Liposomes and Cancer Therapy

Sara Branson
3/8/07
FYS
Liposomes: Packaging the Future of Cancer Treatments
Accounting for nearly one quarter of all deaths in the United States, cancer is a looming threat to people across the world. However, thanks to continued research in the development of more effective cancer fighting treatments, the death rates of cancer victims have significantly decreased from 1950, to present. Fighting cancer relies on three main technologies: chemotherapy, surgery, and radiation. Chemotherapy works via the transfer of cytotoxic drugs to specific locations in the body. The transfer must occur without interaction with healthy cells as the drugs circulate in the bloodstream. In addition, the drug must avoid destruction by the immune system, which recruits phagocytes such as macrophages to destroy foreign substances in the bloods stream. Nanotech biomimetics offers a wide range of utilities to overcome these complications by taking ideas from nature and incorporating them into technology. Liposomes are natural packaging devices flowing through the bloodstream that have been harnessed as drug dispensers for cancer treatments. Its design as well as functional capabilities allow it to deliver cancer treatments to target areas without harming healthy cells and without triggering the immune system.
Liposomes were discovered in 1961, by Alec Bangham at Cambridge University and were first used as drug delivery systems 30 years later (Tianshun). The structure of the liposome enables it to increase the potency while at the same time reducing the toxicity of the drugs it carries. Liposomes exhibit self organization that is triggered when certain phospholipids are exposed to an aqueous environment and utilize the hydrophobic effect to form a spherical lipid bilayer with the hydrophilic phospholipid heads facing out. The aqueous solution that is trapped inside the bilayer provides a carrying space for drugs that is sequestered from the aqueous outer environment. The formed vesicle may range in size from 50 to 200 nm in diameter and may be encased by one layer of phospholipids such as in a unilamellar liposome, or may have several layers that resemble an onion in a multilamellar liposome (Lian).
Although the synthesis of liposomes appears simplistic, serious complications are yet to be resolved with the development of a low cost method of mass production. The success of liposomes as a cheap medical device depends upon the formation of liposomes with adequate drug entrapment capability, appropriate size, relative stability, and drug release capability. Scientists use sources of energy such as sound and heat to agitate phospholipids in an aqueous solution into vesicle form, but they are unable to control the size and structure of the final product. The use of energy stimulated vesicle formation risks denaturing the drugs that are in the aqueous solution that will be enclosed inside the liposome. One of the main complications with liposome use in the human body is that one of the first steps in vesicle formation is to dissolve the lipids in a volatile organic solvent such as methanol. These solvents are often toxic and can affect the inner cargo, destabilize the lipid membrane, or remain as Organic Volatile Impurities (OVI’s) in the lipid membrane where they will later intoxicate healthy cells in the body (Mozafari).
In the medical world, drug companies utilize liposomes as an effective means of drug delivery. Water soluble drugs, including cancer drugs, are inserted in the aqueous compartment inside the phospholipid outer membrane. The liposomes are then introduced into the bloodstream, and the hydrophobicity of the outer bilayer keeps the drugs separated from the blood until the liposomes reach the targeted cells. This process is especially adept for cancer treatments because the phospholipid bilayer keeps toxic drugs from affecting healthy cells and can be modified to “target” cells like macrophages and tumor cells.
In order for drugs to be transferred into a cell, the liposome must interact with the target cell. Interaction occurs through several methods. The liposome may simply bump into the target cell, forming a weak bond with the cell membrane that allows drugs to diffuse directly into the cytoplasm of the cell. Other cells engulf the liposomes with the cell membrane through endocytosis. Once inside, the liposome fuses with a lysosome that contains phospholipases that degrade the liposome and release the drugs. Ligands called opsins are often appended to liposomes and instigate endocytosis by directing the liposome to the target cell. In addition, alteration of the pH inside the water compartment of the liposome creates a charge on the dissolved drug. Once the liposome is engulfed, the liposome will fuse with the organelle encasement and release the drug particles into the cytoplasm (Gregoriadis).
Cancer therapy utilizes specific characteristics of tumor cells in the transfer of cytotoxic drugs from the liposome to the target cells. Healthy blood vessels have an endothelial wall with tightly packed endothelial cells that prevent large molecules in the blood from leaking out of the vessel. The epithelial walls of vessels in tumor sites exhibit EPR, or enhanced permeability and Retention. Due to gaps in the epithelial wall, liposomes that are 400 nm or less can leak into the tumors. Tumors and cancerous lesions are therefore prime targets for liposome drug administration.
The main targets of cancer fighting drugs are TAMS, or tumor associated macrophages. Macrophages are cells in the immune system that originate from white blood cells called monocytes. They function in the immune system as phagocytes, meaning they engulf dangerous and potentially harmful material inside the cell such as pathogens. Instead of aiding in immunity like normal macrophages, TAMS produce chemokines and cytokines that promote tumor growth and metastasis. Scientists hypothesized that they could use liposomes to transfer a cytotoxic drug to the TAMS, which would in turn stop the progression of the tumor.
Consequently, the cytotoxic drug of choice was bisphosphonate clodronate, or Clodrolip. Encapsulated into unilamellar liposomes, this drug is commonly used for its ability to destroy TAMS and therefore cease the production of chemokines and cytokines. Tests performed on mice showed that the liposome administered Clodrolip inhibited tumor growth in 75% to 92% of the cases. Reduction of growth rate of tumor was significant up to nine days after treatment. Clodrolip is one example of an effective drug transferred by liposomes that has can inhibit hard tumor growth and metastasis.
Another liposome-packaged cancer treatment is NOAC. It is cheaply synthesized in lyophilized, or freeze dried liposome form and has high proprietary support for research. The lyophilized package is mass produced in highly purified form in four steps, using the cheap ribonucleotide uradine (“Liposomes: general properties). Through liposome delivery, NOAC has been shown to inhibit growth in breast, prostate, and lung tumors as well as fight leukemia. Research on freshly biopsized cancer cells in ovarian and mammary carcinomas showed NOAC to by highly cytotoxic to the tumor cells. It also showed success in inhibiting growth in melanoma and tumors that exhibited resistance to multiple drugs. Scientists tested NOAC on freshly biopsized human tumors at concentrations from 10 to 100 micromolar. At these concentrations mammary, lung, and ovarian carcinomas as well as non-Hodgkin lymphomas were highly inhibited (Schwendener). Liposomes play an active role in the administration of NOAC, as well as other notable cancer fighting drugs on the market such as Doxorubicin (Doxil) and Daunorubicin (Daunoxome).
Finally, scientists optimize the performance of liposomes through the addition of anti-tumor antibodies to the outer membrane of the liposome, creating what are known as immunoliposomes. Immunoliposomes target the tumor cells and make drug transfer more efficient. In addition, immunoliposomes can be sterically stabilized, meaning they are less likely to be filtered out of the bloodstream by the immune system and are able to circulate for a longer time. This is accomplished through the attachment of hydrophilic polymers or glycolipids to the liposome membrane. The modified liposomes act like targets that fit into receptors on target cells (“Liposomes: general properties”). The added target fragments do not increase the effect of the drug, but allow the drug to reach the target cells faster and circulate longer.
A special case study was performed by scientists on the effects of attaching single chain antibody fragments to liposomes containing cancer fighting drugs. They linked the antibody fragments to liposomes and radioactively labeled them so they could monitor their locations through fluorescence. A control group containing unmodified liposomes and the experimental group of modified liposomes were introduced into the bloodstream of tumor stricken rats at the same time. Two hours after injection, scientists found that the modified liposomes accumulated in tumors in concentrations two to three times that of the unmodified liposomes. However, after an extended period of time, the concentrations evened out. This proved that attaching “target” fragments to liposomes expedited the treatment by targeting the tumor cells. As expected, the drugs inhibited tumor growth in the rats. Overall, the experiment proved the efficiency of drug delivery with target lipsomes versus that of unmodified liposomes.
Liposomes are cheap, effective means of drug transportation in the medical field. They are the key to cancer therapy and the delivery of cytotoxic drugs that would otherwise ravage healthy cells. The intricate packaging system, harnessed from the ideas of nanotech biomimetics, is now the hopeful future of cancer research. Liposomes are simply a nano-scale machine harnessed within the human body to manipulate the placement of drugs that may one day defeat the onslaught of cancer.