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Nanosponges are a type of nanoparticle, often a synthesized carbon-containing polymer. They are porous in structure and can therefore be targeted to absorb small amounts of matter or toxin. Nanosponges are often used in medicine as drug delivery systems or as a way of damage control after a medical injury. They can also be used in environmental applications to clean up ecosystems by performing tasks like purifying water or metal deposits. Nanosponges can be found in nature but are more likely to be synthetically made and implemented for use.

History

Nanosponges were first referred to as “cyclodextrin nanosponges” by DeQuan Li and Min Ma in 1998. This term was used because there is a cross-linked β-cyclodextrin with organic diisocyanates. An insoluble network is present in this structure, which shows a high inclusion constant. These polymers are formed through the reaction of native cyclodextrins with a cross-linking agent, the latter influencing the behavior and properties of the entire unit.

Cyclodextrin nanosponges were not discovered to have potential in being drug carriers until work done by Trotta and colleagues. They performed syntheses of new kinds of cyclodextrin nanosponges that revealed many potential applications that had not been previously considered.

Mechanisms

Molecular cyclodextrin nanosponge structure

Structure

Cyclodextrins are a class of cyclic glucopyranose oligomers, with common structures of α, β, and γ. α-cyclodextrins comprise six glucopyranose units, β- cyclodextrins comprise seven, and γ comprise eight. Cyclodextrins are biological nanomaterials whose molecular structure greatly influences their supramolecular properties. To synthesize cyclodextrins, enzymatic action occurs on hydrolyzed starch.

Cyclodextrin nanosponges are made of a three dimensional cross-linked polymer network. They can be made with α, β, and γ cyclodextrins. The inclusion capacity and the solubilizing capacity of the nanosponges can be tuned according to how much of the cross-linking agent is used.

Functions

Cyclodextrins have a toroidal shape, which allows them to have a cavity inside which can fit other molecules. This useful structure allows them to act as drug carriers in the body, as long as the compounds to be delivered have compatible geometry and polarity with the cavity. To determine when these compounds are delivered, the structure of the cyclodextrin nanosponge can be modified to release its contents sooner or later. Several ligands can be conjugated on the surface of the nanosponge to determine where it will target in the body.

Natural versus Synthetic Nanosponges

How we are now mimicking them synthetically

Coatings (RBC & RBC-PL)

Common pathogens can be toxins that form pores in a cell membrane. These cells target red blood cells. When there are no red blood cells around, these toxins target platelets. Nanorobots with a coating similar to red blood cells and platelets exist, allowing them to be disguised as a red blood cell and/or platelet. These RBC-PL coated nanorobots display efficient propulsion in blood without apparent biofouling. Their movement mimics the movement of natural cells. This ability to blend in enhances their ability to bind to platelet-adhering pathogens. The increased binding ability helps the nanorobots more effectively neutralize toxins because a pathogen that targets these types of cells would be more likely to interact with the nanorobots. This, in turn, increases the amount of collisions and interactions between the nanorobots and the pathogens/toxins. The nanorobots help to absorb and remove the toxins and bacteria. Other functions of these nanorobots are the ability to neutralize cytolytic activity regardless of the molecular structure, enhancing mass transport, and they may also be able to fight auto-immune diseases. Having a natural coating on something synthetic allows the nanorobots to have the benefits of both natural and synthetic materials.

Environmental Application

Purification of Wastewater

Some nanosponges are made to be eco-friendly and have a high concentration of carboxyl groups. They are used to remove metal deposits in wastewater in the oceans, where organisms can absorb these deposits which leads to detrimental build up in their tissue. The concentration of heavy metals grows while going up the food chain as organisms eat other organisms. Being at the top of the food pyramid, humans are most at risk for the detrimental effects of these metals in our food. These effects include allergic reactions, insomnia, vision problems, and can be as extreme as to cause mental disability, dementia, and kidney disease. Unlike many organic pollutants, heavy metals can be removed and destroyed by using nanomaterials like nanosponges. These nanomaterials act as sustainable filtering materials by binding to metals and removing them from wastewater before they disperse into the ecosystem. Using nanosponges for this results in a higher efficiency and lower cost than alternative cleaning methods like ion exchange resins, activated carbon, or other biological agents. Porous materials produced from renewable and low cost sources, like cellulose, chitin, or starch, are one of the most promising classes of absorbents in terms of effectiveness. [add citations throughout this paragraph]

Cyclodextrins (CDs) and amylose are derived from starches and are well known for their peculiar structural features, which leads to complex properties. The internal cavities in these CDs allow sites for hydrophobic or very weakly hydrophilic molecules. In order to properly bind metal to these CDs, dextrins must be chemically changed by adding an acidic functional group . These functional groups are allowed to undergo deprotonation in an aqueous media so the reaction of these with the hydroxyl groups in dextrin allow negatively charged insoluble polymers to be created . These polymers are what are known as nanosponges for their porous characteristic and are able to bond to both organic molecules and metal deposits. These nanosponges can easily be separated from the water after cleaning through simple filtration since they are insoluble in all solvents.

One type of nanosponges begin researched are prepared with beta Cyclodextrins and a linear pea starch derivative called linecaps. Beta cyclodextrins are used due to low cost and medium sized pores allowing for a broad range of guest molecules to be collected. Additionally, it is favored over dextrin polymers as it can interact with transition metals also. Primary and secondary hydroxyl groups can act as coordination sites with some metal ions and CDs can coordinate more than one ion at a time. These two components are reacted with citric acid in water to create the nanosponges using sodium hypophosphate monohydrate as a catalyst for the reaction. These nanosponges were compared to the performance of nanosponges synthesized in the same manner substituting PDMA (pyromellitate substance) for citric acid.

A high number of crosslinks were introduced into the synthesis process in order to allow for a maximum amount of carboxyl groups. This allowed for a higher complexation ability of these nanosponges to other molecules. A high degree of cross linking generally lead to low swellable polymers which are more suited for water treatment as the water will not take up the space meant for metal waste and can more easily be filtered from water after cleaning. Higher contact time lead to higher efficiency of cleaning of nanosponges in wastewater.

It was found at high metal concentrations, pyromellitate was able to absorb more metal deposits. At low concentrations, the both performed near identical. However, in the presence of interfering sea water, citrate nanosponges were able to selectively absorb more metal than the PDMA nanosponges allowing it to be more effective in cleanup of metal from salt water. Although the research of these citric acid nanosponges is still undergoing revision and development, they show promise for being a sustainable way to clean metal deposits from the ecosystem.

Medical Applications

Drug delivery

Nanosponges are being researched to be used for drug delivery systems to treat cancer and infectious diseases. Although nanosponges are one three-thousandth the size of red blood cells they each can carry thousands of drug molecules. They can hide in the immune system where immune cells try to destroy and remove foreign material from the body. Particles coated with membranes from circulating red blood cells cannot be detected. Additionally, particles coated with membranes from circulating white blood cells or leukocytes avoid attack from macrophages.

Major concerns regarding recently developed chemical entities include pharmacokinetic issues as well as poor solubility in water and low bioavailability. These leads to obstacles when using conventional drug dosage forms. Nanosponges can conquer these problems as their porous structure allows them the unique capability to entrap both hydrophilic and hydrophobic drugs and release them in a highly predictable manor. These small sponges travel throughout the body until they reach the targeted site where they bind to the surface and perform controlled drug release. Nanosponge technology is widely explored for its use in drug delivery using oral, parenteral, and topical administration techniques. This may include substances such as antineoplastic agents, proteins and peptides, volatile oils, and genetic materials. These small sponges travel throughout the body until they reach the targeted site where they bind to the surface and perform controlled drug release. Potential applications in target site-specific drug delivery include the lungs, spleen, and liver.

Fight Antibiotic Resistance

Membrane-coated nanosponges could be used to fight antibiotic resistance because they trap and remove toxins from blood. Toxins that attack red blood cells will cling to nanosponges because the sponges are coated with living cells. The sponges absorb the toxins, so they can no longer harm the cells, and the toxins are taken to the liver and broken down.

Detoxification

A study was conducted to study nanosponges ability to absorb pore-forming toxin. Pore-forming toxins (PFTs) are the most common protein toxins found in nature. They disrupt cells by forming pores in cellular membranes which alter the permeability of the cells. Examples of this include bacterial infections and venom. The idea behind this study, was that by limiting PFTs the severity of bacterial infections may be able to be reduced.  The study was conducted using a nanosponge (polymeric core) wrapped in a natural red blood cell membrane bilayer. The polymeric core stabilizes the membrane shell and the membrane bilayer allows the nanosponge to absorb a wide range of PFTs. Testing was done to determine the ability of the nanosponges to neutralize PFTs. Researchers found that the nanosponge absorbed membrane-damaging toxins and diverted them away from their cellular targets. In mice, the nanosponges significantly reduced the toxicity of staphylococcal alpha-hemolysin and improved the survival rate.  The conclusion of this study was that nanoparticles have the potential to be able to treat a variety of diseases and injuries caused by pore-forming toxins.

Treating Ischemic Strokes

Mn₃O₄@nanoerythrocyte-T7 (MNET) nanosponges can regulate oxygen and scavenge free radicals in the event of an ischemic stroke, which is a global leading cause of death and disability. These engineered nanosponges can help attenuate hypoxia after a stroke by mimicking red blood cells and increasing the amount of oxygen in the infarct area. This allows for the extension of the survival time of neurocytes, a crucial part of treating an ischemic stroke because their normal functions must be maintained.

MNET works because it contains hemoglobin, which allows for there to be an oxygen sponge effect. This effect works by releasing oxygen in hypoxic areas and absorbing it in oxygen-rich areas. The sponge effect, along with the free radical scavenging, can successfully and efficiently treat ischemic strokes.

Biomimetic nanoparticles, like MNET nanosponges, can easily pass the Blood-Brain Barrier (BBB). The efficiency of the BBB-crossing of MNET is improved by the T7 peptide, which is critical in treating an ischemic stroke. In a study on middle cerebral artery occlusion (MCAO) rats, those treated with MNET experienced a significant attenuation of neurological damage.

Safety Application

Due to the surface functionalization, nanosponges show broad applications in chemical sensors as well as detection of explosives. The electromagnetic properties of nanoparticles are modified through analyte binding and may be used as a transducer in a chemical sensing system for explosives. One electromagnetic property is surface plasmon resonance (SPR) band of colloidal gold nanoparticles (AuNPs). In AuNPs the free electrons within the metal surface interact with light which results in large oscillations in the surface electromagnetic field. This promotes SPR bands since the particles strongly absorb light at the distinct frequencies of the electrons. This property may be exploited for use in the detection of explosives by Surface Enhanced Raman Spectroscopy (SERS). SERS uses incident light to excite Raman active vibrational modes which scatters the protons and identifies a molecule. When the protons are scattered a unique spectrum can be seen which provides information on connectivity and molecular shape. Comparing this spectrum to a portfolio of known spectra may be used to identify a threat.

Current Research

Current research is being conducted for use of nanosponges in treating bacterial infections (sepsis, pneumonia, and skin and soft tissue infections), viral infections (zika, HIV, and influenza), autoimmune diseases (rheumatoid arthritis, autoimmune hemolytic anemia, immune thrombocytopenic purpura), and venoms (snakes and other animals).

Brain Injury Reduction

Nanosponges have been tested experimentally on mice and have been shown to reduce swelling from brain or head injury. When an injury occurs, tissue in the area of injury will swell and immune cells will race to the damages area. When this injury is in the head, this racing of immune cells will lead to swelling in the brain and can be dangerous because the brain is contained within the cell and therefore there is no place for it to move leading to pressure in the head that can be detrimental. Research suggest nanoparticles can be injected into the head as a way to distract immune cells from rushing to the brain which will reduce swelling.

After head injury, mice were left to be for two to three hours and subsequently injected with biodegradable nanoparticles made from an unspecified but FDA approved polymer which is commonly used in some dissolving sutures. Instead of rushing to the head, some immune cells called monocytes ran towards these nanosponges instead of the brain. The monocytes engulfed the nanoparticles and the cells as well as the nanoparticles are then sent to the spleen for elimination in the body. Because the elimination of these particles can happen so fast, researchers were able to inject mice once more two to three days later to combat inflammation that might come back slowly after injury. Mice with this treatment fared better in recovery than those that did not receive this injection and the injured spot reduced to half its size in mice with the nanoparticle treatment. Mice’s vision cells performed better in response to light and were able to better walk across a ladder after recovering showing improvement in behavior and motor function.

Other potential therapies to treat trauma rely on drugs or other cargo to be sent alongside the nanoparticles however this study was done using bare nanoparticles making it cheaper and safer in trial as less material is injected into the organism.

Researchers have not tested this study on human injury. Factors like severity of injury and general recovery time will determine the effects of sending these nanoparticles inside the body. The way the brain suffers involve more bodily reactions that simply this immune response and if accumulation of nanoparticles if not removed from the body fast enough, they may spread to other parts of the body and cause toxic damage.

Macrophage Biomimetic Nanoparticles for Management of Sepsis

Currently, sepsis treatments are lacking. Most treatments are just supportive and not effective against fighting the infection. Research that uses nanoparticles that are biomimetic to macrophages. The macrophage coating onto the nanoparticle surface increases the surface to volume ratio of the nanoparticle. This increased ratio is important for efficient endotoxin neutralization. These macrophages act as decoys that can bind to and neutralize endotoxins. Without neutralizing these endotoxins, an immune response would be triggered. These nanoparticles are able to sequester proinflammatory cytokines which inhibit the ability to start a septic response. These have been tested in a mouse Escherichia coli bacteremia model, where the nanoparticles were able to significantly increase the survival of the mice by decreasing the proinflammatory cytokine levels and preventing the bacteria from disseminating. This cannot be replicated in the medical field yet, but it shows promise toward being able to treat sepsis.

Limitations of Research

One of the limitations with developing nanoparticles is that they are hard to develop. The use of both natural and synthetic components increases the complexity of development. Another limitation is that it is hard to conduct human studies. As of 2019 no human patient studies had been conducted. Part of this is due to the disease’s nanoparticles are developed for. For example, Dr. Zhang of the Univeristy of California, San Diego suggests that for rheumatoid arthritis this could elicit an immune response, therefore, not fighting the disease but driving it. If neutrophil membranes are used to coat nanoparticles, they contain autoantigens which causes an immune response.