Nanotechnology concerns the investigation and engineering of atomic and molecular structures in objects of size 1-100 nm in size. Nanotherpeutics take the form of liposomes, polymers, nanocrystals, nanogels and nanoemulsions.
Drug nanocrystals are pure solid particles with a mean diameter of less than 1 micrometer with a crystalline character. Nanocrystals are 100% composed of drug or payload, eliminating the need for a carrier. They provide an opportunity to deliver hydrophobic drugs because the nanocrytallization process improves solubility as well as the process benefits stability, bioavailability and dissolution rates. Solubility of hydrophobic drugs is increased due to increased surface area to volume ratio and dissolution rates. Poorly soluble drugs pose a translational hurdle that has been overcome in many instances by using a nanocrystal formulation method.
Nanocrystals are generally produced used two approaches. The first approach includes top-down methods, where large particles are broken down into a smaller size, like media milling (pearl milling) and high-pressure homogenization (HPH). Milling pearls, usually made of stainless steel, glass, zirconium oxide or highly cross-linked polystyrene resin, are put into a milling chamber with stabilizer, drug and dispersion media. HPH methods use sonicators, homogenizers, mortar and pestle or jet mills, to create micronized suspensions, followed by exposure to collisions, strong cavitation and high shear forces by passing through a narrow gap.
The second bottom-up approach is typically precipitation where nanosuspensions are engineered from dissolved small molecules in their corresponding antisolvent using nucleation and crystal growth. An acid-base neutralization step may be used. Nanosuspensions may also be prepared using microfluidic nanoprecipitation, spray drying, electrospraying and using an aerosol flow reactor.
The first marketed nanocrystal drug was Rapamune, an immunosuppressant introduced by Wyeth Pharmaceuticals (Madison, NJ) in 2000. The previous form of the drug, known as Sirolimus (SRL) was poorly soluble and Rapamune, formulated using pearl mill technology increased bioavailability of the oral form of SRL by 21%. Emend launched by Merck (Winehouse Station, NJ) in 2003 was formulated from Aprepitant, a poorly water soluble anti-emetic medication. Triglide initially produced by Skypharma in 2005 and later marketed by Sciele Pharma Inc. (Altanta, GA), is a nanocrystal product derived from fenofibrate to treat hypercholestremia showed improved bioavailability and adhesiveness to the gut wall.
Nanocrystal drugs on the market as of 2019:
Rapamune
Emend
Tricor
Triglade
Megace ES
Invega Sustenna
Cesamet
Avinza
Naprelan
Ritalin LA
The majority of nanocrystal drug products are approved for oral ingestion for diseases other than cancer. For oral products crystals are above the 100-200 nm size range. Nanocrystals can be injected intravenously however dimensions over 100-200nm they could promote macrophage-mediated phagocytosis and rapid blood clearance. The intracellular and intratumoral fate of these drugs is not well understood.
There are challenges relating to control of the drug substance, drug product, manufacturing process and stability of the product. For example, ensure reliability ideal techniques to validate particle size need to be determined. Changes in crystalline structure needs to be monitored during manufacture and shelf life because changes can affect dissolution, stability and bioavailability. Such changes can be evaluated using X-ray powder diffraction, differential scanning calorimetry or spectroscopic methods.
Synthetic polymers that are used for drug delivery include biodegradable aliphatic polymers such as polyactide (PLA), poly lactide-co-glycolide copolymers (PLGA) and poly (e- caprolactone) as well as non-biodegradable polymers including polyacrylates and poly (methyl methacrylate). Natural polymeric nanoparticles are made of alginate, chitosan, albumin and gelatin.
Polymeric nanoparticles can protect against degradation for unstable drug moieties and prevent toxic side effects. For example, polymeric nanoparticles are used with dexamethasone or α-tocopherol succinate palliates cisplatin ototoxicity or damage to the inner ear caused by cisplatin from chemotherapy treatment. Drugs that use polymeric nanoparticles in their formulations include Decapeptyl, Gonapeptyl Depot, Enantone Depot and Abraxane.
Nanogels are composed of flexible hydrophilic polymers. A drug can be incorporated in the nanogel upon swelling in water. Incorporation of the drug results in the formation of solid dense nanoparticles. Nanogels allow the physical encapsulation of bioactive compounds such as DNA, proteins, carbohydrates and drugs. Nanogel preparations on the market include San Care Nanogel, ZyflexNanogel, Augen Nanogel Eye-care Gel, Skin Perfect Brightening Nanogel and Oxalgin.
Nanoemulsions are colloidal drug delivery systems that are thermodynamically stable and enable sterilization by filtration. The oil droplets in aqueous medium form nano droplets. The three types of nanoemulsion are water in oil, oil in water and bi-continuous nanoemulsion.
Liposomes and lipid nanoparticles (LNPs) are similar but slightly different in function and composition. Both are lipid nanoformulations used as drug delivery vehicles and transporting cargo inside a protective outer lipid layer. While liposomes have one or more rings of lipid bilayer surrounding an aqueous pocket, not all LNPs have a contiguous bilayer and some LNPs have a micelle-like structure and encapsulate drugs in a non-aqueous core.
Liposomes were invented in 1965 and are defined as spherical vesicles with an internal cavity that is aqueous surrounded by a lipid bilayer membrane. The term liposome comes from the Greek words ‘lipid’ and ‘soma’, meaning fat and body. The advantages of liposomes as pharmaceutical carriers include protection of the drug against enzyme degradation, low toxicity, flexibility, biocompatibility, biodegradability and non-immunogenicity. Disadvantages include short shelf life, poor stability, low encapsulation efficacy, rapid removal by the reticulodendothelial system, cell interactions or adsorption and intermembrane transfer. Pharmaceutical liposomes are also expensive.
LNPs are produced using high pressure homogenization (HPH), solvent emulsification/evaporation, supercritical fluid extraction of emulsions (SFEE), ultrasonication or high speed homogenization and spray drying. Hot or cold processes are used for HPH. Solid liquid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are two major types of LNPs.
SLNs and NLCs have an average size of 40-1000 nm, spherical morphology and are composed of solid phase lipid and surfactant. The dispersed phase is solid fat and the surfactant is used as emulsifier. SLN lipid components are solid at body and ambient temperatures and may be highly purified triglycerides, complex glyceride mixtures or waxes. To enhance stability surfactants are used and the selection of lipids and surfactants can affect the physiochemical properties and quality including particle size and drug loading. Compared with liposomes, SLNs and NLCs have drug stability, prolonged release. They are safer than polymeric carriers due to avoidance of organic solvents for production. They are amenable to large scale production. LNPs are suitable for encapsulating nucleic acids and are a popular non-viral gene delivery system.
Polyethylene glycol (PEG) is often covalently attached to LNP phospholipids on the outer side which improves stability. Also, PEGylated phospholipids improve the stealth of the drug product as it helps shield from the immune system. The modification prevents blood plasma proteins from absorbing into the liposome surface, allowing more circulation time. Hybrid nanoparticles incorporate PLA or PGLA polymers within a lipid monolayer to facilitate controlled drug release.
Solid liquid nanoparticles (SLNs) are liquid nanoparticles prepared with a solid matrix. SLP avoid the use of organic solvents and use physiological lipids, are biocompatible and allow controlled drug release. However the low drug incorporation, drug expulsion phenomena and irregular gelation tendency makes them less suitable for drug delivery. The antibiotic ciprofloxacin (CIP) has been loaded onto SLNs for superior antibacterial activity.
Nanostructured lipid carriers (NLCs) are modified SLNs with improved stability and loading capacity. NLCs differ from SLNs by composition of the solid matrix and they have improved stability, capacity loading and prevent drug expulsion during storage.
Dendrimers, discovered in the early 1980s are radially symmetric molecules with homogenous and monodisperse structure (molecules of uniform size) consisting of tree-like arms or branches. Rather than a compound, dendrimer is an architectural motif. Dendrimers are hyperbranched macromolecules with tailored architecture with end-groups that can be functionalized to change their physiochemical or biological properties. They hold potential for anticancer therapies, diagnostic imaging and as nano-scale delivery devices.
Due to their step-by-step controlled synthesis dendrimers relate to molecular chemistry and their repetitive structure composed of monomers relates to polymer chemistry. Dendrimers can be synthesized using a divergent approach, which begins with the core and then arms are attached by the addition of building blocks in a step-wise manner. The newer convergent approach begins synthesis from the exterior. Using this strategy, the final generation number is pre-determined. Dendrimers can also be self-assembling.
For biomedical applications dendrimers can be modified to form antibody-dendrimer or peptide-dendrimer conjugates or dendritic boxes to encapsulate desired molecules. Drug-dendrimer conjugates show high solubility, reduced toxicity and selective accumulation in solid tumors. Drug molecules, genetic material, targeting agents or dyes can be encapsulated, complexed with or conjugated to dendrimers. Dendrimer-based metal chelates act as contrast agents for magnetic imaging. Sensor molecules or photosensitizing agents can be attached to dentrimers.
Nanocapsules are vesicles composed of a polymer membrane surrounding an inner core of a desired substance. Successful commercialization of nanocapsule products include Abraxane, Combidex and DuanoXome. Healthcare is the primary application but other applications include food and nutraceuticals, cosmetics and agricultural production. Therapeutic applications include oncology, pain management and endocrinology. Key players in the nanocapsule market include BioDelivery Sciences, Camurus, CARLINA Technologies, Cerulean Pharma Inc., NanoNutra, NanoSphere Health Science, and L’Oreal.Nanocapsules have been formed using graphite, silica, protein and lipids.
Lipid nanocapsules (LNCs) are nanovectors that have biomimetic properties. They are produces using a phase inversion temperature process after the formation of an oil/water microemulsion. The three main components are an oily phase, aqueous phase and nonionic surfactant. LNCs have an oily liquid triglyceride core surrounded by a tensioactive cohesive interface. They have a hybrid structure between polymer nanocapsules and liposomes.
A nanosponge is a technology being developed to overcome problems in drug delivery such as solubility, bio-availability and to allow the precise control of drug release. Nanosponges are tiny mesh-like structures less than 1 micrometers in size that can load hydrophilic and lipophilic drugs. Nanosponges circulate until reaching the defined target site, attach and initiate discharge of drugs in a controlled manner. Parenteral, topical, oral or inhalational dosing can be developed with nanosponges.
Researchers at University of California San Diego, lead by Professor Joseph Wang have developed nanorobots powered by ultrasound that can swim through blood and remove bacteria and toxins. These nanobots are 2 micrometers and composed of human blood cells and gold nanowires. Red blood cells and platelets coat the gold nanowires because red blood cells neutralize toxins and platelets interact with bacteria. They are capable of binding and neutralizing bacteria such as MRSA and their toxins.
Professor Jeremy Bauberg and colleagues at Cambridge and University of Bath developed a tiny engine a few billionths of a meter in size that is biocompatible, cost-effective, and energy efficient. The engines called ANTs for actuating nano-transducers are made of charged gold particles bound together by a temperature-responsive polymer gel, heated with a laser. Elastic energy is stored when the polymer coatings expel water from the gel and collapse. When cooled the particles spring apart and release energy. The researchers aim to use the force produced by ANTs to build machines that are small enough to move in the bloodstream that can swim and pump fluid to sense the environment.
The Wyss Institute is developing DNA nanorobots that are short hexagonal tubes constructed with interwoven DNA that can open along the length like a clamshell. The structure includes a DNA hinge and a pair of twisted DNA fragments which act as latches to hold the device closed. The nanorobot can enclose molecules to be transported to specific areas of the body.
Scientists at the University of Chinese Academy of Sciences and Arizona State University have demonstrated that their DNA nanorobots effectively deliver thrombin to tumor-associated blood vessels in mice and Bama miniature pigs. Their nanobot is functionalized with a DNA aptamer that binds nucleolin, a protein that is expressed on the target tissue, tumor-associated endothelial cells and triggers the release of the drug thrombin, housed inside the nanobot cavity.
