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Posted: Aug 2nd, 2007
Immunological properties of engineered nanomaterials
(Nanowerk Spotlight) The question if certain engineered nanoparticles are toxic, and if yes to what degree, is still one of the major issues that hasn't been properly answered yet. Most studies in the literature thus far have focused on the environmental aspects of nanoparticle toxicity, and these studies have been conducted primarily on industrial or natural/incidental nanoparticles. However, engineered nanoparticles are at the forefront of the rapidly developing field of nanomedicine; and here they are deliberately injected into the body to perform a specific medical application: fluorescent agents for imaging; drug delivery vehicles; or therapeutic agents for the destruction of cancer cells (for instance in thermolysis); just to name a few. A brand new review article provides the first comprehensive summary of the properties of engineered nanoparticles which determine their interaction with components of the immune system. It concludes that nanoparticle-based therapeutics are no more intrinsically immunotoxic than traditional pharmaceuticals, such as biotechnology-derived or small molecules. Moreover, incorporation of traditional drugs into nanotechnology formulations frequently results in a decrease in immunotoxicity compared to the native drug. Although many questions still require thorough investigation, the available data suggest that nanoparticles can be engineered to become the next generation of biocompatible drug delivery platforms.
"A number of pharmaceutical products that involve nanotechnology have already been approved for clinical use, and many others are at different stages of preclinical development" Dr. Marina A. Dobrovolskaia tells Nanowerk. "Indeed, it is estimated that approximately 240 nano-enabled products entered pharmaceutical 'pipelines' in 2006. At present, as the use of nanomaterials in biomedical products is relatively new and no formal evaluation guidelines have been established, the strategies adopted for preclinical studies on these products resemble those undertaken for other pharmaceuticals, including the way immunotoxicity is assessed."
Dobrovolskaia is an Immunologist for the Nanotechnology Characterization Laboratory (NCL), a formal collaboration between the National Cancer Institute (NCI), the U.S. Food and Drug Administration (FDA), and the National Institute of Standards and Technology (NIST).
The NCL performs preclinical characterization of nanoparticles intended for cancer therapeutics and diagnostics. It is a free resource available to investigators from academia, industry, and government laboratories. The NCL is comprised of staff from the fields of chemistry, physics, immunology, cell biology and toxicology, and NCL staff is now familiar with a wide variety of nanoparticle types, such as dendrimers, liposomes, gold colloids, fullerenes, and polymers.
Dobrovolskaia notes that the NCL has seen significant recent success with the use of nanoparticles as platforms or carriers for otherwise insoluble or poorly soluble drugs. Nanoparticle-carried drugs often have altered pharmacokinetics and disposition profiles compared to their native forms – frequently with reduced side effects and improved efficacy.
The NCL is initiating collaborations with drug developers to use nanoparticles as delivery systems to resurrect oncology drugs previously discontinued during clinical trials. "We believe the NCL's many collaborations with small nanotechnology firms and expertise with a variety of nanoparticle drug delivery platforms can help pharmaceutical companies efficiently produce reformulations using nanotechnology."
In their review article in Nature Nanotechnology ("Immunological properties of engineered nanomaterials"), Dobrovolskaia and Dr. Scott E. McNeil, Director of the NCL, analyze the literature and their own data for a broad variety of engineered nanoparticles, and attempt to summarize their interaction with the immune system. They outline key considerations for preclinical immunological characterization of nanomaterials intended for biomedical applications.
Blood contact properties
"Early studies show that modifying the surface of nanomaterials alters the nanoparticle/biological fluid interface and influences the way nanoparticles interact with blood constituents" says Dobrovolskaia. "Furthermore, plasma protein binding is important in determining the in vivo organ distribution and clearance of certain nanotechnology-derived drug carriers."
The structure and composition of nanoparticles need to be engineered in a certain way in order to facilitate the binding of the desired proteins to their surface. It appears that these surface modifications may also be designed to improve nanoparticle - blood compatibility. The NCL review points out that understanding particle structure–activity relationships at the level of interaction with blood cellular and protein components will facilitate the development of a new generation of biocompatible drug carriers.
The trick of successful nanoparticle-based therapeutics is to avoid immunostimulatory or immunosuppressive reactions to the nanomaterials once administered into the body. Immunostimulation means avoiding that the immune system efficiently recognizes the particles as foreign substances and mounts a multilevel immune response against them. Undesirable immunosuppression from other side may decrease body’s own defense against pathogens and cancerous cells.
The review looks at antigenicity (specific antibody response), adjuvant properties (adjuvants are agents added to a vaccine to augment immune
responses toward antigens), inflammatory responses and the mechanisms through which nanoparticles are recognized by the immune system.
"Comprehensive structure - activity relationship studies are necessary to further understand the critical parameters that determine the antigenic and adjuvant properties of nanoparticles" says Dobrovolskaia. "Some studies suggest that nanoparticles can exacerbate allergic reactions and, therefore, careful preclinical characterization is required in all cases."
As a more fundamental issue, scientists know that the way mammalian cells interlaize nanoparticles is influenced by particle size, shape, charge, and surface modification, but the exact mechanism of nanoparticle uptake is still not well understood.
Immunosuppression involves an act, e.g. the effect of a drug, that reduces the activation or efficacy of the immune system. It is usually induced to prevent the body from rejecting an organ transplant or for the treatment of auto-immune diseases.
Dobrovolskaia says that the reviewed studies demonstrate that nanoparticles may be engineered to be immunosuppressive for use as anti-inflammatory therapeutics. She cautions, however, about undesirable immunosuppression. "Will administration of nanoparticles designed for cancer therapy or imaging interfere with the body's immune protection against cancerous cells and bacterial and viral pathogens?"
While most existing research data clearly suggests that nanoparticles interact with the immune system, one of the critical issues today is that there are no agreed-upon guideline for assessing the immunotoxicity of engineered nanoparticles. Dobrovolskaia and McNeil make an attempt to provide a framework of clinical concerns for various aspects of immunotoxicity. In their paper they suggest a number of important parameters to be addressed during an initial evaluation of nanotechnology-derived pharmaceuticals.
"The main challenge in immunological studies of nanomaterials is choosing an experimental approach that is free of false-positive or false-negative readouts" says Dobrovolskaia. "The majority of the standard immunotoxicological methods are applicable to nanomaterials. However, as nanoparticles represent physically and chemically diverse materials, the classical methods cannot always be applied without modification, and novel approaches may be required."