Nanomedicines and Bacteriophages
Bacteriophages are viruses that target bacteria, and exist at the nanoscale, typically around 20–200 nanometers. They generally target single species of bacteria and are well known as an alternative to antibiotics for antibacterial treatment. In recent years, bacteriophages have been used in tissue engineering, cancer treatment, and other fields of bioengineering. This can be done by genetically engineering a phage using a programmable endonuclease such as Crispr Cas-9, or by attaching other enzymes to the capsid (the head) and removing other ligaments of the virus using genetic engineering. For more info, check out my article.
Nanomedicine is the use of particles at the nanoscale to build elaborate systems that can aid in drug delivery, tissue engineering, as well as genetic engineering. Nanoparticles have been engineered to carry CRISPR-cas9, and there are also nano-bots being developed as an agent to detect pathogens. The advantages of using nanotech include the increased surface area to volume ratio, as well as the ability to bypass tissue walls. In short, nanomedicine typically uses very small particles to pass through the barriers of the body and examine small proteins and DNA. Here are a few examples of the applications of nanotechnology in medicine:
Alzheimer’s
Alzheimer’s has no cure, and most therapies only offer temporary relief. Research has found the abnormalities of the brain, such as neuro-plaque and neurofibrillary tangles, are connected to a protein fragment called Ab. neuro-plaque is generally a deposit of the protein, though they are the cause of neurofibrillary tangles when exposed to it. Pharmaceuticals can be used to treat Alzheimer's, except that 98% of drugs can not bypass the Blood-brain barrier, the fence of cells that prevents harmful chemicals from reaching the brain. Since signs of Alzheimer’s are detectable long before symptoms arise, Alzheimer's is very hard to detect.
Nanoparticles are particularly useful because they can bypass the blood-brain barrier or the barrier of cells that prevents harmful materials from reaching the brain. Nanoparticles have a certain trait called multi-functionalization, which allows them to mimic certain physiological processes. by attaching pharmaceuticals and biologicals (genes and whatnot), nanoparticles can ensure over 98% of the remedy reaches the patient.
Nanoparticles are still developing, to the point of developing ‘intelligent’ Nanoparticles that can target a specific region of the brain and provide in vivo imaging. This requires the use of biosensors and other particles to help the NP reach its target.
Cancer
Because of the magnetic traits of nanoparticles, several imaging agents can be attached to nanoparticles to help aid in the high-resolution detection of tumor biomarkers. Better yet, the nanoparticles can deliver pharmaceuticals or can be triggered to radiate heat in the form of x-ray, or light, which destroys cancer cells. Nanomedicine allows for much more localized delivery.
Antimicrobial treatment
Nanoparticles can be used to deliver antimicrobial peptides to target bacteria strains. Nanoparticles can also allow for better imaging. Nanostructures can be built to be eventually inhalable to the patient and allow more efficient localized treatment.
Atherosclerosis
Atherosclerosis is a disease that results from the clotting of the inner walls of the arteries, or the endothelium. Because of the high surface area to volume ratio, nanoparticles can have multiple therapeutic drugs as well as other attachments, and through ligand conjugation, can help nanoparticles to target the specific cells within the artery. this technology is still in development, as proper localization to minimize nanotoxicity is needed. It is important that drug-eluting stents, or medicines that release over time, are formed efficiently with nanotechnology to prevent scarring and ensure good blood flow. In short, this technology can reduce restenosis, and thrombosis, or prevents blood clots that narrow the walls of the vessel.
Summary
In short, nanoparticles have a high surface area to volume ratio and can bypass the walls of tissue because of their size and their ability to mimic physiological processes. This allows for localized targeting of diseases, whether through delivering therapeutic agents, imaging, or targeting certain cells.
How Nanoparticles are Formed
Typically, nanoparticles can be formed from the top-down process, or the bottom-up process
Top-down: Take larger particles, and break them down into smaller nanostructures through a controlled assembly process. This process is best for electronic circuits.
Bottom-Up: Take atoms, and form specific structures by arranging those atoms. The bottom route is best to form specific nanostructures and is done by converting gases into liquid droplets and then condensing those gases, which cause them to grow. This is also how nanoparticles can form within the atmosphere, through volcanic plumes. This process is the main industrial process to produce nanoparticle metals, oxides, polymers, and semiconductors, and form shapes like spheres.
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What are the traits that can be made from nanoparticles?
Fluorescent nanoparticles: nanoparticles that can exhibit light when exposed to a certain light can be formed from calcium phosphate nanoparticles. A particularly notable fluorescent nanoparticle is the quantum dot, which is a crystal nanoparticle composed of several thousand atoms and is luminescent due to quantum confinement and the altered electric density of the state. In short, it reflects light differently. Quantum dots have been used in TVs before and provided enhanced saturation. Gold nanoparticles also exhibit low fluorescence and typically provide imaging for specific cells.
Radioactive nanoparticles: can be formed from gold nanoparticles, and is especially useful for cancer imaging. Radiated heat can also be used to destroy cancer cells, and the radiation allows the specific area to be detected much more easily.
Paramagnetic: or just magnetic attraction to a lesser degree from two or more unpaired electrons to an external magnetic field. Certain paramagnetic nanoparticles include Barium Ferrite and lanthanides are known for their practically high magnetic characteristic, with less nanotoxicity, and are used as contrast agents for magnetic resonance imaging. these particles can be created by coprecipitating iron.
Superparamagnetic: A super magnetic nanoparticle has a much stronger magnetic attraction. These nanoparticles are formed from iron oxides (SPIONS) , cobalt, and Nickel. Super magnetic particles are useful in ensuring uncoated materials attached to the nanoparticle do not aggregate and ensure colloidal stability. in general, magnetic targeting by using SPIONS is an efficient method to target for drug delivery if there is a strong external magnetic field, where the therapeutics can bind to the receptors of cells when in proximity.
Liposomes: a liposome is a tiny vesicle that is made out of the components used to create a cell membrane, and these nanoparticles can hold various items, which can be useful to drug delivery. the membrane is made of phospholipids with a hydrophilic head and a hydrophobic tail. these have been used to interact with cells, though they present disadvantages after long periods of use.
Kosi Gramatikoff
These are the primary types of nanoparticles used for biomedical applications.
Viruses and Nanomaterials
Phages and nanoparticles are at the same scale and have very similar properties, such as multi-functionalization, as well as the ability to attach other enzymes to themselves whether by using the capsid capture moieties or magnetically.
Here are some similarities in treatments:
- Both Phages and nanoparticles can target specific cells (phages require external genetic engineering)
- Both Phages and nanoparticles have been used for drug delivery
- Both have been used for antibacterial treatment
- Both can be used to produce 3d scaffolds
- Both can carry CRISPR-CAS9 (still in development for nanotechnology but is possible.)
Here are some current challenges:
- Both Phages and nanoparticles need to be further localized efficiently. nanoparticles still need to have external biosensors in order to better locate their target. Bacteriophages and the genetic insertion of adenoviral material (the flu) is very risky for cell targeting, and there may be abnormalities
- Nanoparticles have a risk for bioaccumulation, as well as biotoxicity, and bacteriophages can trigger an immune response that can be fatal, cause unknown.
Since each technology has similar characteristics, some projects have utilized both nanotechnology and phages to see how they can optimize certain treatments. It is noted that different species of phages will be used for each project, primarily filamentous phages due to their length and structure.
Tissue Engineering:
Phages have been attached to 3d scaffolds and have been used to form 3d scaffolds using filamentous phages. Scaffolds have also been formed using carbon nanotubes, another form of nanomedicine that is shaped like a tube. It is incredibly strong and shares the same characteristics as other nanoparticles. Phage Capsids can be attached to a 3d printed mineral carbon nanotube to optimize the structure, with growth enzymes and peptides attached to the capsid. from there, the cellular structure of the tissue would develop, and peptides would help catalyze osteogenesis (bone formation) and vascularization (heart formation).
The formation of hydrogels, which are 3d networks from hydrophilic polymers which maintain their structure through physical crosslinking of individual polymer chains, are important for tissue scaffolding and serve as artificial collagen to keep cells communicating. Hydrogels can be formed from phage components by attaching alginates (algae products) and cross-linking other particles. Phages can also be used to create an effective biosensor. Using the polypeptides displayed on the surface of filamentous phage, it can create a biosensor that can detect bacteria by displaying the antigens of the bacteria, as well as using antibodies attached to gold nanoparticles.
The Material Science of Phages
While the primary use of bacteriophages is primarily derived around its existing function as a virus or a vector, there are a variety of ways in which the composition of a virus can be beneficial in areas such as micro-robotics and targeted therapy. For example. The coat proteins of phages are used to bind inorganic materials such as gold nanoparticles, nanotubes, powellite (CaO-MoO3), and lead for nanowires. As mentioned before, the structure of the virus can be used to form scaffolds. There are several considerations before actually beginning the process of engineering a scaffold or constructing a nanostructure, the main component being capsid stability.
Capsid stability refers to the resistance and solubility of the capsid, basically how strong it is. Each species of phage has a very different resistance to temperature, Ph, and solvents. Remember that the capsid is the head of the virus that contains a library of polypeptides.
The main aspects of materials science with bacteriophages include the ability to detect bacteria, which useful for molecular sensing, the advantages of the ease of genetic modification of phages, and using them to produce scaffolds, which can be used to create other products. In short, using phages and pairing them with abiotic nanoparticles provides advantages in certain applications.
Soft Material Science:
Phages are technically soft materials and can be formed into different structures. Studies have shown that when introduced to increased concentration of solvents, that phages, specifically rod-shaped filamentous phages, can form crystalline structures as well as other structures in high concentration. This contributes heavily to the research of liquid diffusion. To elaborate, Brownian motion is the idea that particles move erratically, and the diffusion equation created by Einstein and Smoluchowski can estimate the mean distance and time of a molecule in certain conditions (equation). However, Most macromolecules, including lipids and sugars, do not obey these models. By using phages, there is an accurate crowding agent that provides an accurate model of diffusion within a selected subsystem.
Einstein and Smoluchowski’s equation: D = λ2/2τ
Original study here: A represents the formation of the crystalline structure of rod-like phages. B, C, and D all represent different images of the crystalline structure, examining a blend between isotropic and nematic phase in B, and examining the high-density condensation of phages in D.
Antibacterial treatment:
While Phages are known for their direct antibacterial treatment, viral biomaterials can also be paired with nanotechnology to form nanostructures to combat and target bacteria like wound dressings, packaging, and membranes for water treatment, which can reduce the risk of infection. This is done by combining phages with alginates, natural polymers, and collagen fibers, and can even form an edible Phage antibacterial!
Phage virions can also help stabilize gold nanoparticles, In one process, a T4 phage was oriented to the external electric field by using a dipole moment (separation of charges). This allowed for the protein binding receptors to show on the exterior, allowing interactions between the nanoparticle and the bacteria.
Phages can also be used as biosensors as part of nanoparticles, and there are two main methods. One of which is to attach a probe (a protein that can detect the bacterial surface), which is fast, but not as efficient in detecting bacteria.
In the second method, an analytical signal to detect more bacteria is generated after the invasion and uses the bacteria’s metabolites, progeny virions, and reporter gene products to detect more bacteria by using the genetically modified phage probe. This process is much more efficient, but requires more time, going over an hour to produce efficient results.
Electro-phages
Phages can actually be used as batteries, and in 2006, the M13 phage was used as a template for cobalt oxide nanowires. This template was also used to create a sodium-based battery by synthesizing a triferrous tetrapropylene oxide (Fe3PO4) cathode and using phage binding peptides on the single wall carbon nanotube to make a cathode. This battery can release around 166 milliamps per hour per 10 hours, and the template has been used for a variety of other nanostructures. Now, that might seem bad, except that this battery exists at the nanoscale.
Furthermore, Phage capsids have piezoelectric properties, which means that when pressure is applied to the head of a phage, it generates electricity. This is because there is a dipole (separation of charges) between both sides of the capsid, with the positive amino on one side, while negative charge ions on the other side. Note that this is observed within a specific protein coat (PVII). It has been hypothesized that if you form a wall of condensed phages, it can form an electricity generator.
Conclusion
Nanomedicines and bacteriophages are not separate entities, and each can be used to solve the major issues that are obstacles for nanomedicines. Secondly, that phages are important in the development of biosensors and other materials necessary to improve the development of intelligent nanostructures, meaning that they localize their target without the disadvantages of nanotoxicity of metals.
Sources
https://www.nature.com/articles/s41467-019-10986-4
https://pubs.rsc.org/en/content/articlehtml/2015/cs/c4cs00392f
https://nanografi.com/blog/paramagnetic-nanoparticles/
https://nanoscalereslett.springeropen.com/articles/10.1186/1556-276X-7-144
https://www.cd-bioparticles.com/t/Properties-and-Applications-of-Magnetic-Nanoparticles_55.html
https://www.frontiersin.org/articles/10.3389/fchem.2018.00619/full
