A Review of Recent Advances in the Field of DNA Origami-Based Drug Delivery Methods
Introduction:
Cancer is a disease that has plagued scientists for decades due to its hard-to-target nature. While many diseases can be treated with antibiotics or vaccines that specifically target and kill the intended pathogen, cancer is a disease that uses a persons own cells against them, making it much harder to differentiate between the victim and the enemy. The tough distinction between healthy cells and cancer cells has made modern cancer treatments sub optimal as they destroy cancerous and healthy cells.
This issue has led to a significant amount of research on targeted drug delivery. If there was a way to send chemo drugs specifically to cancer cells, and avoid their healthy neighbors, then the negative effects of cancer treatments would be greatly reduced.
Based on the small scale nature of working with individual cells and drug molecules, nanotechnology seems to be the most promising option for creating these targeted drug delivery techniques. There are many different methods being explored, such as using the plasmonic properties of gold nanoparticles to burn cancer cells from the inside. However, one method that has been gaining a lot of steam is that of DNA Origami.
DNA Origami is a field of nanotechnology in which DNA molecules are used as a construction material rather than an instruction manual. The essential premise is that a long DNA strand of a desired length (the scaffold) can be folded into any arbitrary structure and held together by other short DNA strands (oligonucleotides, the staple strands).
Through these origami structures, containers can be made that hold drug molecules inside of them. Targeting molecules that act as a guide to cancer cells can be attached to these containers. Once inside the cell, some sort of cell specific stimuli can be used to open the container allowing the drug molecule to disperse inside causing cell death.
This article attempts to explore this method by reviewing seven experiments in which DNA origami structures are made with the purpose of creating more precise and controllable drug delivery systems. Through these experiments, recent advances in the field along with current limitations and future improvements are presented.
Review of the DNA origami Design and Testing Process:
The designing process of DNA origami has become more automated in the past few decades. Many platforms exists now, such as caDNAno, which allows a user to design a desired shape which will then be turned into a DNA sequence produced by the program. This has allowed people to focus more on what designs work best for specific applications rather than how to create the designs themselves.
The two essential components of a DNA origami nanostructure (DON) is the scaffold strand and the staple strand. A scaffold strand is a very long single strand of DNA that acts as the base of the structure. For convenience sake, the m13mp18 viral genome of the M13 phage is often used as the scaffold strand for many experiments involving DONs. This is convenient as the genome has a good length at 7,249 nucleotides long, and gets rid of the need for the designer to create their own scaffold strand from scratch. Creating a custom strand can be beneficial however if one needs more control over the placement of certain staples or other molecules on the DON.
Once the design is made, the DNA strands can be ordered from various companies such as Integrated DNA Technologies. One of the benefits of using DNA as a construction material is that they can self assemble into the desired structure. This is due to the precise control one can have over the nucleotide sequence in the DNA strand which significantly effects the way the molecule will naturally fold.
Because of this, many DONs are made using a one pot reaction in which the scaffold and staple strands are put into a solution and thermally annealed. Annealing is the process of heating a solution up and slowly bringing down the temperature until the desired structure is formed.
At higher temperatures the particles in the molecules are moving at high speeds making it hard for them to stick together and form a consistent structure. But as one lowers the temperature, the speed at which these particles move decrease allowing them to stick together easier.
After the structures are created, one must use purification and identification techniques to determine whether the structures formed correctly. One common method of purification is agarose gel electrophoresis. This process consists of letting the DONs move through a gel like substance and examining their paths through the gel. Based on calculations made before hand, one can determine what the path of a correctly formed DON would look like and see how much of the created structures match up with the theoretical predictions.
Further identification can be done through the use of atomic force microscopes (AFMs) and transmitting electron microscopes (TEM). AFMs utilize a fine tip that runs along the surface of the structure measuring the force at each point to create a picture of the DON. This method works well for 2D structures as it allows one to get a visual representation of the structure and whether or not it looks correct.
For 3D structures however, AFMs can be quite damaging due to the forceful nature of the tip, so TEMs are often used which utilize the shooting of electrons through the structure and measuring the levels of scattering at each point to create a visual representation of the DON.
Many other methods are useful such as circular dichroism, uv-visible spectroscopy, FRET and the use of optical tweezers, but the methods provided above seem to be the most commonly utilized.¹
DNA Origami Nanostructures for Targeted Drug Delivery
DONs have many properties that make them excellent for targeted drug delivery. For one thing they are biocompatible. This gives them a far less likely chance of causing harm to the body when compared to other drug delivery techniques such as those that employ gold nanoparticles.
What really makes DONs promising for drug delivery however is the ability to create any arbitrary design. The fact that one can design and create all sorts of shapes and geometries using DNA origami means that different structures can be made for different purposes allowing much more efficiency and precision when delivering drugs.
Not only can one design any desired structure from DNA origami, one can also use the sequence structure of DNA to place other materials, such as drug molecules, on the structure with a precision of a couple nanometers. By identifying the sequence of A, G, T, C molecules at the desired location on the structure, one can create a complimentary strand of DNA that attaches to the molecule of choice so that it will attached directly to the spot.²
To demonstrate the different abilities for control in using DONs for targeted drug delivery, seven experiments utilizing the method have been summarized below.
Nose-Like Cancer Detection DON
In this experiment³, a DON was created to act as a cancer cell detector that was able to distinguish between and identify five different types of cancer cells.
The DON was created by mixing a m13mp18 viral genome scaffold strand with staple strands in a buffer containing Mg2+ ions. The pot was thermally annealed from 95* to 25* over 3 hours. These DONs were triangle in shape with sides of 120nm.
Aptamers (Single, short strands of DNA that selectively bind to a target molecule) were added to the DONs, to control their binding affinities to the five different cancer cell types used in the experiment. Multiple different types of aptamers where added to the DON with each one having a high binding affinity to a different type of cancer cell based on the cell’s surface receptors. To be more specific, the three types were AS1411, MUC1, and EpCAM aptamers.
Cell surface receptors are molecules specific to a certain type of cell. In the same way one can detect what food is in front of them based on its smell, the triangular DON would be able to detect what cancer cell it has approached based on the cell surface receptor it received.
By putting multiple aptamers on one structure, one gets the advantage of a more generalized DON that can detect more than one type of cancer cell. The binding affinity of the DON to the cell could also be controlled by the position of the aptamers onto the DON.
Each DON was loaded with a fluorophore (a chemical compound with the fluorescent property of re-emitting light when experiencing light excitation) to give them the ability to identify each cancer cell. The cell surface receptor that the DON binds with determines the type of fluorescence signal that is created from the structure. By calculating what signal should be released when binding to each type of cell surface receptor and comparing this with the actual results one can see what type of cancer cell the DON made contact with.
To test this idea the DONs where mixed into a solution containing five different cancer cell types. Afterwards, the solution was examined using flow cytometry (a process of letting a solution flow one cell at a time while scattering a laser through the cell to analyze and characterize each cell). Using this method, they were able to analyze the fluorescence signal produced from each cell and then identify the cell itself to test the accuracy of the DONs.
They found that the DONs accurately identified the cancer cell type 38 out of 40 times, for an accuracy of 95%. This experiment shows the creation of a DON that can accurately identify cancer cell types which is very important for the field of DON based targeted drug delivery.
The ability for a DON to detect what type of cell it is attached to leaves open opportunities for a device that can execute cell-dependent actions. Maybe the device attaches to a healthy cell, realizes it and then detaches until it attaches to a cancer cell. Once it determines its attached to a cancer cell, only then will it open up to release a chemo drug. This experiment is just the start of devices with cell dependent instructions.
A DON with Two Locks
In this next experiment⁴, Immunoglobulin G (IgG) antibodies are utilized as a structural element that staple fragments together to form a DON.
IgG antibodies are Y shaped molecules that naturally attach to specific types of antigens in the body. Their Y shape is what allows them to be used as staples.
In the experiment, 20 identical, triangular DON fragments were created and stapled together by these IgG antibodies to form a 3D, hollow icosahedral shell. To be more precise each triangle had two IgG antibodies on each side which connected it to three other triangles to create the shell.
While the structural aspect of the IgG antibody is impressive enough, its the ability for it to respond to stimuli in the form of antigens that makes them super useful for drug delivery related techniques. Say the icosahedral shell is thrown into a solution filled with the IgG antibody’s complimentary antigens, then the antibodies will bind to the antigens instead of the DON causing the shell to burst.
This is exactly what the experiment tested by using antidigoxigenin and antidinitrophenol IgGs. The shells were put into either an antigen free solution or a solution containing the antigen. Using TEMs to analyze each solution it was shown that the shells in the antigen free solution remained intact while the ones in the latter solution appeared to burst.
What gets really exciting about this method is the ability to create an AND gate like opening mechanism using two different types of antibodies. By using two different antibodies, two different antigens are required to burst open the shell.
The experimenters tested this idea with digoxigenin and 2,4-dinitrophenol antigens. Adding digoxigenin or 2,4-dinitrophenol alone did not burst the shell. Only when both antigens were added did the shells burst.
Finally, to test the shells ability to delivery cargo, a HPV-specific antibody was attached to one of the triangle fragments using complimentary DNA strands. The shell then formed around the antibody completely enclosing it. The shell was then put into a solution with the required antigens and sure enough, the shell exploded releasing the HPV-specific antibody out into the open.
The results and principles from this experiment are exciting for many reasons. First IgG antibodies can be altered in a very controllable way using monoclonal antibody generation techniques which would allow one to create an antibody that has a high binding affinity to any type of molecule. This allows for the creation of antibodies that bond to specific cancer cell receptors like described in the previous study.
Furthermore, the fact that multiple antibodies can be used to create an AND gate function means one can create a capsule that requires a sufficient threshold of antigens to be opened. This is useful for cancer cells which are hard to distinguish from healthy cells based on one receptor alone. Multiple receptors can be used as signals which can make DONs more precise and accurate in which cells they release drugs into.
The Use of Different Shapes for DON Delivery Units
One of the important factors in whether a DON drug delivery device is successful is whether the cell internalizes the DON. In other words, is the DON able to make it inside the cell and how much of the DONs are able to do so?
Many factors can affect a DONs ability to enter into the cell such as its size, structure, shape, etc. In this experiment⁵, shape is the primary factor tested by using a donut, disk and sphere shaped DON.
First the structures were mixed into both a Mg2+ buffer solution and a cell media solution to simulate in vitro and in vivo conditions. It was shown that there was no significant degradation of the DONs in the Mg2+ solution. However there was noticeable differences in the stability between the three shapes in the cell media with the donut structure being the most stable. This finding was in agreement with the idea that densely packed DONs are more resistant to degradation.
Next, the experimenters tried testing the loading efficiency of each shape. The drug of choice for this experiment was Doxorubicin (Dox) which is a commonly used chemotherapy drug for cancer treatment. Dox is a popular drug to test with for these type of experiments because it can easily be intercalated into the planer part of a DON. Intercalation is the insertion of a molecule into another structure by imbedding it between the structure’s layers.
After mixing the three types of DONs into a solution containing Dox, it was shown that the sphere was the most efficient in loading the drug while the disc was the least. This backed the idea that maybe hollow 3D structures are the most efficient at loading on drug molecules.
To test the releasing ability of the DONs, the structures where mixed into a Mg2+ buffer solution for 15min and 60min. At each time check point, the amount of Dox left on the structures was determined.
The spheres were shown to have the fastest release rate while the dounts showed the slowest release rate. This lent to the idea that donut shaped DONs were the best of the three options for loading dox into a targeted cell as it could hold the second highest amount and hold them for the longest amount of time. The faster the release rate, the less drug molecule that actually makes it to the cell, hence why the donut was deemed more efficient then the sphere.
Finally, to test the cell internalization of each DON, 5 MUC1 aptamers were added to each structure in roughly the same positions. MCF-7 and MDA-MB-231 cells were used because MCF-7 cells have high MUC1 expression while MDA-MB-231 cells have low MUC1 expression, so they acted as a good distinction as to whether the MUC1 aptamers had any effect on the targeting function of the DONs.
After mixing aptamer modified and non aptamer modified versions of each structure within solutions containing either MCF-7 cells or MDA-MD-231 cells the results showed that the Donut DONs showed the highest rates of internalization into the MCF-7 cells.
It was also shown that levels of cellular uptake between DONs with and without aptamers were much different in solutions containing MCF-7 while the levels were similar in solutions containing MDA-MD-2231 cells showing that the aptamers made a big difference in the DON’s targeting ability.
While the results of this experiment are not all that exciting for the development of DONs as a method for drug delivery, they emphasize the importance that shape and cell type play in the effectiveness of the method.
The influence of these factors shows that research comparing the different shapes and cell types that can be used along with their levels of effectiveness must be done in order to make more optimized drug delivery techniques.
In the future, it would be beneficial to have a database of all the different shapes of DONs and their levels of effectiveness so that one can just input a cell type and get out the best DON for the job.
The Comparison of DONs In Vitro vs In Vivo
In this next experiment⁶, two different DONs, one triangle shaped and the other rod shaped, were used to determine the immunogenetic effects they have on in vivo environments such as mice. Essentially the experimenters wanted to see how an immune system would respond to the introduction of these foreign nanostructures.
In order to get results that would be similar to those when DONs are used in clinical practices, the experimenters upped the dose of DONs used above the amount that's traditionally used in vitro studies involving DONs. To further get a view of how dose effects the immunogenetic effects from DONs, in vitro trials were done as well with a cell media of splenic mononuclear cells.
Through these trials it was shown that the cellular intake of these DONs increased with both time and concentration. They also showed that the immunogenetic effects where time and concentration dependent as well with higher levels of immune cell types being detected as the concentration and time increased.
Next, it was time to see how the immune response played out in vivo by injecting the DONs into mice both through the vein (i.v) and through a body cavity (i.p.). Live images of the mice were taken at 50 minutes and 100 minutes in order to confirm that the distribution of DONs occurred as desired.
After the experiment was done, the mice were euthanized and the organs were collected for analysis. It was shown that 2 hours after the i.v. injection, the DONs where mainly found in the urine, kidneys and liver. In the ip injection, after 2 hours the DONs where found mainly in the urine, reproductive organs, kidneys, stomach, spleen, and liver. No traces of DONs were found in the brain or blood.
An interesting finding was that, in the i.v. injections, the triangle DONs where found at much higher levels in the spleen, liver, kidneys and blood then the rod DONs. This lends to the idea emphasized in the last experiment that the shape of the DON not only effects its ability to be localized into the cells but also in how they distribute throughout the body.
Blood and bone marrow, and splenic mononuclear cells were collected from the mice as well to measure the immune response to the DONs. The findings were consistent with the in vitro trials in that immune responses were detected.
To further simulate what would happen in an actual medical procedure such as chemotherapy, a repeated dosing regime was created where every 2 days for 10 days, mice would be injected with a dose of the DONs similar to that of chemo drugs. This was done through i.p. injection.
24 hours after each injection, blood would be collected to analyze the immune response of the mice by checking the complete blood count (CBC), and analyzing the levels of plasma cytokine/chemokine.
After 10 days of the regime, it was shown that the white blood count levels stayed within the normal range showing that no large scale immune response took place. 5 days in however, monocyte levels increased but returned to normal by day 10. This shows that a pro-inflammatory response occurred due to the DONs which is consistent with claims of a slight inflammatory nature of DONs found in other studies.
An interesting result showed that cytokines where detected at a much higher level in mice injected with triangle shaped DONs vs rod shaped DONs, showing that shape likely plays a big role in the immunogenetic effects of DONs as well.
Overall, this study brought attention to a few important points in this field. For starters, not a lot of studies have been done comparing the effects DONs have in vitro vs in vivo. This is important work to be done because in vitro environments often times don't account for the immunogenetic response that will occur from the DONs in an actual living body.
The literature also lacks experiments comparing the effects shape has on the DONs ability to elicit an immune response in vivo. This will become increasingly more important as these methods head towards human trials. For example, its important to know how much of an inflammatory response these DONs have on the body.
Another thing this experiment does that distinguishes itself from others is the use of higher doses and different timings of injections. Because actual treatments are likely to be more complex then those done in test tubes, experiments that play with and compare different concentration levels and injection regimes will help in making methods become viable for humans.
Targeting DONs Treating Mice with Cancer
In this next experiment⁷, a tube shaped DON was created that could actually target tumor cells in mice and deliver a drug on arrival.
The method of treatment tested involved using the enzyme thrombin to cause thrombosis in the blood vessels that were connected to the tumor cells. Thrombosis occurs when blood cells cluster up, blocking blood from flowing through the vessel. The enzyme thrombin can cause this by turning the fibrinogen in the blood into fibrin which is a more solid and tangled form of the protein. This makes the cells in the vessel more likely to bundle up causing obstruction.
This obstruction can work as a treatment for cancer if it can be precisely placed in the vessels that lead to tumor cells. By blocking off these vessels, a tumor cell can not receive all the materials it needs to survive resulting in the its death. The treatment has its problems though as thrombin can cause thrombosis anywhere in the body. The unspecific nature of this process makes it unsafe to use since it can easily kill healthy cells.
In this study, the researchers hypothesized that the process could be made safer by making it more specific to cancer cells using DONs.
To get started, a rectangular DNA origami sheet, measuring 90 nm × 60 nm × 2 nm, was created as the base of the structure. The thrombin enzymes were then attached to the sheet using complimentary DNA strands with one connected to the thrombin and another connected to the DNA sheet. Using AFM, they were able to confirm this worked at a high accuracy as 4 thrombin molecules were detected on 70% of the DNA sheets.
Using a predesigned aptamer, the DNA sheet was then fastened along the long end forming it into a 3D tube, blocking the enclosed thrombin molecules from the outside environment. This was important as it shielded the thrombin molecules from reacting with fibrinogen outside the DON at undesirable times.
The aptamers used to fastened the structure were also designed to have a high binding affinity to nucleoin proteins. Nucleoin proteins are highly prevalent on the cancer cells used in the experiment. The goal of designing the aptamers in this way was to allow the DON to open in the presence of nucleoin. Once the aptamers holding the structure together got to close to nucleoin, they would bind to the protein instead of the other side of the sheet causing the sheet to open, exposing the thrombin to the cell.
Lastly, some of these DONs had additional aptamers attached to the outside in order to act as a targeting agent. The hope was that these additional aptamers would help the DON more efficiently find and latch onto cancer cells.
Once the structures were created and loaded with the thrombin, experiments took place in which DON injections were given to mice containing human breast cancer cells (cells were artificially inserted into the mice by the researchers).
Using fluorescence imaging, the DONS where shown to progressively accumulate in the tumors of mice with maximal accumulation at 8 hours. Further analysis showed that the DONs containing the additional aptamers accumulated at the target cells 7 times more efficiently then those with no targeting agents over the 8 hour period.
After 24 hours, the fluorescence signals disappeared showing that the body naturally got rid of the DONs and that non of them accumulated in other organs.
Unlike the other trials containing saline, free thrombin, empty nanotubes and unopenable nanotubes, the trials containing the aptamer based DONs showed significant thrombosis after 72 hours, specifically located at the tumor. This demonstrated that the method succeeded at being tumor specific.
Furthermore, after the trials were done, the aptamer based DONs showed significant tumor necrosis while the other trials did not. On top of this, no significant cytotoxic effects were found in the mice from the DONs.
Just like how the last experiment emphasized the importance of in vivo studies, this experiment actually succeeded in showing the effectiveness of DONs in treating a living creature containing cancer cells. More successful experiments like this will be needed in order to get this method to human trials.
A DON that can Open and Close Using pH
In this next experiment⁸, DON capsules were designed with the ability to open and close using pH sensitive latches.
The DON consists of two halves attached together by four staple strands which act as hinges. The dimensions for the fully formed DON are 31 nm × 28 nm × 33 nm while the inner cavity of the structure has dimensions of 11 nm × 12 nm × 13 nm. There are two layers of DNA double helices along the wall of the capsule in order to ensure rigidity and stability for shielding the loaded cargo.
The structure is also designed with 8 latch sites along the perimeter containing staple strands that can later be replaced with strands that possess latch functionality.
To form this latch, there are two components. One component is a DNA duplex which is attached to one half of the capsule. The other component is a single strand DNA molecule attached to the other half of the capsule. Both components have complementary sequences at the tips which allows them to attach together forming a triplex.
The secret is within these complementary sections of the components. DNA is naturally responsive to the pH of its environment based on its sequence. One can control the strength of the latches in different levels of pH by controlling the sequence of the strands that connect together.
After mixing the closed capsules into an acidic solution, it was clear to see that the capsules opened up rapidly after introducing sodium hydroxide (increasing pH). Furthermore, the capsules were shown to close after making the solution more acidic, albeit at significantly lower speeds then when opening.
This method is exciting as pH differs between healthy and unhealthy cells. Healthy cells maintain a intracellular pH of ~7.2 while the extracellular pH is ~7.4. However, cancer cells can be distinguished from healthy cells by having a higher intracellular pH (∼7.3−7.6) compared to its extracellular pH (∼6.8−7.0), a situation that arises from “the multiple altered characteristics of cancer cells.”
To see the possibility of these devices being used as a drug delivery treatment, they tested the DON’s loading ability using gold nanoparticles, and tested the DON’s functionality by using horseradish peroxidase enzymes.
It was shown that gold nanoparticles could be loaded onto the capsules with 40–55% accuracy. It was also shown that HRP enzymes were still fully functional after being loaded into the capsule, by measuring the rate of ABTS oxidation by HRP in the presence of H2O2. This was done at different pH levels, to account for the capsule staying closed or open. While this was good, oxidation reactions still occurred at lower pH levels due to the capsule being to porous which allowed smaller molecules to seep in and react with the HRP.
Despite this, the experiments shows the potential for new developments in this field of DON related drug delivery through the use of reversible processes. By being able to open and close the capsule, one might be able to reuse it whether that be for later in the treatment or for another treatment entirely.
Reversible processes like this also allow for more dynamic DONs which are useful for handling tasks that may require more repetitive actions.
Finally the use of pH as the stimuli for controlling the DON is an interesting one as other methods often require the addition of other, non DNA-based molecules, to react to a stimuli. This often requires more structural changes as well as an increased risk of cytotoxicity.
A Much More Dynamic DON
The next experiment⁹ is not specific to targeted drug delivery, but the method used in it can be applied to DNA origami based drug delivery systems in a way that would give the user much more control over the entire treatment process.
In this experiment, a DON is created that allows for modular adjustment of its length, curvature and twists. The method uses modules that can be made bigger by the introduction of an expansion strand. The DON created in the experiment is 19 x 9 modules with each one having the ability to be individually lengthened.
The ability to individually control each module allows one to have much more control over the structure of the DON. By changing different modules lengths one could make the structure incrementally longer, more curved and more twisted.
The ability to change the size of the module comes from the way its structured. Each module has a DNA duplex formed between a staple strand and the scaffold. It also contains a scaffold loop in the middle.
An expansion strand can be added to mix, causing it to attach to the scaffold loop. When this happens, the expansion strand essentially stretches out the looped strand causing the module to become bigger.
By making the expansion strand’s DNA sequence complimentary to a loop strand’s sequence in one of the DON’s modules, one can use the expansion strand to precisely target that specific module. This allows for the precise control of which modules in the structure expand and which ones do not.
After creating their 19 x 9 module DON sheet, they calculated what the length of the structure would be if the structure was to expand the modules at 6x9, 13x9 and 19x9 units. After running the experiments they found that the results lined up closely with the theoretical calculations.
Similar experiments were done to alter the structures curvature and twists with the results lining up with theoretical calculations to a similar degree. For example, the curvature of the object could be changed by only expanding modules on one side, forcing the other side to curve inward to compensate. The structure could also be twisted by expanding only the perimeter modules which would cause it to twist in the same way a DNA double helix does.
Finally to test the controllability of a 3D DON, they rolled the 19 x 9 module sheet into a tube and did more experiments on it. Sure enough, the length, curvature and twist tests returned results of similar accuracy to the ones with just the sheet.
While very rudimentary, the ability to have such gradual control over the structural properties of a 3D DON could mean great improvements in the drug delivery techniques out there.
One could possibly make a multi-purpose capsule that can change shape to account for the size of the molecules its supposed to hold. A tube could be made that releases some molecules while not releasing others. A DON could be created with the ability to change shape based on what type of cell its in leading it to have cell dependent reactions. The possibilities are endless.
Conclusion
Based on the studies reviewed, its clear that there are many improvements being made in the field of DON based drug delivery. Researchers are increasingly finding out ways to get more control over DONs while also making them more dynamic and reusable.
It is also important to note the need for more research into the factors that influence the effectiveness of DONs such as shape, size, structure, and cell type. More in vivo studies are also necessary in order to figure out the immune response that DONs will cause in humans as well as their levels of toxicity.
Right now is an exciting time to be alive as the status quo of having generalized cancer treatments that kill both cancer and healthy cells is slowly being broken with the advent of these new nanotechnologies. Hopefully the promise that DNA origami shows will be enough to make treatments that fight cancer cells, and cancer cells only.
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