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Liposomes Targeted to MHC-restricted Antigen Improve Drug Delivery and Anti-melanoma Response
Liposomes are becoming an increasingly, potentially popular way to administer drugs to a patient that has cancer, so the most amount of toxicity can get to the tumor specifically without getting to other unwanted areas of the body. A common problem with chemotherapy is that the drug can affect non-cancerous cells which can be potentially very toxic to those cells and kill them instead of just the tumor cells. This is common since cells that are cancerous are always trying to find ways to evade cell death (Hanahan & Weinberg, 2011). This can lead to problems when the drug starts affecting healthy cells which can lead to patient death if not monitored or regulated carefully.
Melanoma is a very common cancer that can be very aggressive and difficult to control if not caught early (Saeed et al., 2019). Chemotherapy is a very popular treatment for Melanoma, but the risk factors can be off-target toxicity to healthy cells. Since Melanoma is an aggressive cancer a lot of times a higher drug dose is needed, but with these sorts of risk factors with the drug toxicity going to an unwanted cell there must be ways to figure out how to make these drugs more target specific.
Liposomes are a lipid-based molecule that can encapsulate a drug of your choice, sometimes within the bilayer if it is hydrophilic or among the lipids if it is hydrophobic. Drugs encapsulated by the liposome when given to the patient can keep the drug from breaking down until it is in the targeted tumor cell. (Saeed et al., 2019). They are covered in a protective coating that keeps them circulating in the blood longer and from breaking down which helps them accumulate in the tumor. This can be even more improved by using antibodies on the liposome.
Target specificity can be even more improved upon when you add antibodies to something. One of the goals of improving cancer treatment is to increase target specificity while decreasing off-target toxicity. Antibodies that target tumor-specific antigens would, therefore, increase the targeted toxicity wanted for cancer cells and hopefully keep the drug out of the healthy cells (Hanahan & Weinberg, 2011).
In this study Saeed et al. looked specifically at cancer germline antigens and focused on MAGE-A1 because it is tumor selective and doesn’t appear in healthy tissues. Which would decrease the effect it would have on healthy cells. The liposomes were specifically targeted to M1/A1 epitope which is a target for T-cells and is expressed on melanoma cells. They used scFvs, antibodies without Fc, to target M1+/A1+ melanoma cells, which are antigen positive cells, to hopefully see the drug accumulate more in tumors. They used an antibody without the Fc region to hopefully increase the specificity of targeting tumor cells. The antigen they were targeting was MAGE-A1/HLA-A1 (M1/A1) and they used T-cell receptor (TCR) like antibodies G8 and Hyb3 (Saeed et al., 2019)
Doxorubicin (DXR) is the drug they chose to encapsulate in the liposome because the drug is very well studied and understood. They first checked to see if the DXR remained encapsulated with minimal leakage, and the results showed that there was less than 10% leakage at 24 hours which allowed them to move to test in vivo because the immunoliposomes were stable enough to hold DXR without having to high of an off-target toxicity in healthy cells (Saeed et al., 2019). They also saw that 24 hours after exposure DXR was still in the liposomes and not released allowing time for the antibodies to find the tumor-specific antigens for release into the tumor cell. So, when they add the positive antigen the DXR should be internalized when they have the MAGE scFvs. When testing the uptake of DXR they used targeted and non-targeted DXR liposomes and saw that there was higher uptake of the targeted DXR immunoliposomes, which are liposomes with scFvs (Saeed et al., 2019). This showed that with these antibodies the liposomes were tumor-specific which could decrease off-target toxicity.
They next wanted to look at the toxicity delivered to melanoma cells in vitro in hopes that it could then be tested in vivo. When the liposomes that had DXR scFv antibodies there was higher cytotoxicity in the cells than when there was no specific antibody on the DXR liposomes (Saeed et al., 2019). This showed that when there is the scFv paired with the DXR liposomes there is antigen-specific killing in those tumor cells.
When observing the tumors that they treated with the immunoliposomes that were carrying DXR they saw that there was tumor inhibition in the G43 tumors. Some of the tumors from the G43 line went in to complete remission and remained that way for the duration of the experiment. Once they did this in vitro they moved in vivo and did this experiment in mice. When this experiment was done in mice it almost doubled the lifespan of the mice compared to the control mice with just the tumors and no treatment. Through this, they were able to show that treatments with the antibody specific liposomes with DXR increased the lifespan of the mice as compared to the non-specific antibody liposomes (Saeed et al., 2019).
With all of these experiments that they ran, they were able to show that when TCR-like antibodies were paired with liposomes it increased the targeting specificity to the tumor cells. There was also stabilization of the liposomes which allows it to circulate longer in the bloodstream allowing the liposome time to find the tumor cells. With the M1/A1 antibodies that are paired to the liposomes containing DXR, there was an increase in the uptake of these liposomes in the tumor cells which can lead to the cell-specific killing of melanoma tumor cells. There was also more toxicity delivered to the tumor cells when the DXR was in the liposomes with scFv (Saeed et al., 2019).
All of these findings point to potentially better treatment for patients with cancer specifically melanoma. This therapy could really improve the increased lifespan of the patient, but also it can limit the effect of healthy cells receiving the toxic drug. This can improve some of the potential side effects that come with taking a drug and overall quality of life.
Future development of this type of treatment can be to test on other types of cancers. Showing that this worked with decreasing tumor growth and even some of the tumors going into remission is very promising for melanoma, but there are a lot of other cancers. So, more research on how liposomes could improve the outcome of other cancers is a potential next step to improve cancer therapy and treatments.
- Hanahan, D., & Weinberg, R. (2011). Hallmarks of Cancer: The Next Generation. Cell, 646-674.
- Saeed, M., Zalba, S., Seynhaeve, A., Debets, R., & Ten Hagen, T. (2019). Liposomes targeted to MHC-restricted antigen improve drug delivery and antimelanoma response. International Journal of Nanomedicine, 2069-2089.
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