The healthcare field, for example, utilises nanomaterials in a variety of ways, with one major use being drug delivery. One example of this process is whereby nanoparticles are being developed to assist the transportation of chemotherapy drugs directly to cancerous growths, as well as to deliver drugs to areas of arteries that are damaged in order to fight cardiovascular disease. Carbon nanotubes are also being developed in order to be used in processes such as the addition of antibodies to the nanotubes to create bacteria sensors.
In aerospace, carbon nanotubes can be used in the morphing of aircraft wings. The nanotubes are used in a composite form to bend in response to the application of an electric voltage. Elsewhere, environmental preservation processes make use of nanomaterials too - in this case, nanowires. Applications are being developed to use the nanowires - zinc oxide nanowires - in flexible solar cells as well as to play a role in the treatment of polluted water.
In the cosmetics industry, mineral nanoparticles — such as titanium oxide — are used in sunscreen, due to the poor stability that conventional chemical UV protection offers in the long-term. Just as the bulk material would, titanium oxide nanoparticles are able to provide improved UV protection while also having the added advantage of removing the cosmetically unappealing whitening associated with sunscreen in their nano-form.
The sports industry has been producing baseball bats that have been made with carbon nanotubes, making the bats lighter and therefore improving their performance. Further use of nanomaterials in this industry can be identified in the use of antimicrobial nanotechnology in items such as the towels and mats used by sportspeople, in order to prevent illnesses caused by bacteria. Macromolecules , 49 22 , Macromolecules , 49 21 , Macromolecules , 49 19 , Boles , Michael Engel , and Dmitri V.
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Smith , Bradley D. Olsen , and Wei-Ren Chen. ACS Macro Letters , 4 2 , Likhtman , and Bradley D. Cheng , and Tianbo Liu. Macromolecules , 48 3 , Cheng , and Xue-Hui Dong. Journal of the American Chemical Society , 4 , The Journal of Physical Chemistry C , 1 , Macromolecules , 47 24 , Cheng , and Yiwen Li. ACS Macro Letters , 3 9 , Macromolecules , 47 17 , Langmuir , 30 32 , Journal of the American Chemical Society , 30 , Macromolecules , 47 14 , Macromolecules , 47 13 , Jacobs , Juan L.
The nanoparticle is about times larger than the zinc atom. Some of the properties of nanoparticles depend on their large surface area to volume ratios. For solid substances, the smaller its particles , the greater the surface area to volume ratio. A cube-shaped nanoparticle has sides of 10 nm. Calculate its surface area to volume ratio. In general, diffusion and NP size are inversely correlated [ 26 ]. Small size NPs can diffuse freely across tumoral tissue and present a widespread distribution within normal tissues.
However, small NPs can easily and quickly clear out. Size is important for other purposes such as when NPs are applied as imaging agents helping to distinguish normal and pathological tissues because they appear only on the tumor periphery thanks to their bigger size.
As previously discussed, the biomolecules adsorption onto the NP surface is directly related with their opsonization and clearance capacity. Therefore, it is related with the blood concentration along with time.
In general, NPs are eliminated from the human body by renal and hepatobiliary routes and need to be done for clinical approval in a reasonable timeframe.
Then, drug conjugated NPs must be designed to avoid quick clearance and long period of body maintenance. As is expected, surface chemistry, shape, and NP size influence elimination. For example, surface chemistry is quite critical in the clearance efficiency -even for small NPs- and polyethylene glycol PEG coating promotes more efficient hepatobiliary clearance [ 27 ].
Another point is the NP size. The hydrodynamic NP size has a strong influence on the renal clearance, where the glomerular pores are a physical barrier [ 23 , 28 ]. Although NPs in biological systems are surrounded by large quantities of biomolecules, depending on the different factors that characterize the biological environment. The NP promotes multiple and different interactions. Multifunctional NPs as nanomedicines see Figure 2 are embedded in human proximal fluids, inside cells, and inside culture media among others [ 29 ].
This implies a huge variety of different microenvironments with additional challenges for the design and development of NPs suitable to be functional in all kinds of conditions. However, depending on the medium conditions like pH [ 30 ], ionic strength, oxygen levels, organic matter, etc. This is especially relevant because it may be the origin of a heterogeneous morphology, which might be correlated with a lack of stability and immuno-biocompatibility of these nanomaterials [ 33 ].
NP aggregation and agglomeration have been recognized to affect cellular uptake and even induce potential toxicity based on the nanoparticle composition and the cell type [ 34 ].
Aggregation and agglomeration effects are often used in nanotechnology, but both terms are commonly mistaken.
Aggregation indicates strongly bonded or fused particles and it occurs when the Van der Waals attractive forces between particles are greater than the electrostatic repulsive forces produced by the nanostructure surface [ 34 , 35 ]. On the other hand, agglomeration indicates more weakly bonded particles and it does not require a definite pattern, shape, and size [ 35 ].
Pellegrino F. Zook M. They used this method to show how silver NP agglomeration affects hemolytic activity. The main factors that will determine the type of interactions between NPs are: the complementarity between nanomaterials and their distance and geometry [ 38 ]. In addition, it is also essential to know what the main interactions drivers are in an NP assembly. For example, Van der Waals forces form nanocrystal superlattice membranes, electrostatic interactions obtain colloidal dimers, and magnetic interactions where iron oxide NPs coated with azobenzene-terminated catechol ligands self-assemble by UV-light-induced, or even molecular force [ 38 ].
An example that demonstrates the importance of the complementarity between the materials and the influence of the forces used in such an interaction is one discussed by Pileni and co-workers. They stress the difference of using octanoic and dodecanoic acids as organic ligands in magnemite NPs in the absence only with dipolar forces between the magnetic nanoparticles and the presence of Van der Waals interactions, when the distance is small [ 39 , 40 ].
On the other hand, an interaction between molecules on surfaces is highly dependent on surface functionalization Figure 3. This implies the presence of reactive chemical moieties on the surface being homo-functional or hetero-functional depending on whether there is only one chemical group on the surface or whether different chemical reactive groups co-exist [ 41 ].
Schematic representation of the strategy to couple nanoparticles and biomolecules or other nanoparticles. Due to their composition and structure, the surface might not allow different types of interactions.
Thus, for example, circulatory cells are covered by a lipid bilayer with proteins and polysaccharides that, depending on the NP exposed groups, will favor one type of interaction mechanism [ 42 ]. Another example includes the proteins affected by their molecular weight, charge greater adsorption near the isoelectric pH , or its stability that influences the number of binding points [ 43 ]. A soft protein layer has a low structural stability and a greater number of active centers to interact with, besides other influencing physicochemical factors on the surface i.
Another remarkable feature is the size, including those with a size comparable to that of the NP, which will be more easily adsorbed. Lastly, it is not only necessary to consider the concentration or size of NPs, but also the species and quantity of resulting products from chemical interactions between NPs.
There is a wide-open variety of biomolecules, which could interact directly onto the NPs surface or through other biomolecules coating the NPs surface Figure 2. These layers of coating biomolecules are directly related with the type of organism, biological fluid, cells, etc.
According to the literature, the most relevant interacting biomolecules to the NP surfaces are proteins and nucleic acids [ 44 ]. In addition, the proteins are critical on the immune-biocompatibility of the nanomaterials. Nucleic acids have many different applications as a consequence of its physicochemical stability, mechanical rigidity, easy accessibility, and its high specificity of base pairing, which results in a suitable receptor for molecular nano-construction [ 46 ].
Regarding interactions with human biomolecules, two factors must be considered in the description of the interaction [ 23 ].
The first one is that NPs in biological systems are surrounded by multiple potentially interacting biomolecules that may modify and saturate their surface. Therefore, custom modified NPs are the ones that may interact specifically with the biomolecules of interest later on. The second factor is NP entering pathways into the human body. This depends on the way it can influence the force of the interaction. For example, NPs entering by inhalation strongly interact with the pulmonary system proteins and phospholipids.
Two immobilization mechanisms have been studied through an interaction with different types of biomolecules [ 45 ]: by simple absorption or by chemical linkages.
The immobilization of enzymes on NPs through adsorption is a very useful method because it takes place through non-covalent forces hydrogen bonding, ionic interactions, and Van der Waal forces , mainly through negatively charged phosphate groups and hydrophobic moieties not disturbing the initial structure of the enzyme or its active site. Immobilization through chemical linkages may lead to the immobilization of biomolecules on a biocompatible matrix, such as within phospholipid bilayers, not interacting with the native structure of the biomolecule and altering its biological activity.
We also find two other types of interaction mechanisms with cells: ligand-receptor interaction and chemical conjugation [ 47 ]. An example of the first interaction method is the NP surface functionalization with a receptor, such as streptavidin-biotin. Its non-covalent interaction results in a greater bond strength, which provides resistance to pH, temperature variations, and denaturants. In addition, they have a greater binding affinity to cells. Chemical conjugation simply consists of the coupling of functional groups such as thiol groups to the NP surface, which favors subsequent binding to the cell and, in turn, reduces the toxicity of this interaction.
A disadvantage of this method is that, in terms of biomedical applications, the covalent binding of the drug to the NP restricts its efficient release, which limits its effectiveness. NPs undergo different changes in a concrete environment such as the generation of a coating protein corona once plasma proteins are adsorbed on its surface. Therefore, it is necessary to study the NP states and characteristics prior to interaction assays [ 48 ].
Many NP-based investigations focus on issues affecting NP characteristics and, subsequently, their impact on cellular internalization and biodistribution. Centi J. GNRs are gold NPs that are elongated along one direction with characteristic optical properties, which depend on the particle size and shape [ 51 ].
They are attractive in biomedical optics because of their special and intense absorption band near infrared light — nm. Other important features of GNRs include their coating, which are crucial for their biological applications, i.
In addition, their shape and size are critical for modulating cellular penetration, intracellular localization, and bio-distribution. GNRs may become coated with, which may modify their conformation and cause a loss of their biological activity. Bovine Serum Albumin has been chosen as a protein target to investigate NPs coating with polyethylene glycol NP-PEG exposition to biological fluids because it is the most abundant protein in the blood and can transport metal compounds.
The Tatini J. The physicochemical properties of NPs Figure 4 , some already commented represent their identity and influence on the synthetic moieties incorporated [ 52 ] among all including size, shape, surface, coating and morphology, surface charge, solubility, chemical composition, crystalline structure, and, lastly, the agglomeration status.
These properties will also play a characteristic role in relevant mechanisms such as cellular biocompatibility studies. Schematic illustration of the main physicochemical properties of nanoparticles governing interaction mechanisms in biological systems. Size plays an important role in interactions with the biological system and many biological NP-related mechanisms such as cellular uptake and particle processing efficiency in the endocytic path depending on it [ 53 ]. Additionally, the ion release rate, the smaller size, the faster release rate, and the interactions with cell membranes [ 54 ].
In general, there is a size-dependent NP toxicity and, therefore, their ability to enter in the human system. Therefore, their contacting surface will increase, which makes penetration into the body easier and increases their toxic effect [ 54 ].
NP sizes less than 50 nm through intravenous injection connect to all tissues faster and exert stronger toxic effects [ 55 ]. NP sizes greater than 6 nm cannot be excreted by the kindness and accumulate in specific organs [ 57 ]. For example, cadmium selenide quantum dots contact stays in the tissue, which causes hepatotoxicity [ 58 ].
Sonavane et al. They observed that smaller ones stayed longer in the bloodstream and accumulated to a greater extent in all organs [ 59 ]. Shape is a physicochemical property that influences the toxicity of materials [ 60 ]. NPs have different shapes and structures such as tubes, fibers, spheres, and planes. Therefore, it may also influence their endocytosis process, internalization, bio-distribution, and elimination.
For example, spherical nanoparticles of similar size have been found to be easier and faster internalized by endocytosis than rod-shaped nanoparticles, which is explained by a greater membrane wrapping time required for the elongated particles. In addition, the spherical ones are relatively less toxic [ 21 ].
NP-cell interactions and solubility depend on the nature of the NP surface [ 61 ]. NP surface coating alteration can modify their magnetic, electrical, chemical, and optical properties, which affects their cytotoxic properties by influencing pharmacokinetics, distribution, accumulation, and toxicity [ 62 ]. Surface charges determine the response of the organism to changes in NP shape and size in the form of cellular accumulation, called colloidal behavior [ 63 ].
The effect of surface chemistry on NPs affects absorption [ 64 ], colloidal behavior, plasma protein binding [ 65 ], and crossing the blood-brain barrier [ 66 ]. The NP cytotoxicity increased with an increase in surface charge [ 67 ]. This suggests that higher positive charges get greater cell electrostatic interactions and, consequently, greater endocytic uptake.
However, the uptake of positively charged NPs may produce higher toxicity than negatively charged [ 68 ]. NPs with a positively charged surface tended to accumulate more in tumors than negatively charged ones most likely because positively charged density can be more easily separated in the interstitial space and, therefore, internalized by tumor cells [ 56 ].
Surface chemical modification is an important strategy utilized in biomedical applications to decreases toxicity, increase stability, and to control and modulate cellular internalization [ 69 ]. Surface functionalization is predominantly comprised by polyethylene glycol PEG , the negative carboxyl group, and neutral groups like hydroxyl group, and amine groups [ 67 ]. For example, the NP surface can be functionalized by proper polymers such as PEG to reduce non-specific binding and to get specific binding to cell receptors [ 70 ].
Hydrophobicity is another key factor that also affects pharmacokinetics and bio-distribution [ 70 ]. NPs with a 2more hydrophobic surface tend to absorb plasma proteins, which reduces the time spent in the bloodstream [ 71 ].
A computer molecular simulation study revealed that the surface membrane uptake of hydrophobic C60 agglomerates is thermodynamically favored than semi-hydrophilic ones because of the interior membrane hydrophobicity space in cells [ 72 ]. NPs chemistry is another fundamental factor contributing to cell interactions. Regarding particle chemistry, Griffitt et al. In addition to these characteristic properties of NPs, their state of aggregation must also be taken into account.
Aggregation depends on the surface load, material type, and size, among other factors. It has been shown that higher NP concentrations result in higher aggregation and, consequently, lower toxicity [ 74 ].
Accordingly, macrophages remove large particles more efficiently and easily than small ones, which evade this defense mechanism more easily [ 75 ]. Since NPs are injected into the bloodstream, they are exposed to a large amount of biomolecules that form a corona around them [ 76 ] Figure 5. Protein corona is mainly composed of proteins with different affinity interactions: immunoglobulin G, serum albumin, fibrinogen, clusterin, and apolipoproteins [ 77 ]. Therefore, NPs experiment changes in their physicochemical properties and their biological identity once the protein corona is formed.
Therefore, in order to know the possible adverse effects of the physicochemical, kinetic, dynamic, and thermodynamic interactions of NPs, the characterization of these NP-protein interactions has become one of the main challenges of nanomedicine. Schematic protein corona formation. Then, the nanoparticle is coated with proteins, which are abundant and highly mobile II.
Lastly, the protein species are exchanged over time, which results in hard corona of strongly bound proteins III. When NPs are incubated in a biological medium, a competitive dynamic process between soluble biomolecules and surface take place to form the protein corona.
This process is based on the affinity adsorption of proteins on NP surfaces and on protein-protein interactions. According to the Vroman effect [ 78 ], the first are bound to NP surface proteins with a high concentration and low affinity and then are gradually replaced by higher affinity proteins present in low concentrations.
The protein corona is classified into hard and soft depending on the duration of protein exchanges. Hard corona is a bound layer of proteins with high affinity and long exchange time. Proteins of the hard corona form the closest layer to the NP surface, so they are susceptible to thermodynamically favorable conformational changes irreversible depending on the chemistry functionalization, the hydrophobicity or hydrophily, the nature of proximal biological fluid, and the temperature [ 79 ].
Soft corona is a low affinity layer of proteins with a fast exchange over time. A recent model [ 80 ] suggests that hard corona is bound in a hard way to the NP surface and the soft corona is not directly bound to the NP but with a certain low degree of biomolecule interactions.
As a result, the protein concentration, particle size, type of nanomaterial, and the surface properties are factors determining the layers of biomolecules and the protein corona density [ 81 ]. Depending on the type of administration routes, NPs are subjected to interactions with different kind of biomolecules [ 82 ].
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