In the hopes of mitigating chemotherapy's side effects, scientists have explored delivery systems that target tumors more effectively.
Ttuhsc’s Ninh (Irene) La-Beck, Pharm.D., Received A Five-Year Grant From The Nih-Nci To Study How Nanoparticles Interact With The Immune System And Cancer So That New Drug Delivery Systems Can Be Developed. Image Credit: Texas Tech University Health Sciences Center.
Among these researchers is Ninh (Irene) La-Beck, Pharm.D., from the Department of Immunotherapeutics and Biotechnology at Texas Tech University Health Sciences Center (TTUHSC) Jerry H. Hodge School of Pharmacy. La-Beck recently received a five-year, $2.49 million grant (‘Cholesterol Metabolism in the Pharmacology of Liposomal Therapeutics’) from the National Cancer Institute at the National Institutes of Health. She says the grant allows her to investigate how nanoparticles interact with the immune system and cancer so that new drug delivery systems can be developed.
Nanoparticles, approximately the size of a virus particle, show considerable promise in transporting drugs to tumors, presenting a potential solution to chemotherapy challenges. A notable nanoparticle delivery approach involves employing liposomes, artificial spherical sacs crafted primarily from cholesterol and non-toxic phospholipids (lipids containing a phosphate group), to transport drugs to the intended tumor site.
The thing that's really attractive with using a nanoparticle in cancer treatments is that the nanoparticle is much larger than chemotherapy molecules. Because it's larger, it is less likely to leak out and go to other healthy tissues, so it potentially causes fewer side effects.
Ninh (Irene) La-Beck, Scientist, Texas Tech University Health Sciences Center
Utilizing nanoparticles like liposomes for drug delivery enhances drug accumulation within the tumor while minimizing the impact on healthy tissue. La-Beck highlighted that various liposomal chemotherapies have received approval for cancer treatment. However, lipid nanoparticles, including liposomes, also engage with the immune system, albeit their influence on the tumor's immune environment remains largely unexplored.
In contrast to regular blood vessels, tumor blood vessels exhibit heightened permeability and accelerated growth alongside the tumor. La-Beck underscored that this increased permeability enables nanoparticles to infiltrate the tumor while circumventing normal tissue.
Every time the heart pumps, more of the drug leaks out from the blood vessels and into the tumor tissue where it accumulates over time. This means the concentration of the chemotherapy increases, and we think that helps the drug to work better.
Ninh (Irene) La-Beck, Scientist, Texas Tech University Health Sciences Center
Numerous nanoparticles have gained approval for administering cancer therapies, demonstrating notably improved safety profiles. For instance, doxorubicin, a commonly employed drug for breast cancer treatment, is associated with heart toxicity, imposing a ceiling on the maximum dose viable for patients.
La-Beck adds, “Some patients have pre-existing heart conditions, and they can't even get doxorubicin. But we’ve found that when we put it into a nanoparticle, there's very little heart toxicity, so it's very successful in that respect. The problem is that we don't actually see the improvement in efficacy that we anticipated; we see better safety, but we don't see better efficacy. Why is that if we're supposedly getting more of the chemo into the tumor?”
In an earlier study, La-Beck showcased that employing liposomes comprised of phospholipids and cholesterol, akin to those utilized in patients, led to a twofold increase in tumor size in mice. This effect was attributed to the suppression of their immune response against specific tumors. Recently, she pinpointed macrophages, cells adept at detecting, consuming, and eliminating harmful agents, as responsible for these adverse outcomes.
Moreover, initial findings from La-Beck's research reveal that liposomal cholesterol undergoes metabolism, forming oxysterols (oxidation-produced derivatives of cholesterol) recognized for their ability to modify macrophage functionalities.
La-Beck adds, “Based on this, we theorize that liposomal oxysterols cause macrophages to suppress antitumor immunity and enhance tumor growth.”
La-Beck's laboratory has been diligently tackling this issue by delving into the reciprocal relationship between the body and nanoparticles, examining both how the body processes the nanoparticles and the impact of nanoparticles on the body. Several years ago, their investigations revealed a substantial interaction between nanoparticles and the immune system.
Specifically, in the case of liposomes, these nanoparticles are identified by the immune system, triggering a response akin to the reaction toward any perceived external threat. Ordinarily, macrophages play a role in consuming and eliminating these perceived threats, subsequently presenting components of these pathogens to T-cells. T-cells, another facet of the immune system, generate an antigen-specific response designed to recognize and counteract the specific pathogen.
La-Beck emphasized the pivotal role of macrophages in the initial elimination of nanoparticles and in initiating additional immune responses directed at these nanoparticles. Her early investigations indicated that certain responses triggered by these interactions are, in fact, beneficial. These responses prompt immune cells to generate molecules that aid in stimulating an immune reaction targeted at combating cancer cells.
La-Beck explains, “We also discovered that some of these immune responses are bad because they stimulate molecules to be released that actually can suppress certain parts of the immune system and promote tumor cell growth. So, the immune system is a double-edged sword: if it’s out of control, you get bad things, but if it’s right, you get the good effects.”
In her grant-funded research, La-Beck will concentrate on the cholesterol component within the liposome delivery system. She highlighted that when the body metabolizes excessive cholesterol incorrectly, it can lead to various conditions such as atherosclerosis. Additionally, this aberrant cholesterol metabolism might be implicated in the development of Alzheimer's disease and various forms of cancer.
The bottom line is these nanoparticle delivery systems have a huge potential to help make treatments better, but there’s a lot we don't understand about how they affect the immune system. If we do not figure that out, then we cannot fully exploit their therapeutic potential. That’s basically what the grant is about.
Ninh (Irene) La-Beck, Scientist, Texas Tech University Health Sciences Center