For decades, the pharmaceutical industry has focused its drug-development strategies around the use of organic or biologically derived compounds. Among numerous successes are also a multitude of failed drug products due to a variety of factors including solubility, stability, biopersistence, and undesired secondary or “off-target” effects. However, in recent years, advances in the study of the therapeutic effects of inorganic compounds, particularly at the nanoscale level, have opened new and exciting avenues for therapeutic intervention.
Indeed, nanotechnology is currently being viewed as a therapeutic enhancement or even a potential lifeline for numerous existing and flawed drug candidates, as various nano-sized 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, nano-sized (less than 100 nm) carrier. These nano-carriers can be functionalized by the addition of the active drug compound, as well as targeting molecules. In some instances, the nano-carriers can act as a protective shell, protecting the contents of its precious, and sometimes toxic payload until it has reached its desired location.
Numerous drug candidates are being reformulated and re-examined in the context of such nano-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 the platinum-based, anti-cancer drug, cisplatin.
As 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. Nano-based carriers provide the ideal opportunity to overcome these undesired side effects and, as such, numerous strategies are currently being employed to safely carry the drug to its desired locale in both preclinical and clinical trial settings.1
While using nanotechnology as a platform for drug delivery is helping to revitalize chemotherapeutic research, a separate branch of nano-based compounds bearing their own intrinsic bioactivity are making inroads in a variety of other 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 not seen in larger, bulk structures. These activities are dependent not only on their chemical composition, but also on their size, shape, and surface charge.
These engineered bioactive nanoparticles cover a broad range of organic, inorganic, and synthetic formulations and are currently being exploited for diagnostic and therapeutic uses.2 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 found in inorganic nanoparticles. While several inorganic formulations featuring yttrium, platinum, and cerium-based nanoparticles have been assessed in various biological test beds, the greatest amount of advancements 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 and nitrogen species (ROS and RNS, respectively).
Numerous human diseases and pathologies feature a component of oxidative damage, with these damaging free radical species that, when unregulated, can destroy proteins, nucleic acids, and lipids and trigger cell and tissue death. In particular, diseases of the central nervous system (CNS), such as neuro-degenerative diseases (ND) have been particularly associated with high degrees of oxidative damage. As such, numerous antioxidant therapies aimed at treating ND diseases have been attempted in the past. 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).
A New Intervention Emerges
Enter the ceria nanoparticles as a novel intervention to overcome these limitations of traditional antioxidants. Numerous reports on the bioavailability and toxicity of ceria nanoparticles highlight the importance of size and stabilization of the materials. Smaller sized particles (<5 nm) have been reported to cross the BBB and perform disease-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.3
While the earliest proof-of-concept preclinical uses of ceria focused on localized delivery to the eye for the treatments of retinal degeneration, more recent studies have demonstrated efficacy in ND diseases and pathologies of the CNS. In vitro studies have utilized models of both ischemic stroke and Alzheimer's disease to demonstrate amelioration of free radical damage leading to increased neuro-protection. Importantly, the studies in the ischemic stroke model demonstrated that the 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 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 lasting and meaningful impact on some of these debilitating and deadly ND 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 its preclinical work in preparation for filing 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, like many of the bio-active nanomaterials, can further be functionalized with other compounds and molecules. It is, therefore, possible to imagine a “dual hit” drug strategy where a functionalized nanoparticle is able to exert its intrinsic bioactivity while also delivering another active compound.
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 various physiochemical properties of these nanoparticles influence these 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.
This article was written by Brad Stadler, PhD, EVP, Biologics, Cerion Advanced Materials, Rochester, NY. He is also the COO of Cerion NRx, a joint venture, drug-development subsidiary of Cerion. For more information, visit here.