Stability

The ability of multifunctional nanoparticles to combine targeting, therapeutic, and imaging modalities is a key aspect of their versatility and anticipated clinical impact.50-52 With such complex compositions, the stability of all the components in nanoparticles is essential to their biological function. Premature release of any of the components from the composite preparation may render it ineffective. For example, in a nanodelivery system containing a targeting agent and a drug, the nanoparticles with the drug cannot bind to the desired targeting site if the targeting agent is prematurely cleaved or released. If the drug is prematurely released, even if the nanoparticle reaches its target, there will no longer be a therapeutic benefit.53 For this reason, it is important to determine the in vitro functional component stability under physiological conditions.

For a nanomaterial providing targeted or timed-release drug delivery with an encapsulated drug, the release profile should be determined at different ionic strength, pH, and temperature conditions. Examples of such conditions include the stability at pH 7.4, in buffers such as phosphate buffered saline (PBS), and serum at 37°C. There are many nanoparticle designs being pursued which incorporate the selective release of components triggered by an external stimulus after targeted delivery. If a therapeutic attached to a nanoparticle uses a cleavable linkage, the efficiency of release should be determined under the expected cleavage conditions.54

In cases where a metal complex is used (for example, a Gd chelate for enhanced MRI contrast), the stability constants for the encapsulation or complexation should be determined, since any release of free heavy metal will increase the in vivo toxicity of the preparation.55 The potential in vivo application of quantum dots has raised some concerns that the CdSe core might be exposed by the breakdown of its protective polymer or inorganic shell, releasing the highly toxic heavy metal Cd2+ ions into the bloodstream.56 The quantum dot shells have been designed to be protective, but their long-term stability (e.g., susceptibility to Cd leaching) has not been established. Studies conducted on primary hepatocytes in vitro suggest that CdSe core quantum dots may be acutely toxic under certain conditions.57 Other studies suggest that under physiological conditions, appropriately coated quantum dots do not expose the host organism to toxic levels of the core material.58-60 Apparently conflicting evidence as to the safety of quantum dots highlights the necessity of clearly and objectively establishing the stability of these nanoparticles under physiological conditions using standardized methodologies.

It is also important to determine the stability of the nanoparticle under nonphysiological conditions to account for the effects of short-term and long-term storage, lyophilization, ultrafiltration, thermal exposure, pH variation, freeze-thawing, and exposure to light.

In summary, adequate physicochemical characterization of nanomaterials should be included as an essential requirement for preclinical characterization. Just as molecular characterization forms the basis of dosing and toxicity studies for small molecule therapeutics and diagnostic compounds, physicochemical characterization provides the foundation for dosing and toxicity studies for nanomaterials intended for clinical applications. Standardized protocols are being established by Standards Developing Organizations, such as the International Standards Organization (ISO) and American Society for Testing and Materials (ASTM), for characterizing the many types of biomedical nanomaterials being developed today for human use. Additionally, standardized reference material (SRM) will enable analytical technologies to be calibrated and protocols to be tested for consistency and to facilitate inter-laboratory comparisons.

To better control for the results of in vivo studies of nanomaterial absorption, distribution, metabolism, elimination, and toxicity, it will be necessary to examine the material in the same physicochemical state as would be found under physiological conditions. Particle-specific attributes that should be evaluated include surface characteristics, chemical composition, shape, size, and ligand dispersity. Additional properties that are influenced by experimental conditions include solubility, stability, protein binding, and aggregation state. Knowing the exact physiological conditions in different tissues and organs and developing a means to either replicate those conditions or measure physicochemical properties in situ is a significant challenge. But continued studies in this area will provide further data to elucidate the linkages between physicochemical characteristics of nanomaterials and their biological effects (i.e., SARs).

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