Emily Xu, Grade 11, ISEC 2015 First Place Winner
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Cancer. More than 1 out of every three people will develop it in their lifetime, and it proves to be fatal in 7.6 million of those people per year (1). Ever since President Nixon officially declared the “war on cancer” forty years ago, the National Cancer Institute has poured 90 billion dollars into research to curb this so-called “emperor of all maladies”, yet a cure still remains elusive. What may be the cause of this puzzling stalemate between nature and human intellect? The largest problem is simply one of language. When people refer to HIV, Lupus, or Polio, they are referring to a very specific spectrum of infective agents. However, cancer is not just one disease, rather it is hundreds, if not thousands, of diseases lumped together by common characteristics. Each individual type of cancer can acquire its oncogenic roots differently, and cancers that arise from the same cell type can be quite different. Cancer is also caused by the interaction of hundreds of mutations, so it is an extremely daunting task to try to find a way to identify and interfere with specific pathways. Additionally, tumors have the ability to metastasize, which makes them very difficult to treat. These metastases are completely different from the primary tumor due to independently accumulated mutations and therefore call for different treatments (2,3). While some current cancer treatments have been effective in killing or removing cancer cells, such as surgery and radiation therapy, many times these treatments also end up killing healthy cells as well, forcing scientists to utilize the “therapeutic index”, which measures the chances of killing the tumor, versus the chances of killing a normal cell (4).
In the face of all these formidable challenges, researchers have increasingly turned to a new interdisciplinary solution to treat cancer, targeted therapy. This new solution comes at the confluence of nanotechnology, biomolecular engineering, materials chemistry, and other fields to develop more effective drug delivery tools and techniques. The amalgamation and the interaction of these fields confer many advantages over traditional cancer treatment options. Because the size of the particles in these drug delivery systems are measured in nanometers, the toxicity of many of these targeted therapies decrease significantly. Introduction into the body also becomes a more manageable task since the particles can be immediately absorbed into human tissues. It has even been reported that inhaled nanoparticles could reach the bloodstream from the lungs and make their way into other targeted sites, such as the liver or heart. Through the manipulation and selection of certain chemical materials, these particles can also be programmed to only release the drug when placed in a certain environment, making treatment more personalized and tumor specific (5).
Researchers from Brown University and the University of Rhode Island have utilized this strategy to develop a solution that takes advantage of the acidity of cancer cells. They have employed gold nanoparticles tethered to pHILPs (pH low-insertion peptides), natural acid-seeking compounds, to hone in on the high acidity of the malignant cells. Then they focus the energy of radiation into the area directly around the cancer cells. The radiation causes the nanoparticles to release a stream of electrons, inflicting damage on nearby cells. This nanoparticle harnesses the Auger effect, which allows gold atoms to interact with radio waves to release extra electrons due to the unique arrangement of electrons orbiting gold atoms. These effects allow for a very localized reaction. The team of researchers employed computer simulations and models to establish the quantitative details along with the convoluted calculations that creating this nanoparticle necessitated (6).
Physics and the properties of light and magnetism have also been enlisted in the fight against cancer to not only create new nanoparticles that can carry drugs, but also ones that can enhance the crude, but widespread, treatments used today. Researchers have used magnetic nanoparticles to deliver heat directly to cancerous tumors. Applying heat directly to tumors allows for increased efficacy of radiotherapy and chemotherapy and reduces the needed dose. These magnetic nanoparticles made out of iron oxide are just a few tens of nanometers in diameter. They heat up when exposed to a powerful magnetic field and direct that heat to the tumors. Choosing the right kind of particle is crucial because different structures of nanoparticles deliver different doses of heat (7). Another study at Oregon state has developed a new system to selectively insert naphthalocyanine into cancer cells to allow for more accurate surgical removal of solid tumors and to eradicate any remaining cancer cells. Naphthalocyanine is special in that when exposed to near-infrared light, it can make a cell glow as a guide for surgeons. It allows them to know where to cut. It can also produce reactive oxygen species which can also kill the cancer cells directly. These two characteristics make it extremely attractive as a two-prong solution to cancer treatment. However, a couple problems with this compound are that it isn’t water soluble and it has a tendency to aggregate inside the body, so the researchers added a dendrimer, which is a special water-soluble nanoparticle, to encapsulate the napthlaocyanine. Dendrimers can slip easily into any tumor, but will largely spare any healthy tissue. To append to the list of positive attributes of this solution, not only was the phototherapy successfully shown to destroy malignant tumors, but the laboratory mice also showed no apparent side effects or weight loss after the surgery (8).
Because of the thorough design that goes into these nanoparticles, different drugs can be combined to increase the efficacy of the treatments and to even target some of the harder to kill cancer cells.
A research team at the Cancer Science Institute of Singapore demonstrated the use of nanotechnology alongside existing chemotherapy drugs as agents against chemoresistant cancer stem cells. What makes cancer stem cells unique is their usually high resistance to chemotherapy, which can lead to cancer recurrence. The nanoparticle that was developed was termed nanodiamond-epirubin drug delivery complex. As the name suggests, the widely used chemotherapy drug epirubicin was attached to nanodiamonds, which are carbon structures with a diameter of around five nanometers. This combination of the chemotherapy drugs with the nanomaterials allowed for a broader range of protection in a capsule that is both safer and more effective. (9)
In a recently published article, a team of researchers used graphene strips to carry two anticancer drugs, namely TRAIL and doxorubicin, in a sequential manner to cancer cells, with each drug targeting the particular part of the cell where it has the highest efficacy. TRAIL, which is an anticancer protein, serves as an active targeting molecule that can bind directly to the cancer cell’s surface. Therefore, it is most effective when delivered to the external membrane of the cancer cell. On the other hand, doxorubicin works by intercalating DNA and it most effective when delivered to the nucleus. The scientists utilized doxorubicin’s molecular structure to bind it to graphene and peptides to similarly bind TRAIL to the graphene. When this nanoparticle first comes into contact with a cancer cell, the receptors on the surface of the cell latch onto the TRAIL. The cell then absorbs the remainder of the graphene with doxorubicin, beginning a process to trigger cell death (10).
This same group of researchers has also devised “nanodaisies” that have demonstrated promise to treat leukemia, breast, prostate , liver, ovarian and brain cancers. These “nanodaises” are made with a polymer called polyethylene glycol (PEG), which has long strands with shorter strands branching on either side. The researchers then utilized the hydrophilic properties of PEG and the hydrophobic properties of anti-cancer drugs camptothecin (CPT) and doxorubicin to create this daisy-shaped drug cocktail. The resulting particle is only 50 nanometers in diameter, which allow for easy delivery into the patient via injection. Once inside the patient, the nanodaisies are absorbed by the cancer cells and the two drugs attack the nucleus via different mechanisms, which allows for a proven increase in efficacy of this approach (11).
New drug delivery systems are not only combining cancer drugs with other cancer drugs, but also with DNA as well. Jordan Green of the Johns Hopkins University School of Medicine Biomedical Engineering Department designed a nanoparticle delivery system that targets deadly brain gliomas rat models and it has been shown to significantly extend the lives of those treated rats. These nanoparticles are loaded with DNA encoding for the HSVtk protein. This gene produces an enzyme that converts ganciclovir–which in its natural state has no effect on cancer cells– into a potent destroyer of glioma cells. This team tested a variety of polymer structures for their ability to encapsulate and deliver DNA into the rat glioma cell lines. Their tests found that the polymer known as PBAE447 was the most efficient in delivering the gene and was shown to be 100% effective in killing both of the glioma cell lines when combined with ganciclovir. Similar results were found using live rat models as well. This system avoids the problems associated with viral delivery methods such as toxicity, a triggered immune response against the virus, and the possibility for the virus itself to induce tumorigenesis. It is far more effective than traditional drug and radiation therapies (12).
However, these improvements do not come without a cost. It is predicted that these new treatments will have a significant cost in research and production. Others worry that like many antibiotic resistant bacteria, cancer cells will also become resistant to these targeted therapies. In the future, this would necessitate the use of even harsher drugs to treat patients for the same diseases (13). Another huge concern that critics of targeted therapy have is the permanence of the nanoparticles. While some have the ability degrade and dissolve easily, others that aren’t degradable or soluble can accrue in the human body for a sustained period of time.
Despite still being in a state of infancy, targeted therapy is making significant strides in prevention, detection, and eradication of what has been largely known throughout the course of human history as an incurable disease. With new discoveries and advances in nanotechnology, biomedical engineering, and chemistry occurring daily, this interdisciplinary approach is quickly gaining more and more traction from oncologists and researchers worldwide. To neglect the sophisticated advantages of targeted therapy is to forgo one of the most promising interdisciplinary innovations in cancer treatment that may finally put a cure for cancer within reach.
References:
- Knapton, S. (2014, August 29). Let’s stop trying to cure cancer, says cancer professor. Retrieved September 28, 2015, from http://www.telegraph.co.uk/news/science/science-news/11062255/Lets-stop-trying-to-cure-cancer-says-cancer-professor.html
- Gorski, D. (2011, February 14). Why haven’t we cured cancer yet? Retrieved September 28, 2015, from https://www.sciencebasedmedicine.org/why-havent-we-cured-cancer-yet/
- Gorski, D. (2011, April 26). The complexity of cancer: A science-based view. Retrieved September 28, 2015, from https://www.sciencebasedmedicine.org/the-complexity-of-cancer/
- Anders, C. (2012, February 7). Cancer is just as deadly as it was 50 years ago. Here’s why that’s about to change. Retrieved September 28, 2015, from http://io9.com/5883180/why-havent-we-cured-cancer-yet
- (n.d.). Retrieved September 28, 2015, from http://ec.europa.eu/health/scientific_committees/opinions_layman/en/nanotechnologies/l-2/6-health-effects-nanoparticles.htm
- P. Antosh, et al., Enhancement of radiation effect on cancer cells by gold-pHILP. Proceedings of the National Academy of Science of the United States of America 112, 5372-5376 (2015).
- L. Dennis, et al., Internal Magnetic Structure of Nanoparticles Dominates Time-Dependent Relaxation Processes in a Magnetic Field. Advanced Functional Materials 25, 4300-4311 (2015).
- Tarantula, B. S. Doddapaneni, C. Schumann, et al., Napthalocyanine-Based Biodegradable Polymeric Nanoparticles for Image-guided Combinatorial Phototherapy. Chemistry of Materials 27, 6155-6165 (2015).
- Wang, X.C. Low, W.Hou, L.N. Abdullah, T. B. Toh, M. A. Rashid, D. Ho, E. Chow. Epirubicin-Absorbed Nanodiamonds Kill Chemoresistant Hepatic Cancer Stem Cells. ACS Nano 8,12151-12166 (2014).
- Jiang, W. Sun, et al.,Furin-Mediated Sequential Delivery of Anticancer Cytokine and Small-Molecule Drug Shuttled by Graphene. Advanced Materials 27, 1021-1028 (2015).
- Tai, R. Mo, Y. Lu, T. Jiang, Z. Gu, Folding Graft Copolymer with Pedant Drug Segment for Co-delivery of Anticancer Drugs. Biomaterials (2014).
- Mangraviti, et al., Polymeric Nanoparticles for Nonviral Gene Therapy Extend Brain Tumor Survival in Vivo. ACS Nano 9, 1236-1249 (2015).
- The Promise of Targeted Therapy. (n.d.). Retrieved September 28, 2015, from http://cisncancer.org/research/new_treatments/targeted_therapy/promise.html