Noninvasive Management of Coronary Artery Disease Using Nanotechnology

Pearl Ayamba, Justin James, Marzea Makarrama, Mahmuda Ahmed

English 21003

Professor Susan Delamare

May 14, 2019

Abstract

Providing long-term, safe, and effective treatments for managing coronary artery disease (CAD) is crucial due to its high mortality rates. Nanotechnology provides an alternate non-invasive approach for treating CAD due to it being less invasive and more effective. Hua & Wu (2018), Zhao et al. (2014), Winter et al. (2006), Myerson et al. (2011) among others, all provide supporting data for using nanotechnology in CAD treatment. These articles are used to provide evidence for how nanotechnology can be used in managing CAD by regulating lipoproteins, reducing angiogenesis, modulating macrophage levels, and decreasing intra-arterial thrombosis. Rhee & Wu takes into account the limitations of this approach as there needs to be examination for biocompatibility of nanomaterials for potential toxicity in the host (2013). This paper analyzes the various complications associated with coronary artery disease and reaches a common ground in terms of the best treatment methods of CAD. Our consensus, despite the given limitations, nanotechnology is a safer, faster, and less invasive way in treating CAD compared to traditional treatments.

Noninvasive Management of Coronary Artery Disease Using Nanotechnology

Coronary artery disease (CAD) causes atheroma, which is the breaking down of arteries with the excess buildup of plaque, which is abnormal fatty deposits (“Atheroma”, 2003). The buildup of plaque makes blood vessels narrow, resulting in lower blood flow (“Coronary Artery Disease,” 2019). Due to its susceptibility to rupture, plaque can trigger blood clots (Ashley & Naibauer, 2004). This, along with other complications involved in CAD, stem from a variety of activities or habits that do not favor the ability of the heart to function properly.

Current treatment of CAD include lifestyle changes, medication, and procedures. Lifestyle changes include stop smoking, healthier and more nutritious meals and snacks, exercising, losing excess weight, and lowering stress (“Coronary Artery Disease,” 2019 para. 1-10). Medications include beta blockers, which slows heart rate, decreases blood pressure, and reduces risk of heart attacks, and aspirin, which is a blood thinner (para. 6). Other medications include cholesterol modifiers and nitroglycerin which decreases the amount of cholesterol in the blood and dilates coronary arteries, respectively (para. 6). The current procedures include coronary artery bypass surgery, which is very invasive, and angioplasty and stent placement, which are not as invasive but still have major complications (para. 4).

Despite this amount of medication and treatments for CAD, according to the Center for Disease Control and Prevention (CDC), in the United States, it is estimated that about 630,000 Americans die from heart disease, which is equivalent to 1 in 4 deaths (CDC, 2017). Furthermore, the CDC reports that CAD is the most common form of heart disease, which kills at least 370,000 people annually (CDC, 2017).

Due to these staggering statistics, it is evident that innovative therapeutic interventions, such as targeted nanomedicine, is necessary for decreasing the prevalence of this health outcome. According to Dictionary.com, nanotechnology is technology that is less than 100 nanometers used for controlling atoms and molecules (“Nanotechnology”, 2019). The merge between nanotechnology and medicine occurred in the early 1960s after Albert Hibbs’ idea of creating micro machines that performs surgery at the cellular level (Ambesh et al., 2017). From that point to the current, much research has been done on using nanotechnology as a targeted drug delivery system in different disease models.

One of these diseases is CAD. Currently, extensive research is being done in using nanotechnology to noninvasively manage CAD. Nanotechnology can be used to clear up the plaque formed in the artery. Using this method provides the opportunity to target more than one artery at a time, making it as effective as bypass surgery. Due to these reasons, using nanotechnology has great potential as a noninvasive treatment for coronary artery disease.

Literature Review

Nanotechnology provides a targeted therapeutic delivery to specific cells, which drastically decreases the total drug consumption and severity of side effects (Hua & Wu, 2018). This study explains that the drugs used in nanotechnology typically are encapsulated within these nanostructures and are only released at specific points in the body (2018). Due to the vascular permeability and decreased lymphatic drainage induced by inflammation in many diseases, nanotechnology is efficient in the bodily retention and increased action of the medication (Hua & Wu, 2018).

Managing low-density lipoprotein (LDL) and high density lipoprotein (HDL) levels is crucial in CAD treatment. Since CAD worsens due to narrowing of the heart vessels from LDL deposits on the vessel walls, a lot of research has been done in using nanotechnology to lower LDL levels and increase HDL levels (Zhao et al., 2014). Zhao et al. explain that HDL is significant in managing CAD because HDL lowers the cholesterol that is being transported by the LDL (2014). In their study, Cho et al. created HDL-like nanoparticles that showed reduced aortic plaque volume and reduced cholesterol content by 30% to 40% (2014). This nanomedicine study demonstrates that nanotechnology has great potential to affect plaque by managing the levels of HDL and LDL in the goal of treating CAD.

Another characteristic of CAD is angiogenesis, which is the formation of new arteries within plaque that causes intraplaque hemorrhage (Winter et al., 2006). Winter et al. explain that the treatment for anti-angiogenesis is fumagillin, but high doses of it causes neurocognitive impairment (2006). In order to combat this, they delivered fumagillin encapsulated in paramagnetic nanoparticles tagged with integrin which has a high affinity for plaque (2006). In this study, the nanoparticles were injected into rabbits, and the scientists developed MRI and post processing techniques to examine angiogenesis. Winter et al. showed that targeted therapy with the drug results in significant decrease in angiogenesis as compared to non-treated rabbits (2006). This study demonstrates the nanoparticles can be used to treat CAD, by decreasing angiogenesis.

Macrophage cells play an important role in CAD by releasing chemicals that promote plaque rupture (Nakashiro et al., 2016). According to Nakashiro et al., pioglitazone decreases macrophage polarization, which decreases the release of chemical that promotes plaque rupture (2016). This study used bioabsorbable (lactic-go-glycolic-acid) nanoparticles to deliver pioglitazone in mice to determine whether there was a decrease in fibrous caps, which acts as a marker for plaque rupture. It resulted in a decrease in fibrous caps in mice that were administered pioglitazone nanoparticles compared to control mice that were not administered the drug nor the nanoparticles. This study demonstrates the potential for the use of nanoparticles in the management of CAD.

Another noninvasive method of managing CAD using nanotechnology is by affecting intra-arterial thrombosis. Intra-arterial thrombosis is when arteries are clogged by ruptured plaques resulting in heart attacks (Ambesh et al., 2017).  PPACK is an anticoagulant, which decreases the possibility of thrombosis, however, when used alone, it is too dangerous for it decreases the body’s ability to produce blood clots when healing cuts (Myerson, He, Lanza, Tollefson, &Wicklin, 2011). In a study, the authors synthesized perfluorocarbon core nanoparticles with PPACK and administered this in mice with carotid artery injury (Myerson et al., 2011). They found that nanoparticles with PPACK outperformed heparin, a commonly used anticoagulant, and PPACK alone. This is another study that exemplifies the advantage using nanotechnology to manage CAD.

Discussion

From the aforementioned articles, it can be seen that using nanotechnology for treating CAD will limit the side effects that other invasive treatment methods provide. This innovative measure is more effective for treating CAD than traditional treatments for CAD, such as fumagillin, pioglitazone, and heparin. For this reason, nanotechnology is very useful and effective for CAD management. Like any other new design, nanomedicine has its constraints. However, these are only emerging because of the experimental design of nanomedicine, with further research these hindrances can be controlled.

Limitations

As summarized by Rhee & Wu, all the implications of nanomedicine have been applied through in vitro measures (2013), or through in vivo experimentation on animals. However, there are no accounts of clinical testing on patients with CAD. Also, there needs to be examination for biocompatibility of nanomaterials for potential toxicity or host immune response (Rhee & Wu, 2013). Not everyone’s body will react the same when inserting nano carriers into them. For such cardiovascular diseases, if careful precautions are not taken, it may lead to adverse effects. One safety measure is with the manufacturing process of nano-machines, even the tiniest speck of contaminant can result in impaired nano- infrastructure (Ambesh et al., 2017). Another, is the direct toxicity inside the living cell based on the chemical format of the nanoparticles (Ambesh et al., 2017).  Legislative limitations include the Food and Drug Administration (FDA) not providing a particular definition for nanotechnology and related areas (Soares, Sousa, Pais, & Vitorino, 2018). They will continue post-market monitoring for products containing nanomaterials to protect consumers (FDA’s Approach to Regulations, 2018).

Conclusion and Future Studies

The main purpose behind nanomedicine as being considered a treatment for CAD is because the current methods of treatments are risky, and are not permanent solutions to the problem. Many patients return to the hospital due to the risk of plaque reformation and stents collapse in narrow heart vessels. Another current treatment issue is being unable to target specific fat in the body when injecting HDL to balance the level of LDL, which came with the risk of protective fat surrounding the organs becoming damaged. However, with the precision abilities of nanomedicine, it will be possible to have a less invasive and more targeted procedure, which decreases the risk of death during surgery or going through painful recovery.

Researchers continue to plan future methods to use nanomedicine. One plan is to equip nano-particles with immune stimulating molecules. Once injected into the patient, it can strengthen the body’s own immune system to detect and fight diseases which were not recognizable before. A big step forward that is a concern for many, is having a consensual clinical trial. Nanotechnology has only been tested in animals or in a test tube; therefore, researchers are concerned with how the nanotechnology will react in humans. Once further research is done on nanotechnology in managing CAD, this innovative measure can hopefully bring drastic change to the management and health outcome of CAD.

References

Atheroma. (2003). In Merriam-Webster.com. Retrieved from https://www.merriam-webster.com/dictionary/atheroma.

Ambesh, P., Campia, U., Obiagwu, C., Bansal, R., Shetty, V., Hollander, G., & Shani, J. (2017). Nanomedicine in coronary artery disease. Indian heart journal, 69(2), 244–251. doi:10.1016/j.ihj.2017.02.007. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414944. Pubmed

Cannon, C. P., Steinberg, B. A., Murphy, S. A., Mega, J. L., & Braunwald, E. (2006). Meta-Analysis of Cardiovascular Outcomes Trials Comparing Intensive Versus Moderate Statin Therapy. Journal of the American College of Cardiology, 48(3), 438-445. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16875966. Pubmed

Center for Disease Control and Prevention. (2017). “Heart Disease Facts” National Center for Chronic Disease Prevention and Health Promotion, Division for Heart Disease and Stroke Prevention. Retrieved from https://www.cdc.gov/heartdisease/facts.htm.

Coronary Artery Disease. (2019, February 14). Cleveland Clinic. Retrieved from https://my.clevelandclinic.org/health/diseases/16898-coronary-artery-disease.

FDA’s Approach to Regulation of Nanotechnology Products. (2018, March 23). Retrieved from https://www.fda.gov/science-research/nanotechnology-programs-fda/fdas-approach-regulation-nanotechnology-products.

Hua, S., & Wu, S. Y. (2018). Editorial: Advances and Challenges in Nanomedicine. Frontiers in pharmacology, 9, 1397. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281879/. Pubmed

Myerson, J., He, L., Lanza, G., Tollefsen, D., & Wickline, S. (2011). Thrombin-inhibiting perfluorocarbon nanoparticles provide a novel strategy for the treatment and magnetic resonance imaging of acute thrombosis. Journal of thrombosis and haemostasis, 9(7), 1292–1300. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3686484/. Pubmed

Nakashiro, S., Matoba, T., Umezu, R., Koga, J., Tokutome, M., Katsuki, S., . . . Egashira, K. (2016). Pioglitazone-Incorporated Nanoparticles Prevent Plaque Destabilization and Rupture by Regulating Monocyte/Macrophage Differentiation in ApoE −/− Mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 36(3), 491-500.

doi: 10.1111/j.1538-7836.2011.04339.x. Pubmed

Nanotechnology. (2019). In Dictionary.com. Retrieved from https://www.dictionary.com/browse/nanotechnology.

Rhee, J. W., & Wu, J. C. (2012). Advances in nanotechnology for the management of coronary artery disease. Trends in cardiovascular medicine, 23(2), 39–45. doi:10.1016/j.tcm.2012.08.009 Pubmed

Soares, S., Sousa, J., Pais, A., & Vitorino, C. (2018). “Nanomedicine: Principles, Properties, and Regulatory Issues.” Front. Chem. 6:360. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109690/. Pubmed

Winter, P.M., Neubauer, A.M., Caruthers, S.D., Harris, T.D., Robertson, J.D., Williams, T.A.,… Lanza, G.M. (2006). “Endothelial ανβ3 Integrin–Targeted Fumagillin Nanoparticles Inhibit Angiogenesis in Atherosclerosis.” Arteriosclerosis, Thrombosis, and Vascular Biology, 26(9): 2103-2109. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16825592. PubmedZhao, Y., Black, A. S., Bonnet, D. J., Maryanoff, B. E., Curtiss, L. K., Leman, L. J., & Ghadiri, M. R. (2014). In vivo efficacy of HDL-like nanolipid particles containing multivalent peptide mimetics of apolipoprotein A-I. Journal of lipid research, 55(10), 2053–2063. doi:10.1194/jlr.M049262. Pubmed