One advantage of nanoparticles for therapeutic delivery is that nanoparticles can be targeted to specific locations within the body. Once the particles have reached their destination, they can act as a reporter, release a compound, or be remotely heated to damage biological structures in close proximity. Targeting is typically accomplished by modifying the surface of the nanoparticle with a chemical or biological compound. In some cases, the nanoparticle targeting is passive where the accumulation in a particular target area (such as a tumor) is primarily due to the nanoparticle size. For example, Nanospectra Biosciences is using gold nanoshells to passively accumulate at tumor sites through a phenomenon known as Enhanced Permeability and Retention (EPR), where the increased tumor vasculature accelerates the deposition of circulating nanoparticles directly into the tumor. In other cases, biological molecules that can recognize an analyate are attached to the nanoparticle surface. The most common recognition elements are antibodies and DNA. To bind a targeting agent to the surface of a nanoparticle, the nanoparticle surface is modified with attachment points (e.g. carboxylic acids) and a heterobifunctional linker is used to link the attachment point to a binding site on the antibody or DNA. One common binding chemistry that we use at nanoComposix is NHS-EDC coupling where carboxylic acids are linked to free amines on the target biological molecule. In addition to binding a targeting agent, in many cases the particle must also be blocked with additional polymers or biomolecules to prevent non-specific binding to other biological entities within the body.
Nanoparticles can carry thousands of drug molecules embedded within or attached to the surface of the particle. The particles can be engineered to release the molecular cargo over time, allowing for a sustained delivery of a therapeutic, or a sudden triggered release may occur due to changes in local environment or external stimuli. When combined with a targeting component, the therapeutic can achieve localized delivery of a toxic compound reducing the total dose necessary to achieve efficacy and potentially reducing or even eliminating harmful side effects associated with direct intravenous delivery of the drug. One mechanism of delivery is to use a core/shell nanoparticle where the core is filled with either a solid or high concentration liquid formulation of the drug to be delivered. The shell layer controls the rate at which the drug diffuses out of the core. Silica shells that are porous with a well-defined thickness can provide precise control over the diffusion delivery rate. Additionally, the silica shell layer can be chemically modified to have an affinity for the drug itself. In this case, the large surface area of the porous shell can be utilized to hold and then release the delivered compound. More complex nanoparticle delivery devices that include a “trigger” can also be fabrciated. The trigger can be due to pH, heat, light, or the presence of molecules such as salts or other signaling molecules. Only when the trigger is initiated will the drug release from the particle providing further localization of the therapeutic treatment.
One of the most promising therapeutic applications of nanoparticles is the ability to locally generate heat. Plasmonic nanoparticle can be engineered to efficiently absorb light and convert the absorbed energy to heat, which is then released to the surrounding environment. By changing the size and shape the plasmonic nanoparticle, the peak absorbance wavelength can be moved into the near-infrared region of the spectrum where skin and other biological tissues are relatively transparent. Plasmonic photothermal therapies based on gold nanoshells are currently in clinical trials for head and neck cancer. A video describing the procedure is here.
Image from nanospectra.com
Sienna Biopharmaceuticals is developing a Silver Plasmonic Therapy for treating acne and permanently removing hair. The technology is based on nanoComposix silver nanoplates that have a peak absorption wavelength tuned to match the skin penetrating lasers used in dermatology clinics.
By introducing the particles into a hair follicle, localized heating can be used to modulate the oil production of the sebacia gland or to disrupt the stem cells that produce hair.
Magnetic nanoparticles can also be used for heating where instead of light, an oscillating electromagnetic field is used to generate heat-inducing eddy currents in the nanoparticles causing them to heat. While the equipment utilized to generate the magnetic field is complex, this treatment can be applied to areas in the body that are difficult to penetrate with light.
In order for nanotherapies to be effective, the particles have to circulate for a sufficient amount of time in the blood stream to reach their target. In addition to any targeting functionality, the particles must have a surface that allows them to remain unaggregated and to avoid being recognized by the body’s immune system. Typically, particles for nanobiotechnology will be coated with a polyethylene glycol (PEG) coating which provides both stability and stealth properties for increasing circulation. If targeted, the antibody or other targeting agent is often linked to the outer surface of the PEG coating. With the proper coating, the particle can avoid macrophages and achieve long circulation times.
Fate and Transport
After the in-vivo injection of nanoparticles into the blood stream, the particles will typically be removed by the liver and spleen. Uptake by the macrophages in the liver and spleen is usually preceded by opsonization, recognition by the macrophages and phagocytosis. Opsonization is where plasma proteins deposit on the surface of the particles to signal the Kupffer or reticular mcrophages to recognize and eliminate them from circulation. Kupffer cells are located inside the blood vessels of the liver and are the most active phagocytes for macrophage uptake for particles that are less than 100 nm in diameter. Particles that are engineered to evade the Kupffer cells, are often sequestered in the spleen. If particles enter a tissue, they may get directed to a regional lymph node for clearance. Very small particles can also be eliminated by the kidney but only if the particles are less than ~10 nm in diameter. The primary parameters determining the blood clearance pharmacokinetics are hydrodynamic size and stability, core size, core morphology, surface coating, surface charge and zeta potential, and protein absorption. All factors are important in designing a system that maximizes circulation time and minimizes toxicity.
Regulation and the FDA
Due to the scientific and regulatory complexity, bringing new nanotherapeutics to market is a challenging and long time frame project. However, the technology has the potential to revolutionize therapeutics and many companies are in active Phase I and Phase II trials with nanoparticle based drugs. Once a particular nanomedicine technology shows promise in the laboratory, the next step is to start building a design history file that documents the experiments conducted and serves as a foundation for a first regulatory filing. At this stage, it is typically required that the manufacturing methods of the particles be transferred to a quality system for GMP manufacturing. At nanoComposix we produce a wide variety of nanomaterials under our ISO13485/GMP quality management system and can help assist in the transfer to manufacturing for pre-clinical and clinical studies.
Nanomedicine Applications at nanoComposix
Examples of both internally developed and partnered nanobiotechnology projects at nanoComposix include:
- Topical theraputical for acne and permanent hair removal
- Particles for photothermal skin cancer treatment
- Hollow porous silica shells for targeted drug delivery
- Ultrabright fluorescent tags for in-vivo imaging
- Magnetic heating particles for cryo-thawing
For more information on collaborating on emerging nanomedicine applications please contact us.