Brad Stadler, Ph.D. Executive Vice President, Biologics Cerion Advanced Materials
For decades, the pharmaceutical industry has focused its drug development strategies around the use of organic or biologically derived compounds. Many of these compounds succeeded as drug products, but an even larger number failed due to a variety of factors including solubility, stability, biopersistence, and undesired secondary or off-target effects. To improve the success-to-failure ratio, the pharmaceutical industry is broadening its outlook. For example, the industry is showing interest in the therapeutic potential of inorganic compounds, particularly at the nanoscale level. Recent advances in the study of inorganic nanomaterials are opening new and exciting avenues for therapeutic intervention.
Indeed, nanotechnology is currently being viewed as a therapeutic enhancement or even a potential lifeline for many struggling drug candidates, compounds that are active but somehow flawed, usually in terms of delivery. Various nanoscale platforms offer the potential to ferry these active compounds to target tissues and cells with greater selectivity, improving their efficacy as well as reducing off-target effects. In many of these cases, the nanotechnology contribution is in the form of an inert, nanoscale (less than 100 nanometer) carrier. These nanocarriers can be functionalized by the addition of the active drug compound, as well as targeting molecules. In some instances, the nanocarriers can act as a protective shell, protecting its precious (and sometimes toxic) payload until it has reached its desired location.
Many drug candidates are being reformulated and reexamined in the context of such nanotechnology-based drug delivery platforms, particularly in the chemotherapeutic space. Perhaps no compound better illustrates the cross-section of the therapeutic potentials of both inorganic compounds and nanotechnology than cisplatin, a platinum-based anticancer drug and one of the earliest examples of the utility of inorganic therapeutic agents. Cisplatin and its derivatives have been used extensively as chemotherapeutic agents; however, their efficacy is somewhat tempered by their high degree of toxicity.
The side effects caused by cisplatin and its derivatives could be overcome if developers seize the opportunity represented by nanocarriers. Already, developers are employing a variety of nanocarrier strategies to safely transport the drugs to their assigned targets. These strategies are even being evaluated in preclinical and clinical trial settings (Chem. Rev. 2016 March 9; 116(5): 3436–3486).
Besides serving as drug delivery platforms, nanomaterials may exert their own intrinsic bioactivities and contribute directly to a variety of therapeutic and diagnostic areas. The seminal musing of Richard Feynman and consequent decades of nanotechnology research have established that materials at the nanometer scale possess unique properties. These properties, which are unavailable in larger, bulk structures, are dependent not only on a material’s chemical composition, but also on its size, shape, and surface charge.
Engineered bioactive nanoparticles cover a broad range of organic, inorganic, and synthetic formulations that are currently being exploited for diagnostic and therapeutic uses (Biochem. Pharmacol. 2014 Nov 1; 92(1): 112–130). The inherent bioactivities being exploited in these compounds include paramagnetism, hyperthermia, radiosensitization, and antioxidant activity, to name a few.
Recently, intensifying efforts have been made to unlock the therapeutic potential of the intrinsic antioxidant capabilities of inorganic nanoparticles. While several inorganic formulations featuring yttrium-, platinum-, and cerium-based nanoparticles have been assessed in various biological testbeds, the greatest progress to date has been seen in the field of cerium nanoparticles.
The therapeutic potential of cerium dioxide, or ceria, nanoparticles lies in the fact that the surface cerium atoms can exist in either +3 or +4 oxidation states and act as facilitators of redox reactions. By essentially mimicking the activities of the endogenous antioxidant enzymes superoxide dismutase (SOD) and catalase, the ceria nanoparticles can function catalytically and recycle their activity as they scavenge and detoxify reactive oxygen species (ROS) and nitrogen species (RNS).
The harms of many human diseases and pathologies include oxidative damage, which is caused by free radical species that can, when unregulated, destroy proteins, nucleic acids, and lipids as well as trigger cell and tissue death. In particular, diseases of the central nervous system, such as neurodegenerative diseases, have been particularly associated with high degrees of oxidative damage. As such, numerous antioxidant strategies aimed at treating neurodegenerative diseases have been attempted. These strategies have largely failed due to limitations in bioavailability, an inability to act on multiple ROS/RNS species, high levels of dosing required for these compounds sacrificial, or the inability to cross the blood-brain barrier (BBB).
Enter the ceria nanoparticles as a novel intervention to overcome these limitations of traditional antioxidants. Many reports on the bioavailability and toxicity of ceria nanoparticles highlight the importance of size and stabilization of the materials. Smaller particles (<5 nm) have been reported to cross the BBB and perform modifying functions in disease models, and the method of stabilization is seen to be important in determining biodistribution and persistence of the compound. Of particular note, ceria has been reported to have a residence time in tissues on the order of months, suggesting that careful toxicological assessment of the long-term effects of ceria exposure will be required (Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2016)
While the earliest proof-of-concept preclinical use of ceria focused on localized delivery to the eye for the treatment of retinal degeneration, more recent studies have demonstrated efficacy in neurodegenerative diseases and pathologies of the central nervous system. In vitro studies have employed models of both ischemic stroke and Alzheimer’s disease to demonstrate the amelioration of free radical damage leading to increased neuroprotection. Importantly, the studies in the ischemic stroke model demonstrated that ceria scavenges multiple forms of ROS and RNS.
Of late, studies from multiple groups using varying ceria nanoparticle formulations have demonstrated therapeutic effects in in vivo models of disease and injury, including traumatic brain injury, Parkinson’s disease, multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). In the rodent MS model studies, ceria compounds were demonstrated to maintain a long-lasting antioxidant effect out to one month following the final injection of the compound. Additionally, animals in both the MS and ALS studies demonstrated not only a reduction in disease severity but also improved performance in motor tests.
These preclinical findings provide a glimmer of hope that these novel nanotherapeutic compounds could have a lasting and meaningful impact on some of these debilitating and deadly neurodegenerative diseases, which currently suffer from a dearth of meaningful drug candidates. At this time, at least one drug development company, Cerion NRx (Rochester, NY), is advancing relevant preclinical work. The company is preparing to file an investigational new drug application for the therapeutic use of its ceria-based drug.
Much like the inert, nano-based drug delivery vehicles described above, ceria nanoparticles and many other bioactive nanomaterials can be further functionalized if they incorporate auxiliary compounds and molecules. It is, therefore, possible to imagine a “dual hit” drug strategy in which a functionalized nanoparticle exerts its intrinsic activity while delivering a compound that possesses its own independent activity.
As more preclinical and clinical studies of bioactive nanomaterials are enacted, it will be important to undertake a careful examination of the pharmacodynamics, biodistribution, and persistence of these materials in vivo. Additionally, an understanding of how the physiochemical properties of nanoparticles can influence pharmacological factors will be critical. In the case of ceria, it is already appreciated that the size, charge, synthesis method, and choice of stabilizers can impact these dynamics in vivo.
The example of these cerium-based nanoparticles is but one of many exciting new avenues of therapeutic and biomedical applications for nanoparticle research. As highlighted here, the unique properties of these nanomaterials offer a tantalizing new array of opportunities for both existing compounds and novel formulations and are certain to provide fertile grounds for drug discovery work in the years to come.
Bradford Stadler, Ph.D. ([email protected]), is executive vice president, biologics, Cerion Advanced Materials. Dr. Stadler drives research and development for biologic and therapeutic applications of the company’s nanoparticle technologies, including neurodegenerative disease therapeutics (Cerion NRx), nucleic acid transfection, antimicrobials, and drug delivery. He is the chief operations officer of Cerion NRx, a joint venture and drug development subsidiary of Cerion.