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Nanomaterials are engineered structures with at least one dimension of 100 nanometers or less. These materials are increasingly being used for commercial purposes such as fillers, opacifiers, catalysts, semiconductors, cosmetics, microelectronics, and drug carriers. Materials in this size range may approach the length scale at which some specific physical or chemical interactions with their environment can occur. As a result, their properties differ substantially from those bulk materials of the same composition, allowing them to perform exceptional feats of conductivity, reactivity, and optical sensitivity. Possible undesirable results of these capabilities are harmful interactions with biological systems and the environment, with the potential to generate toxicity. The establishment of principles and test procedures to ensure safe manufacture and use of nanomaterials in the marketplace is urgently required and achievable.

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Toxic Potential of Materials at the Nanolevel

Although humans have been exposed to airborne nanosized particles (NSPs; < 100 nm) throughout their evolutionary stages, such exposure has increased dramatically over the last century due to anthropogenic sources. The rapidly developing field of nanotechnology is likely to become yet another source through inhalation, ingestion, skin uptake, and injection of engineered nanomaterials. Information about safety and potential hazards is urgently needed. Results of older bio-kinetic studies with NSPs and newer epidemiologic and toxicologic studies with airborne ultrafine particles can be viewed as the basis for the expanding field of nanotoxicology, which can be defined as safety evaluation of engineered nanostructures and nanodevices. Collectively, some emerging concepts of nanotoxicology can be identified from the results of these studies. When inhaled, specific sizes of NSPs are efficiently deposited by diffusional mechanisms in all regions of the respiratory tract. The small size facilitates uptake into cells and transcytosis across epithelial and endothelial cells into the blood and lymph circulation to reach potentially sensitive target sites such as bone marrow, lymph nodes, spleen, and heart. Access to the central nervous system and ganglia via translocation along axons and dendrites of neurons has also been observed. NSPs penetrating the skin distribute via uptake into lymphatic channels. Endocytosis and biokinetics are largely dependent on NSP surface chemistry (coating) and in vivo surface modifications. The greater surface area per mass compared with larger-sized particles of the same chemistry renders NSPs more active biologically. This activity includes a potential for inflammatory and pro-oxidant, but also antioxidant, activity, which can explain early findings showing mixed results in terms of toxicity of NSPs to environmentally relevant species. Evidence of mitochondrial distribution and oxidative stress response after NSP endocytosis points to a need for basic research on their interactions with subcellular structures. Additional considerations for assessing safety of engineered NSPs include careful selections of appropriate and relevant doses/concentrations, the likelihood of increased effects in a compromised organism, and also the benefits of possible desirable effects. An interdisciplinary team approach (e.g., toxicology, materials science, medicine, molecular biology, and bioinformatics, to name a few) is mandatory for nanotoxicology research to arrive at an appropriate risk assessment.

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Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles

Rapid growth in nanotechnology is increasing the likelihood of engineered nanomaterials coming into contact with humans and the environment. Nanoparticles interacting with proteins, membranes, cells, DNA and organelles establish a series of nanoparticle/biological interfaces that depend on colloidal forces as well as dynamic biophysicochemical interactions. These interactions lead to the formation of protein coronas, particle wrapping, intracellular uptake and biocatalytic processes that could have biocompatible or bioadverse outcomes. For their part, the biomolecules may induce phase transformations, free energy releases, restructuring and dissolution at the nanomaterial surface. Probing these various interfaces allows the development of predictive relationships between structure and activity that are determined by nanomaterial properties such as size, shape, surface chemistry, roughness and surface coatings. This knowledge is important from the perspective of safe use of nanomaterials.

Understanding biophysicochemical interactions at the nano–bio interface

Liposomes — microscopic phospholipid bubbles with a bilayered membrane structure — have received a lot of attention during the past 30 years as pharmaceutical carriers of great potential. More recently, many new developments have been seen in the area of liposomal drugs — from clinically approved products to new experimental applications, with gene delivery and cancer therapy still being the principal areas of interest. For further successful development of this field, promising trends must be identified and exploited, albeit with a clear understanding of the limitations of these approaches.

Recent advances with liposomes as pharmaceutical carriers.

Targeting of drugs

Intracellular transport is often accomplished by means of vesicular carriers that eventually deliver membrane proteins and lipids to target organelles by means of membrane fusion. The rudimentary knowledge of the mechanisms of membrane fusion and complexity of intracellular fusion systems, still validate the use of (semi-)artificial systems to advance this knowledge. One of the systems employed relies on the use of an amphipathic net-negatively charged peptide (WAE), consisting of only 11 amino acids [1]. Whereas the free peptide displays no significant fusion activity, membrane fusion is strongly promoted when the peptide is anchored to a liposomal membrane. Fusion is optimal at neurtal pH and occurs in essentially a non-leaky fashion. Structural studies, using Fourier transform infrared spectroscopy, and the application of various 11-mer WAE ' mutantsα revealed that-helicity, accomplished by peptide coupling, confers fusogenicity to WAE. Apart from fundamental aspects of the fusion event as such, this system also lead to the development of novel applications such as the delivery of membrane reconstituted proteins into cell-size giant unilamellar vesicles via WAE-mediated fusion. This procedure provides a valuable tool in structure/function studies of transmembrane proteins, as analyzed by single-molecule optical microscopic techniques [2]. Also, molecular insight into the mechanism of WAE-induced fusion has been instructive in interpreting structural details of the fusion of Golgi membranes, fusing with liposomes or among themselves, induced by the p97/p47 protein complex. Thus, we have demonstrated that the cytosolic ATPase p97, in association with its cofactor p47, suffices to mediate rapid membrane fusion [3]. P97/p47 particularly promotes fusion of phosphatidylethanolamine (DOPE)-containing vesicles, and data obtained in a pure Golgi system in which the PE pool was modulated, suggest that such a dependence also exists in situ. The specific inhibition of fusion by compounds that interfere with DOPEα s propensity to adopt the hexagonal (H II) phase indicates that the mechanism of fusion involves nonbilayer phase formation. Consistently, lysophosphatidylcholine inhibits p97/p47 induced fusion between the Golgi vesicles and the liposomes, implying that fusion proceeds according to a so-called

Dick Hoekstra

Papers

Targeting of drugs

On the mechanism of protein-induced membrane fusion: From model to biological membranes

Organelles in eukaryotic cells: Molecular structure and interactions

Membrane Flow, Lipid Sorting, and Cell Polarity: Role of a Subapical Compartment

Advances in Molecular and Cell Biology