequence, conjugates remain in the circulation longer than the parent drug or protein. A prolonged circulation time allows for less frequent administration and results in increased extravasation of drug due to the EPR effect and, consequently, a higher drug concentration at the site of action.
Dendrimers are highly branched polymers consisting of an initiator core; interior layers composed of repeating units; and terminal moieties that can be functionalized to modify solubility, miscibility, and reactivity of the resulting macromolecule. From a drug-carrying perspective, dendrimers are relatively new. High loadings of drug can be incorporated into the dendrimer core or attached to the terminal moieties on the dendrimer surface. Dendrimers are particularly attractive for ocular, pulmonary, and oral drug delivery.
Polyplexes are complexes of polymers and DNA with promising benefits for gene therapy.
Polymeric micelles comprise an internal zone known as the "core" and an external zone known as the "shell" formed by amphiphilic block copolymers such as poly(propylene oxide), poly(L-amino acids), and poly(esters). The advantages of polymeric micelles for drug delivery include solubilization of poorly soluble molecules and sustained drug release due to drug encapsulation protecting the drug from degradation and metabolism. Polymeric micelles can also enhance the delivery of drugs to desired biologic sites, thereby improving therapeutic efficacy and attentuating unwanted adverse effects.
Liposomes are self-assembled vesicles that possess a central aqueous cavity surrounded by a lipid membrane formed by a concentric bilayer(s) (also known as a lamella[e]). When liposomes come in contact with biologic cells, they tend to unravel and merge with the membrane of the cell, releasing their payload of drugs or other agents. Liposomes can be designed to achieve various functions, including the protection of the active ingredient from degradation in the GI tract, the transport of drugs to sites of action, and prolongation of the residence time of the active ingredient in vivo.
Solid lipid nanoparticles are synthesized from solid lipids. These nanoparticles demonstrate excellent physical stability and protect the incorporated drug from chemical degradation; however, low drug loading capacity is a disadvantage. Studies suggest it will be possible to develop a range of dosage forms, allowing solid lipid nanoparticles to be delivered by most routes of administration.
Polymeric nanoparticles consist of two main forms: polymeric nanocapsules and polymeric nanospheres. Polymeric nanocapsules can be prepared from natural and synthetic materials such as chitosan and poly(lactide-co-glycolide), respectively. From a drug delivery perspective, polymeric nanocapsules demonstrate a high drug loading capacity and facilitate increased drug bioavailability and controlled drug release. Other applications of polymeric nanocapsules include the detection, diagnosis, and treatment of disease, and imaging. Polymeric nanospheres differ from polymeric nanocapsules, because drug is physically and uniformly dispersed in a dense polymeric matrix with the former.
Magnetic nanoparticles have two therapeutic applications: drug delivery and therapeutic hyperthermia. The former application involves drug-coated magnetic nanoparticles that are generally >50 nm in size. After IV administration, these nanoparticles are directed to the site of drug action using a magnetic field. Subsequent retention of the nanoparticles at the site of action is also achieved using a magnetic field, and this facilitates localized drug release. By comparison, magnetic nanoparticles for therapeutic hyperthermia are smaller in size (~5 nm). Hyperthermia via hysteresis energy loss results when an external alternating magnetic field is applied to the magnetic nanoparticles. A typical outcome of therapeutic hyperthermia is tumor cell necrosis.
An example of a nanotechnology-based device for vaccine delivery is the Nanopatch®, used in people to deliver vaccines dermally. The Nanopatch® is a silicon wafer the size of a postage stamp with thousands of projections (>20,000/cm3), each of which is ~100 μm long and with a tip diameter of ~1 μm. The tips of the projections are dry coated with vaccine at the nanoscale; hence, there is no requirement for refrigeration of the vaccine during storage and transport. When the device is applied to a patient's skin, the projections protrude into the wet cellular environment below the skin surface; on wetting, the vaccine is delivered in <2 min. Only one one-hundredth of the dose delivered conventionally by a needle and syringe is administered to achieve a comparable immunologic response, which is consistent with skin having more immune cells than muscle.
Nanotechnology-based vaccines may decrease unwanted inflammatory response. For example, studies have shown that the delivery of 50 nm ovalbumin adjuvant coupled to polystyrene nanobeads to sheep do not cause inflammatory reactions at the injection site. This outcome is thought to be attributed to the fact that adjuvants at the nanoscale mimic the size of viruses, which are well tolerated by cells.
Nanoclays have numerous applications, including the delivery of agrochemicals and the control of blue-green algae in waterways, and many potential applications in human and veterinary medicine. For example, nanobiohybrids are nanoclay hosts with various biologic materials such as DNA intercalated between the layers that have potential applications in gene therapy. The nanobiohybrid host system is comprised of magnesium-aluminum layered double hydroxides wherein the positive charge of the sheets of magnesium and aluminum hydroxides is balanced by the negative charge of hydrated anions. Through ion exchange, the interlayer anions can be replaced with negatively charged biomolecules such as DNA. After delivery to a biologic system, nanobiohybrids are phagocytosed, and the biologic material released from the inorganic host either by dissolution of the inorganic host in the acidic environment of lysosomes or through reverse ion-exchange within the cellular fluids.
Gold nanomaterial is biocompatible, and when formulated as gold nanoparticles it is used in the diagnosis and treatment of diseases such as cancer. For therapeutic purposes, gold nanoparticles are coated with disease-specific surface moieties and a hydrophilic substance such as polyethylene glycol to prolong circulation time. Near infrared irradiation is used to visualize and destroy gold-targeted cancer cells by optical hyperthermia.
Carbon nanotubes are being investigated as nanovector systems. These nanomaterials have a high optical absorbance at infrared frequencies and may in the future be used in a similar manner to gold nanoshells. The possible longterm toxicity of carbon nanotubes due to bioaccumulation is currently under investigation.
Quantum dots are luminescent semiconductor crystals with unique optical properties, including high-level fluorescence, long-term stability, simultaneous detection of multiple signals, and tunable emission spectra. In the future, they may be used as a multifunctional therapeutic for lymph node mapping, identification of molecular targets, photodynamic therapy, drug delivery, and surgical oncology. Quantum dots with cadmium selenium/zinc sulfide cores with sizes ranging from 13–24 nm emit different narrow wavelengths of detectable light. This capability would allow detection of heterogenous tumors by coating quantum dots of different core sizes, and therefore emitting different wavelengths of light, with different cancer-specific antibodies to help understand optimal tumor therapy. The in vitro toxicity associated with the core of quantum dots (eg, cadmium selenium) can generally be overcome by coating the core with other metals such as zinc sulfide or adding a protective hydrophilic coating (eg, polyethylene glycol). Further research is necessary to evaluate the longterm stability of quantum dots in vivo, which is a major barrier to clinical translation.
Increased bioavailability as well as improvements in targeted and controlled delivery of existing drugs and their application through nanotechnology should improve ease of administration and safety and efficacy profiles for both animals and people.
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* This is the Veterinary Version. *