Immunoreactivity of Nanoparticles
Author: Tilda Barliya PhD
As nanotechnology progresses from research and development to commercialization and use, it is likely that manufactured nanomaterials and nanoproducts will be released into the environment.
Adverse effects of nanoparticles on human health depend on individual factors such as genetics and existing disease, as well as exposure, and nanoparticle chemistry, size, shape, agglomeration state, and electromagnetic properties. Animal and human studies show that inhaled nanoparticles are lessefficiently removed than larger particles by the macrophage clearance mechanisms in the lung,causing lung damage, and that nanoparticles can translocate through the circulatory, lymphatic, and nervous systems to many tissues and organs, including the brain.
The key to understanding the toxicity of nanoparticles is that their minute size, smaller than cells and cellular organelles, allows them to penetrate these basic biological structures, disrupting their normal function. Examples of toxic effects include tissue inflammation, and altered cellular redox balance toward oxidation, causing abnormal function or cell death. http://arxiv.org/ftp/arxiv/papers/0801/0801.3280.pdf
Some NPs happen to be toxic to biological systems, others are relatively benign, while others confer health benefits. As current knowledge of the toxicology of ‘bulk’ materials may not suffice in reliably predicting toxic forms of nanoparticles, ongoing and expanded study of ‘nanotoxicity’ will be necessary. For nanotechnologies with clearly associated health risks, intelligent design of materials and devices is needed to derive the benefits of these new technologies while limiting adverse health impacts.
Human skin, lungs, and the gastro-intestinal tract are in constant contact with the environment. While the skin is generally an effective barrier to foreign substances, the lungs and gastro-intestinal tract are more vulnerable. These three ways are the most likely points of entry for natural or anthropogenic nanoparticles. Injections and implants are other possible routes of exposure, primarily limited to engineered materials. Due to their small size, nanoparticles can translocate from these entry portals into the circulatory and lymphatic systems, and ultimately to body tissues and organs. Some nanoparticles, depending on their composition and size, can produce irreversible damage to cells by oxidative stress or/and organelle injury.
Are they biocompatible? Do the nanoparticles enter the lymphatic and circulatory systems? If not, do they accumulate in the skin and what are the long-term effects of accumulation? Do they produce inflammation? If they enter the lymphatic and circulatory system, is the amount significant? What are the long-term effects of this uptake? Related to the beneficial antioxidant properties of some nanomaterials, long-term effect need to be studied, in addition to the short-term antioxidant effect. What is the long-
term fate of these nanoparticles? Are they stored in the skin? Do they enter circulation? What happens when the nanoparticles undergo chemical reactions and lose their antioxidant properties?
For a full view of the questions needed to be addressed please visit. http://bdds.fudan.edu.cn/…/fdfa2aa9-df2b-4c9f-a2a5-a33ee29acb76.pdf
The answers to some of these questions are known, and will be presented in the chapter dedicated to nanoparticles toxicity, however most of the remaining questions still remain unanswered.
The immunostimulatory properties of nanoparticles discussed here include their antigenicity, adjuvant properties, inflammatory responses and the mechanisms through which nanoparticles are recognized by the immune system. Since this is a very complicated mechanism , the factors affecting the immune response are summaried here:
Size
- Th1/Th2 stimulation
- Adjuvent properties
- Internalization/phagocytic uptake
- Hapten properties
- Particle clearance
Charge
- Toxicity to immune cells
- Binding plasma proteins
- Particle clearance
- Immune cell stimulation
Hydrophobicity
- Interaction with plasma proteins
- Internalization/phagocytic uptake
- Immune cell stimulation
- Particle clearance
Targeting
- Immunogenicity
For example: In general, cationic (positively-charged) particles are more likely to induce inflammatory reactions than anionic (negativelycharged) and neutral species. For example, anionic generation- 4.5 PAMAM dendrimers did not cause human leukocytes (white blood cells) to secrete cytokines53 but cationic liposomes induced secretion of cytokines such as TNF, IL-12 and IFNγ. Systemic administration of another cationic nanoliposome alone or in combination with bacterial DNA did not induce cytokine production but increased the expression of DC surface markers, CD80/CD86, which are important in the inflammatory response.
Trace impurities within the nanomaterial formulation can also frequently induce an inflammatory response. Early studies suggest that carbon nanotubes induce inflammatory reactions, but a more recent study shows that they don’t when they are purified.
Another consideration in the inflammatory response is maintaining the Th1/Th2 response — the inflammatory reaction. triggered by Th cells that direct and activate other immune cells such as B and T cells and macrophages to secrete different cytokines. This response is important for protecting against cancer cells and pathogens and to avoid hypersensitivity (undesirable and exaggerated immune response) reactions. Several studies have addressed the influence of nanoparticles on Th1 and Th2 responses. Large (>1 μm) industrialized particles induced the Th1 response, whereas smaller ones (<500 nm) were associated with Th2.
In contrast, some small engineered nanoparticles such as 500 nm PLGA, 270 nm PLGA65, 80 nm and 100 nm nanoemulsions, 95 nm and 112 nm PEG–PHDA nanoparticles, and 123 nm dendrosome induced the Th1 response, while 5mn 5th generation PAMAM dendrimers didn’t cause overall inflammatory reaction in vivo but weakly induced Th2 cytokine production.
Therefore, more structure–activity relationship studies are required to understand how size, surface modification and charge of engineered particles influence the Th1/Th2 balance
Particle stimulation of adaptive (acquired) immunity has also been described. For example, small (<100 nm) polystyrene particles promoted CD8 and CD4 T-cell responses and were associated with higher antibody levels than larger (>500 nm) particles. Understanding the mechanisms requires further investigation, and is important for nanovaccine formulation development.
Phagosome-mediated processing and presentation of nanoparticles may differ from that of ‘canonical’ antigens. Certain biodegradable nanoparticles can be taken up through conventional pathogen-specific routes and can stimulate inflammatory reactions just like pathogens
More mechanistic studies are required to understand how the immune system manages non-biodegradable components of nanoparticles (for example, metallic cores). Many questions remain regarding processing of multi-component and multi functional nanoparticles. Are the individual components (the coating, core, and so on) stable inside the phagosome or do they separate? Are the biodegradable and non-biodegradable components processed together or individually?
Immunotoxicological analysis of new molecular entities is not a straightforward process, and there is no universal guide for immunotoxicity.
Conclusions:
The mechanism of cellular uptake of nanoparticles and the biodistribution depend on the physico-chemical properties of the particles and in particular on their surface characteristics. Moreover, as particles are mainly recognized and engulfed by immune cells special attention should be paid to nano–immuno interactions. It is also important to use primary cells for testing of the biocompatibility of nanoparticles, as they are closer to the in vivo situation when compared to transformed cell lines.
Understanding the unique characteristics of engineered nanomaterials and their interactions with biological systems is key to the safe implementation of these materials in novel biomedical diagnostics and therapeutics.
The main challenge in immunological studies of nanomaterials is choosing an experimental approach that is free of falsepositive or false-negative readouts. 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. For example, many nanoparticles absorb in the UV–Vis range and some particles may catalyse enzyme reactions or quench fluorescent dyes commonly used as detection reagents in various end-point or kinetic assays. These and other methodological
challenges in preclinical evaluation of nanoparticles are reviewed in detail elsewhere.
Both ‘classical’ and novel imunotoxicological assessments of nanomaterials clearly need a scrupulous stepwise validation, standardization, and demonstration of their physiological relevance.
Industry, academics, and federal agencies are now collaborating to identify critical parameters in nanoparticles characterization and to establish acceptance criteria for nanomaterial-specific assays.
Ref.
1.Cristina Buzea, Ivan. I. Pacheco Blandino, and Kevin Robbie. Nanomaterials and nanoparticles:Sources and toxicity. Biointerphases vol. 2, issue 4 (2007) pages MR17 – MR172 http://arxiv.org/ftp/arxiv/papers/0801/0801.3280.pdf
2. Marina A. Dobrovolskaia* and Scott E. McNeil. Immunological properties of engineered nanomaterials. Nature Nanotechnology 2007; 2; 469-479. http:// bdds.fudan.edu.cn/…/fdfa2aa9-df2b-4c9f-a2a5-a33ee29acb76.pdf
3. Kunzmanna A, Anderssonb B, Thurnherrc T, Krugc H, Scheyniusb A, Fadeel B. Toxicology of engineered nanomaterials: Focus on biocompatibility, biodistribution and biodegradation. Biochimica et Biophysica Acta (BBA) – General Subjects. Volume 1810, Issue 3, March 2011, Pages 361–373 http://www.sciencedirect.com/science/article/pii/S0304416510001145
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