Use of Sonoporation to Increase Pancreatic Cancer Treatment Efficacy Without Additional Toxicity

 

                Figure 1 Changes in overall survival across multiple cancers between 1971 and 2011.        

Credit: Cancer UK; from (2) Cancer Research UK. (2019, July 19). Cancer survival for common cancers. Retrieved October 14, 2020, from https://www.cancerresearchuk.org/health-professional/cancerstatistics/survival/common-cancers-compared.

    Pancreatic Ductal Adenocarcinoma (PDAC) is currently one of the most difficult to treat types of cancer, with an overall five-year survival rate of only 9%, and an increase in death rates between 2012 and 2016 (1). There has been very little progress in PDAC treatment efficacy despite decades of research. This in in contrast to many other cancer types which have seen significant improvements in available treatment options, as seen in figure 1 (2). This sets PDAC apart as an area of particular importance for developing effective treatment strategies to try to overcome many of these difficulties. 

    PDAC is a disease that develops from non-malignant precursor lesions that progress slowly, often taking years to adapt a metastatic phenotype and developing into an advanced stage invasive cancer(3,4). At this point, disease progression becomes much more rapid, contributing to the poor survival rates (5). This pattern of progression is perhaps the largest hurdle that clinicians need to overcome, as during this long period of growth and development most patients experience no symptoms at all, making early detection or treatment next to impossible (6). Because of this, when most patients are finally diagnosed the disease is already at an advanced stage, with less than 20% of PDAC diagnoses shown to be surgically resectable due to tissue invasion or metastasis (7). This puts an emphasis on the need for non-surgical treatment options, but these treatments have many of their own problems.

    PDAC is characterized by a highly desmoplastic and fibrotic microenvironment surrounding the tumor core, packed with immune cells and cancer-associated fibroblasts that produce large amounts of extracellular matrix factors (8). This microenvironment serves to isolate the tumor core, which is the reason why most patients are asymptomatic. However, it also serves as very effective barrier for chemotherapy treatments (9), and because most drugs have difficulties reaching the tumor core they are developed to act on, even the most promising drugs will inevitably prove ineffective. Currently, the most effective chemotherapeutic agent is FOLFIRINOX, which is a combination of oxaliplatin, irinotecan, fleurouracil, and leucovorin that has been shown to increase overall survival by 11.1 months (10). However, this efficacy comes with a price of high toxicity, with serious side effects including severe fatigue, sensory neuropathy, anemia, thrombocytopenia, and diarrhea. Because of the toxicity of FOLFIRINOX, many patients are not able to receive this treatment due to poor health. As a way of providing some treatment to patients who cannot withstand the toxicity of FOLFIRINOX, gemcitabine along with albumin-bound paclitaxel (nab-paclitaxel) can be administered to increase overall survival by 8.5 months with a much better safety profile (11, 12). However, these patients have to settle for suboptimal therapy, so there is certainly a need to find a way to increase the efficacy of chemotherapy in these patients without increasing toxicity.  

Figure 2 Visualization of microbubble forces in sonoporation. 

From (14) Fan, Z., Kumon, R. E., & Deng, C. X. (2014). Mechanisms of microbubble-facilitated sonoporation for drug and gene delivery. Therapeutic delivery, 5(4), 467-486.

doi:10.4155/tde.14.10

    To address this issue, studies are being performed using sonoporation in conjugation with less toxic PDAC treatments including gemcitabine and paclitaxel to try and elicit a more effective response. Sonoporation involves the use of microbubbles that, along with ultrasound stimulation, can result in temporary formations of small pores in the nearby cells (13). These pores are created by the forces generated by the microbubbles as they are manipulated by the ultrasound waves (14). The different types of forces can be seen illustrated in figure 2. The idea behind using this technique is that creating these pores will facilitate drug entry into cells, both increasing efficacy and reducing the required dose.

Additionally, sonoporation can be localized to very specific areas depending on ultrasound administration, and the process is very safe, as microbubbles have been used for many years as a contrast agent in ultrasound imaging (15).

Figure 3 Overall survival increases seen in patients treated with gemcitabine + sonoporation. 

From (17) Dimcevski, G., Kotopoulis, S., Bjånes, T., Hoem, D., Schjøtt, J., Gjertsen, B. T., . . . Gilja, O. H. (2016). A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer. Journal of Controlled Release, 243, 172-181.

doi:https://doi.org/10.1016/j.jconrel.2016.10.007

    Initial tests of this technique applied in orthotopic xenograft mouse models of PDAC demonstrated a significant decrease in tumor volume compared to normal gemcitabine treatment alone, as well as an increased survival rate in the mice treated with sonoporation (16). These results were very promising, and prompted a shift to human clinical trials to understand if sonoporation could result in more effective treatments without toxicity. Testing sonoporation + gemcitabine chemotherapy in patients with inoperable pancreatic cancer proved quite successful. Median survival of patients was increased from 8.9 months to 17.6 months, and patients were able to undergo more cycles of chemotherapy. Many patients also experienced an overall decrease in tumor volume (17). These results are very promising, and demonstrate the potential utility of sonoporation in conjunction with chemotherapy as a means of increasing treatment efficacy without putting the patient at a higher risk of toxicity. However, much work remains to be done to determine the ideal conditions to ensure the greatest efficacy increase while maintaining a safe profile. 

By Zeke Rozmus, A Master of Medical Science Student at the University of Kentucky

 References:

1.    Siegel, R. L., Miller, K. D., & Jemal, A. (2019). Cancer statistics, 2019. CA Cancer J Clin, 69(1), 7-34. doi:10.3322/caac.21551

2.    Cancer Research UK. (2019, July 19). Cancer survival for common cancers. Retrieved October 14, 2020, from https://www.cancerresearchuk.org/health-professional/cancer-statistics/survival/common-cancerscompared

3.    Hidalgo, M. (2010). Pancreatic cancer. N Engl J Med, 362(17), 1605-1617. doi:10.1056/NEJMra0901557

4.    Yachida, S., Jones, S., Bozic, I., Antal, T., Leary, R., Fu, B., . . . Iacobuzio-Donahue, C. A. (2010). Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature, 467(7319), 1114-1117. doi:10.1038/nature09515

5.    Yu, J., Blackford, A. L., Dal Molin, M., Wolfgang, C. L., & Goggins, M. (2015). Time to progression of pancreatic ductal adenocarcinoma from low-to-high tumour stages. Gut, 64(11), 1783-1789. doi:10.1136/gutjnl-2014-308653

6.    Bekkali, N. L. H., & Oppong, K. W. (2017). Pancreatic ductal adenocarcinoma epidemiology and risk assessment: Could we prevent? Possibility for an early diagnosis. Endoscopic ultrasound, 6(Suppl 3), S58-S61.

doi:10.4103/eus.eus_60_17

7.    Sohn, T. A., Yeo, C. J., Cameron, J. L., Koniaris, L., Kaushal, S., Abrams, R. A., . . . Lillemoe, K. D. (2000).

Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg, 4(6), 567-579. doi:10.1016/s1091-255x(00)80105-5

8.    Dauer, P., Nomura, A., Saluja, A., & Banerjee, S. (2017). Microenvironment in determining chemo-resistance in pancreatic cancer: Neighborhood matters. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.], 17(1), 7-12. doi:10.1016/j.pan.2016.12.010

9.    Oberstein, P. E., & Olive, K. P. (2013). Pancreatic cancer: why is it so hard to treat? Therapeutic advances in gastroenterology, 6(4), 321-337. doi:10.1177/1756283X13478680

10.  Conroy, T., Desseigne, F., Ychou, M., Bouché, O., Guimbaud, R., Bécouarn, Y., . . . Ducreux, M. (2011).

FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. New England Journal of Medicine, 364(19), 1817-1825. doi:10.1056/NEJMoa1011923

11.  Von Hoff, D. D., Ervin, T., Arena, F. P., Chiorean, E. G., Infante, J., Moore, M., . . . Renschler, M. F. (2013).

Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine. New England Journal of Medicine, 369(18), 1691-1703. doi:10.1056/NEJMoa1304369

12.  Ellenrieder, V., König, A., & Seufferlein, T. (2016). Current Standard and Future Perspectives in First- and Second-Line Treatment of Metastatic Pancreatic Adenocarcinoma. Digestion, 94(1), 44-49. doi:10.1159/000447739

13.  Delalande, A., Kotopoulis, S., Rovers, T., Pichon, C., & Postema, M. (2011). Sonoporation at a low mechanical index. Bubble Science, Engineering & Technology, 3(1), 3-12. doi:10.1179/1758897911Y.0000000001

14.  Fan, Z., Kumon, R. E., & Deng, C. X. (2014). Mechanisms of microbubble-facilitated sonoporation for drug and gene delivery. Therapeutic delivery, 5(4), 467-486. doi:10.4155/tde.14.10

15.  Erchinger, F., Dimcevski, G., Engjom, T., & Gilja, O. (2011). Transabdominal ultrasonography of the pancreas: basic and new aspects. Imaging in Medicine, 3, 411-422. 

16.  Kotopoulis, S., Delalande, A., Popa, M., Mamaeva, V., Dimcevski, G., Gilja, O. H., . . . McCormack, E. (2014). Sonoporation-Enhanced Chemotherapy Significantly Reduces Primary Tumour Burden in an Orthotopic Pancreatic Cancer Xenograft. Molecular Imaging and Biology, 16(1), 53-62. doi:10.1007/s11307-0130672-5

17.  Dimcevski, G., Kotopoulis, S., Bjånes, T., Hoem, D., Schjøtt, J., Gjertsen, B. T., . . . Gilja, O. H. (2016). A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer. Journal of Controlled Release, 243, 172-181.

doi:https://doi.org/10.1016/j.jconrel.2016.10.007

 

High Blood Pressure in the US: A Pharmacological and Cultural Problem

 

Extracted from source 3: Holland, K. (2020, June 17). High Blood Pressure: Causes, Symptoms, Medication, Diet, and More. Retrieved October 03, 2020, from https://www.healthline.com/health/high-blood-pressure-hypertension 

     It is no surprise that high blood pressure remains a growing problem in the United States. In 2018, alone half a million deaths were attributed to complications associated with hypertension (1). The current leading cause of death for the United States is heart disease with hypertension contributing greatly to the fatalities (2). With a rise in the overall number of hypertension cases in the US, the amount of prescribed blood pressure medication has also been on the rise. Currently, the American Heart Association guidelines define hypertension as a blood pressure at or above 130/80 mmHg with stage 2 hypertension being above 140/90 mmHg (1). The current treatment for diagnosed high blood pressure is usually a high blood pressure medication (4). Common hypertension medications include diuretics, beta blockers, ACE inhibitors, alpha blockers, calcium channel blockers, and central agonists. Medication options are prescribed by the physician based on their potential to alleviate the symptoms that the patient presents as well as incur the side effects. Most treatment options are coupled with medication as well as changes in lifestyle to help alleviate symptoms of high blood pressure. Unfortunately, it appears that most patients are reluctant to major lifestyle changes but instead prefer to rely on the use of medications. 

    With the increasing percent of the population succumbing to high blood pressure and the associated cardiovascular diseases, it is important to spread awareness of treatment options as well as advocate for lifestyle changes. Unfortunately, the issue of high blood pressure is very complicated and ingrained within layers of socioeconomic and health predispositions. While blood pressure medications have been shown to significantly reduce the risk of cardiovascular disease, taking these medications in concert with a healthy lifestyle and diet are also important. 

Image extracted from source 1: Facts About Hypertension. (2020, September 08). Retrieved October 03,  2020, from https://www.cdc.gov/bloodpressure/facts.htm 

    It is also important to acknowledge that cases of hypertension have increased with change in diagnostic guidelines as well as the increased availability of healthcare services in less affluent areas. Most high blood pressure cases in the United States have appeared to be in the southern regions with 32 – 38% of adults 20 years and older being diagnosed with hypertension (1). Young adults in the US have been shown to have increased sodium and potassium in their diets that have helped to contribute to increased levels of high blood pressure (7).  In other countries, it has be shown that governmental regulations to lower salt concentrations by 30% has led to a reduction of 10 mmHg in the average population (8). Other ways to help lower high blood pressure without the use of medication include regular exercise, healthier diet, limiting caffeine and alcohol use, cutting out smoking, and reducing daily stress(9). Ultimately the use of medications to lower hypertension is effective, but it is important to improve daily lifestyle habits in order to continually improve blood pressure. The use of medication is not intended to be used to maintain the diet and lifestyle that had led to the initial hypertension.  

Image extracted from source 11:  Socioeconomic Environment. (n.d.). Retrieved October 03, 2020, from https://www.healthandenvironment.org/environmental-health/environmental-risks/socioeconomic-environment 

    Ideally, the goal would be to overall lower the number of hypertension cases in the United States, however it is important to acknowledge the many barriers that limit this success. Unfortunately, studies have shown that socioeconomic status is directly tied to increased risk of developing cardiovascular disease (10). Lower income areas have less access to both healthy foods as well as workout facilities that are prominent in much more affluent areas. This perpetuates the cycle of increased blood pressure as lower income families are not only constantly under immense stress financially, but also faced with the fact that heavily processed foods are more readily available and cheaper than fresh produce. Not only are they disadvantaged with the limited resources available, but also, they are less likely to seek medical care unless necessary due to fear of healthcare costs.  

    While it is encouraging that there has been more attention focused on the prevalent problem of increased blood pressure in the United States, it is important to understand this problem is not easily fixed by just prescribing hypertension medication. These medications do help to decrease blood pressure in patients that have already presented hypertension symptoms, however it is equally crucial to focus on preventative measures. There must be efforts in culturally changing lifestyles and diet by making healthier food options readily available as well as providing opportunities to improve the overall health of those that would not have the opportunity otherwise. The problem has been identified and medications have been used to mitigate outcomes, but the focus must turn to preventing the problem in the first place.  

By James Warinner, A Master of Medical Science Student at the University of Kentucky 

 References

1. Facts About Hypertension. (2020, September 08). Retrieved October 03, 2020, from https://www.cdc.gov/bloodpressure/facts.htm
2. FastStats - Leading Causes of Death. (2020, February 06). Retrieved October 03, 2020, from https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm
3. Holland, K. (2020, June 17). High Blood Pressure: Causes, Symptoms, Medication, Diet, and More. Retrieved October 03, 2020, from
https://www.healthline.com/health/high-blood-pressure-hypertension
4. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. (2003). McLean, VA: International Medical Pub.
5. Types of Blood Pressure Medications. (n.d.). Retrieved October 03, 2020, from https://www.heart.org/en/health-topics/high-blood-pressure/changes-you-can-make-to-manage-high-blood-pressure/types-of-blood-pressure-medications
6. Shah, S. J., & Stafford, R. S. (2017). Current Trends of Hypertension Treatment in the United States. American Journal of Hypertension, 30(10), 1008-1014.
doi:10.1093/ajh/hpx085
7. Chmielewski, J., & Carmody, J. B. (2017). Dietary sodium, dietary potassium, and systolic blood pressure in US adolescents. The Journal of Clinical Hypertension, 19(9),
904- 909. doi:10.1111/jch.13014
8. Barrera, L. (2018). High Blood Pressure prevention and control: From evidence to action. Colombia Médica, 49(2), 137-138. doi:10.25100/cm.v49i2.3940
9. 10 drug-free ways to control high blood pressure. (2019, January 09). Retrieved October 03, 2020, from https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-depth/high-blood-pressure/art-20046974
10. Conen, D., Glynn, R. J., Ridker, P. M., Buring, J. E., & Albert, M. A. (2009). Socioeconomic status, blood pressure progression, and incident hypertension in a prospective cohort of female health professionals. European Heart Journal, 30(11), 1378-1384. doi:10.1093/eurheartj/ehp072
11. Socioeconomic Environment. (n.d.). Retrieved October 03, 2020, from
https://www.healthandenvironment.org/environmental-health/environmental-
risks/socioeconomic-environment

One Pill Fits All: The 3D Printing of Drugs

 

Image from: https://www.the-scientist.com/news-opinion/on-the-road-to-3-d-printed-organs-67187

 The other day I sat with my grandmother, watching her set up her pillbox. There were morning and night pills, once-daily pills, twice-daily pills, big pills and small pills. I sat there thinking, “I can hardly go a week without losing my wallet or keys; there is no way I could ever be so organized as to keep straight this medication regimen”. I thought there must be a better answer for this, and thankfully, scientists over the last 40 years have been working diligently on a solution: 3D printing of drugs. First patented in the 1986 by Charles Hull⁵, this technology is the precipice at which the future of personalized medicine lies; it could truly be the next major revolution in treating patients who are vulnerable to drug toxicity or failure to follow recommended therapies. With 3D drug printing, the possibility exists that instead of 16 pills per day, my grandmother could take one pill, with exactly the right concentration of each active pharmaceutical ingredient (API) personalized to her needs.

Additive manufacturing, or 3D printing, has been a rapidly expanding field in which innovation has driven this technology to applications in practically every industry which currently exists. The market for 3D printing is valued at $13.68 billion dollars for 2020, and is predicted to grow up to a worth in excess of $35B¹² as aggressive research and development takes place over the next several decades. There are several techniques with which an object can be created; each involves a layer-by-layer manufacturing process in which the object is first designed from a computer, and then the blueprint is transmitted to the printing equipment (for additional information into how 3D printing works, I suggest this video). This technique has been used already in the medical field for decades; there are people walking around with 3D printed limbs, rib cages, and jaws. Much like these devices are custom made for individuals, the pharmacotherapy of the 55% of American people who take a prescription medicine can be customized in the same way. Indeed, with Americans taking more prescription drugs than ever, it is no shock that 1.3 million people have ended up in the emergency room to be treated for adverse events related to their medications⁷. This serves as a crucial reminder that we must work to reduce inadvertent drug overdoses and toxic interactions, and increase patient compliance and overall prognosis through their polypharmacy regimens.  All of these  can potentially be accomplished by 3D printing medicines.

Figure 1: Dose flexibility scheme shown for different patient populations, where each pill has precisely the amount of API needed. 

3D drug printing has several key advantages over traditionally mass-produced pills^3,8,9:

1)     Provides dose flexibility, with tailored release profiles and pharmacokinetics

2)     Reduces waste in terms of mass-manufacturing and transport of conventional drugs

3)     Provides opportunity for mass production in remote locations (i.e. disaster zones, outer space, etc.)

The dose flexibility is the most commonly toted benefit, and for good reason.  Being able to change not only the identity of the API as well as their shape can alter the way drugs are released and transported around the body, enhancing both pharmacokinetics and pharmacodynamics of the medicine. 

Figure 2: Printlets showcasing the variety of shapes that can be created. Pills which are less dense will increase the speed of absorption. Also, compliance of pediatric patients may increased by utilizing more interesting shapes and incorporating various flavors. From:  https://www.ondrugdelivery.com/personalising-drug-products-using-3d-printing/

    It is well known that  drug therapy is complicated for certain populations. For example, older people generally have several comorbidities, which may have disease-related decreases in organ functioning. Pharmacogenomics studies have revealed that many of us have different levels of expression for metabolic enzymes which has implications for drugs toxicity.  As an example, we have discussed, warfarin in our 422G course, which is metabolized by a CYP2C9 enzyme. This particular enzyme has common genetic frequencies across patients with different ages and ethnicities⁶.  Thus,  for a patient with abnormal CYP2C9 expression, critically dangerous levels of warfarin can be avoided by taking a 3D printed drug. Children also have a documented need for customized medications.  According to the European Medicines Agency, many products are simply not produced in doses or formulations which meet the safety standards for pediatrics¹¹. Because drugs can be designed with precise spatial control and geometries, fewer excipients and APIs are needed as well¹. This could substantially bring down medication costs for drugs, especially those of rare diseases such as spinal muscular atrophy, where one annual course of treatment can run about $2 million². When one thinks about the logistical benefits of 3D printing, it is easy to see the carbon footprints of mass-scale drug production begin to slowly dissipate. Fuel and energy consumption, as well as the necessary resources to maintain those drugs which are temperature sensitive, would drop to more sustainable levels⁸, and bring cost savings in the billions according to FDA Commissioner Scott Gottlieb⁷. Lastly, 3D printing requires few resources in terms of space and operation of the equipment. This would provide critical medications at the point of care for patients in areas which aren’t reliably accessible can drastically improve outcomes of patients who otherwise may have gone untreated³.

       As we continue to navigate the technologies being developed at break-neck speeds, we must also keep in mind the ethical and regulatory considerations necessary to harness the power of these technologies and ensure they are applied in a safe manner to the global population. The first truly 3D printed drug was brought to market in 2016 by Aprecia⁴, a major milestone in the industry of pharmaceuticals. However,  there are still many hurdles we must cross before 3D drug printing reaches its full pharmacologic potential. Currently, the FDA has not been able to fully translate the regulatory pathways used for conventional drug manufacture to that of 3D printing of drugs, a process known as good manufacturing practices.  These practices state that all parts of the additive manufacturing printer must be able to be easily cleaned, and the printer must be validated to fabricate the pills between acceptable parameter ranges. Quality control of the products remains a big concern as the safe level of reproducibility of certain products has not been achieved. New challenges surrounding personal data security, counterfeit production, and as previously stated, translating the good manufacturing practice protocols from traditional drug production to 3D printed medications, will continue to slow the progress of bringing this technology to mass scale^9,12,13. Currently, none of the various techniques used to 3D print medications are fool-proof; some printers fabricate pills which are too friable, and others use heat or lasers which may degrade the API¹². Until these regulatory needs are met, unfortunately, we are stuck with our imperfect prescribing system. However, the good news is that the FDA and the federal government are continuing to allocate funds to develop the clarity and architecture needed to one day bring 3D drug printing to the masses awaiting its life-saving benefits.

 For more information on this topic, I suggest this Ted talk by Daniel Kraft, who describes the process of biomanufacturing pharmaceuticals, and its application to personalized medicine. https://www.youtube.com/watch?v=-RkhAP0_ms4

By Amy L. Rice, Post-Baccalaureate student at the University of Kentucky 

 References

1.     1.Awad, A., Trenfield, S. J., Goyanes, A., Gaisford, S., & Basit, A. W. (2018). Reshaping drug development using 3D printing. Drug Discovery Today, 23(8), 1547-1555. doi:https://doi.org/10.1016/j.drudis.2018.05.025

2.    2.  Chase, L. (2020, August 25). 10 Most Expensive Drugs in the U.S., Period - GoodRx. Retrieved September 22, 2020, from https://www.goodrx.com/blog/most-expensive-drugs-period/

3.   3.  Fan, D., Li, Y., Wang, X., Zhu, T., Wang, Q., Cai, H., . . . Liu, Z. (2020, January 28). Progressive 3D Printing Technology and Its Application in Medical Materials. Retrieved September 19, 2020, from https://www.frontiersin.org/articles/10.3389/fphar.2020.00122/full

4.   4.  FDA approves first ever 3D printed drug product: Spritam. (2017, June 08). Retrieved September 19, 2020, from https://www.europeanpharmaceuticalreview.com/news/33832/fda-approves-first-ever-3d-printed-drug-product-spritam/

5.   5. Hull, C. W., Modrek, B., Parker, B., Freed, R. S., Almquist, T., Spence, S. T., Albert, D. J., Smalley, D. R., Harlow, R. A., Stinebaugh, P., Tarnoff, H. L., Nguyen, H. D., Lewis, C. W., Vorgitch, T. J., Remba, D. Z., & Vinson, W. B. (1986). U.S. Patent No. US5137662A. Washington, DC: U.S. Patent and Trademark Office.

6.    6. Koukouritaki, S. B., Manro, J. R., Marsh, S. A., Stevens, J. C., Rettie, A. E., McCarver, D. G., & Hines, R. N. (2004). Developmental Expression of Human Hepatic CYP2C9 and CYP2C19. The Journal of Pharmacology and Experimental Therapeutics, 308(3), 956-974. doi:10.1124/jpet.103.060137

7.   7.   Lynch, M. (2019, February 01). Next step in personalized medicine enabled by 3D printing. Retrieved September 22, 2020, from https://www.outsourcing-pharma.com/Article/2019/02/01/Personalized-medicine-enabled-by-3D-printing

8.   8. Preidt, R. (2017, August 03). Americans Taking More Prescription Drugs Than Ever. Retrieved September 22, 2020, from https://www.webmd.com/drug-medication/news/20170803/americans-taking-more-prescription-drugs-than-ever-survey

9.   9. Prasad, L. K., & Smyth, H. (2016). 3D Printing technologies for drug delivery: A review. Drug Development and Industrial Pharmacy, 42(7), 1019-1031. doi:10.3109/03639045.2015.1120743

10 10.  Sandler, N., & Preis, M. (2016). Printed Drug Delivery Systems for Improved Patient Treatment. Trends in Pharmacological Sciences, 37(12), 1070-1080. doi:https://doi.org/10.1016/j.tips.2016.10.002

1111. Scordo, M. G., Aklillu, E., & Ingelman-Sundberg, M. (2001). Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population. British Journal of Clinical Pharmacology, 52(4), 447-450. doi:10.1046/j.0306-5251.2001.01460.x

1212. Trenfield, S. J., Awad, A., Goyanes, A., Gaisford, S., & Basit, A. W. (2018). 3D Printing Pharmaceuticals: Drug Development to Front-line Care. Trends in Pharmacological Sciences, 39(5), 440-451. doi:10.1016/j.tips.2018.02.006

1313. Zhu, X., Li, H., Huang, L., Zhang, M., Fang, W., & Cui, L. (2020). 3D printing promotes the development of drugs. Biomedicine and Pharmacology, 131. doi:https://doi.org/10.1016/j.biopha.2020.110644

1414. 3D Printing Market Size & Share: Industry Trends Report, 2027. (2020, February). Retrieved September 22, 2020, from https://www.grandviewresearch.com/industry-analysis/3d-printing-industry-analysis

 

 

Machine Learning and Drug Discovery

 

(Figure 1). Image extracted from source 1: Uma Introdução à tecnologia Deep Learning para Produção. (n.d.). Retrieved September 29, 2020, from https://www.cognex.com/pt-br/blogs/deep-learning/what-is-deep-learning?page=404

    Have you ever wondered what Machine Learning really is? This is a term that gets thrown around a lot, but how does that differ from conventional programming? Well, machine learning is the branch of computer science that studies and develops learning algorithms for machines. In conventional programming the goal is to give the computer specific instructions -algorithm - to perform the desired task.  On the other hand, in machine learning the goal is to create a generalized set of instructions which allows the machine to learn from data/experience and generate its own algorithms to perform the desired task ². One example I like to use to depict this difference is chess. Imagine you had never played chess before and I gave you two manuals. The first manual consists of a over a billion positions in the chess board and the exact move you should play when faced with each position. However, the second manual consists of a couple pages explaining how each piece is allowed to move, the goal of the game, and the few exceptions to the rules ³. In this case the first manual would be comparable to regular programming while the second manual resembles machine learning. With the first manual you would not need to know anything about chess and you would still be able to play very effectively, whereas with the second manual you would need to play/watch many games to achieve a similar level of play. Just like humans, machine learning systems require extensive training to become proficient at a task. Because of this kind of similarity to us it is considered a form of artificial intelligence (AI). 

  

(Figure 2) “Regular Programming Vs Machine Learning”. Created by Author using Adobe Illustrator.

   Aside from serving as inspiration for great dystopian movie franchises such as The Terminator and The Matrix, AI is actually becoming a very useful tool in modern society. One of the most promising fields for the application of AI is pharmacology. Here machine learning has been used to predict interactions between drugs and their targets, generating new useful molecules, and predicting absorption, distribution, metabolism, excretion, and toxicity ⁴.  The vast amount of data generated by experiments and clinical trials over the years is a rich tool for the development of systems that can improve the process of drug discovery ⁵. These improvements would not only help bring about more effective drugs but could also address a major barrier to drug development, the extensive time and money that is required for this process. Currently it takes about 1-2 billion dollars and 12-15 years of research to develop a drug from scratch ⁶.

    But how are these machine learning algorithms able to extract information from complex chemical     structures? One way this can be accomplished is through a technique called one-hot encoding. This is     how it works, first, we must take a graphical chemical structure, translate it into the SMILES chemical language, and then transform it into a binary table as shown in the figure below ⁷. This step makes it easier for machine learning algorithms to work with the data. Once chemical structures are written in this format, they can be integrated with other information about properties of the molecules such as target interactions, toxicity, distribution, etc. Data on a large number of drugs allows AI systems to generate algorithms capable of inferring structures for new molecules with the desired properties. Even-though this process is still in the early experimental stages, it has already shown promise by aiding in the discovery of new dopamine receptor ligands ⁸.

(Figure 3) “One-hot Encoding Workglow”. Image extracted from source 7: Blaschke, T., Olivecrona, M., Engkvist, O., Bajorath, J., & Chen, H. (2018). Application of Generative Autoencoder in De Novo Molecular Design. Molecular Informatics, 37(1–2), 1700123.

    We are just starting to scratch the surface of what AI aided drug development can accomplish. With further improvements in computational power, learning algorithms, and the increasing amount of data available these techniques should become more efficient and widespread throughout the years ⁹. Another interesting area for development will be the integration of drug discovery and pharmacogenomics through machine learning. One day this technology may assist us in developing drugs catered to people with variants of a gene that render conventional treatments less effective or dangerous. With that being said, there will still be plenty room for humans to work in drug development. The goal is not to substitute people but rather to integrate machine and human intelligence so that both sides can work where they are best suited ¹⁰. In this manner, machines will be able to provide us with insight and improve the quality of our work. I believe that AI has great potential in many areas of human endeavor including drug development. But as any other powerful new tool we must be wise in going forward to augment its benefits while deterring its pitfalls.

 

    

By: Bernardo Aguzzoli Heberle

References:

1.      Uma Introdução à tecnologia Deep Learning para Produção. (n.d.). Retrieved September 29, 2020, from https://www.cognex.com/pt-br/blogs/deep-learning/what-is-deep-learning?page=404

 2.      Michie, D., Spiegelhalter, D. J., & Taylor, C. C. (1994). Machine learning. Neural and Statistical Classification, 13(1994), 1-298.

3.      Silver, D., Hubert, T., Schrittwieser, J., Antonoglou, I., Lai, M., Guez, A., Lanctot, M., Sifre, L., Kumaran, D., Graepel, T., Lillicrap, T., Simonyan, K., & Hassabis, D. (2018). A general reinforcement learning algorithm that masters chess, shogi, and Go through self-play. https://doi.org/10.1126/science.aar6404

 4.      Hessler G, Baringhaus KH. Artificial Intelligence in Drug Design. Molecules. 2018;23(10):2520. Published 2018 Oct 2. doi:10.3390/molecules23102520

 5.      Jing Y, Bian Y, Hu Z, Wang L, Xie XQ. Deep Learning for Drug Design: an Artificial Intelligence Paradigm for Drug Discovery in the Big Data Era [published correction appears in AAPS J. 2018 Jun 25;20(4):79. Xie XS [corrected to Xie XQ]]. AAPS J. 2018;20(3):58. Published 2018 Mar 30. doi:10.1208/s12248-018-0210-0

 6.   DiMasi, J.A.; Hansen, R.W.; Grabowski, H.G. The price of innovation: New estimates of drug development.

 7.      Blaschke, T., Olivecrona, M., Engkvist, O., Bajorath, J., & Chen, H. (2018). Application of Generative Autoencoder in De Novo Molecular Design. Molecular Informatics, 37(1–2), 1700123. https://doi.org/10.1002/minf.201700123

 8.      Madapa S, Gadhiya S, Kurtzman T, Alberts IL, Ramsey S, Reith M, Harding WW. Synthesis and evaluation of C9 alkoxy analogues of (-)-stepholidine as dopamine receptor ligands. Eur J Med Chem. 2017 Jan 5;125:255-268. doi: 10.1016/j.ejmech.2016.09.036. Epub 2016 Sep 14. PMID: 27688181; PMCID: PMC5148686.

 9.      Dana D, Gadhiya SV, St Surin LG, et al. Deep Learning in Drug Discovery and Medicine; Scratching the Surface. Molecules. 2018;23(9):2384. Published 2018 Sep 18. doi:10.3390/molecules23092384

 10.    Topol, E.J. High-performance medicine: the convergence of human and artificial intelligence. Nat Med 25, 44–56 (2019). https://doi.org/10.1038/s41591-018-0300-7

Vitamin E as a potential treatment for Alzheimer’s disease

                                                                                        (From Reference 15)

   

Alzheimer’s disease is a neurodegenerative disorder that represents up to 80% of dementia-related cases, worldwide.¹ It is clinically characterized by the onset of episodic memory-loss that intensifies over time, along with a gradual loss in other cognitive functions.  At the cellular level, Alzheimer’s disease is accompanied by neurofibrillary tangles (NFT’s), amyloid plaques, and loss of neuronal synapses in the brain.² It is difficult to correctly label the pathogenesis of Alzheimer’s disease because manifestations can appear up to 30 years prior to symptom onset.³ There have been a number of proposed hypotheses attempting to explain why Alzheimer’s disease occurs. In 1907, Alois Alzheimer made a breakthrough when he characterized the “plaques” and “tangles” of the disorder. The roles of amyloid and tau protein have remained central in determining pathogenesis in hypotheses such as the amyloid cascade hypothesis.⁴

The amyloid cascade hypothesis proposes that the excessive accumulation of plaques composed of amyloid-beta (Aβ) protein directly induces the clinical manifestation of Alzheimer’s disease (Figure 1).  These plaques induce neurodegeneration through neural inflammation, damaged immunological mechanisms and free radical activity. Similarly, the hyper-phosphorylation of tau proteins induces the accumulation of NFT’s.⁵ Other theories place an emphasis on the role of age-related mitochondrial changes that induce a cascade of molecular events, including the amyloid pathway.⁶ Concerns about these proposed mechanisms have risen because there is not sufficient evidence that they directly cause Alzheimer’s disease. More recently, pathologists believe that the pathogenesis of this disorder is more complex and multifactorial.⁷

                                            Figure 1.¹⁶ Amyloid plaques on neurons in Alzheimer’s 

Despite the complex events that must occur to cause Alzheimer’s disease, there is an increasing amount of evidence pointing to a common factor, oxidative stress (OS).  The role of OS in disease is attributed to the formation of reactive oxygen species (ROS) through the metabolism of oxygen from within the mitochondria. ROS go on to cause structural and functional changes in a number of biomolecules.⁸ Patients with Alzheimer’s disease have elevated amounts of OS markers in their blood serum, which are easily detected in lipids, proteins, nucleic acids, and sugars. In the early stages of the disorder, cerebral glucose metabolism is reduced, which may be accompanied by metabolic malfunctions and the production of ROS. Several other factors may contribute to an increased susceptibility of the brain to OS, including: the high demand and consumption of oxygen, the high concentrations of polysaturated lipids seen in axons, and the lack of endogenous antioxidants to help fend off ROS.⁹

There has been increasing support for the development of antioxidant therapy for Alzheimer’s disease, with a positive emphasis on the use of vitamin E.  Plant-based oils, nuts, seeds, fruits, and vegetables such as sunflower seeds, mangos, avocados, and almonds are a good source of this vitamin.¹⁰ Vitamin E is a collective term that describes a family of 8 naturally-occurring homologues that possess strong antioxidant properties (Figure 2). Vitamin E has a wide variety of biological functions that differ based on the isoform, yet all have strong antioxidant capabilities and are known as free-radical scavengers.¹¹

Figure 2.¹⁷ The mechanism by which vitamin E protects cells from reactive oxygen 

A recent meta-analysis of 51 studies that compared the blood serum vitamin E levels of Alzheimer’s patients to cognitively functional control subjects found that vitamin E levels were 11% lower in Alzheimer’s disease patients.¹¹ Several other studies have been conducted to investigate the relationship between vitamin E intake and Alzheimer’s disease. A number of these studies suggests that the intake of dietary vitamin E reduces the risk of developing and slowing the progression of Alzheimer’s disease to a greater extent than taking vitamin E supplements. However, several of these studies failed to detect any significant association between the intake of vitamin E and any changes in the disorder.¹³

Despite there being substantial evidence of elevated oxidative stress in Alzheimer’s disease, the role of vitamin E as a potential treatment has not proven to be fruitful. Perhaps previous studies have had issues determining a baseline level of vitamin E in patients with Alzheimer’s and maybe not all subjects had depleted their endogenous vitamin E levels enough to see any changes. Yet, there were still quite a number of studies that provided significant results suggesting that the dietary intake of vitamin E is more effective in reducing the risk of developing the disorder than through supplementation. However, if the dietary intake of vitamin E is deficient, it is recommended that supplementation is used either in tandem with diet (if some vitamin E is obtained from diet) or as the only source of the vitamin (if vitamin E levels are severely low).¹⁴ The quest to find a cure for Alzheimer’s disease has baffled scientists for over a century, yet further investigation of antioxidant therapy could yield the most promising treatment.  

By: Joseph Weed, A Master’s of Medical Science Student at the University of Kentucky

References:

1.     Prince M., Wimo A., Guerchet M., Ali G.C., Wu, Y.T., Prina, N. Alzheimer’s Disease International. World Alzheimer Report; Alzheimer’s Disease International: London, UK; 2015.

2.     Cui Y., Liu B., Luo S., et al. Alzheimer’s disease neuroimaging initiative. Identification of conversion from mild cognitive impairment to Alzheimer’s disease using multivariate predictors. PLoS One. 2011;6(7):e21896. doi:10.1371/journal.pone.0021896.

3.     Ashraf G.M., Chibber S., Zaidi S.K., et al. Recent updates on the association between Alzheimer’s disease and vascular dementia. J Med Chem. 2016;12(3):226–237. doi:10.2174/1573406411666151030111820.

4.     Alzheimer A., Stelzmann R.A., Schnitzlein H.N., Murtagh F.R. An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin Anat. 1995;8(6):429–431. doi:10.1002/ca.980080612.

5.     Mecocci P., Boccardi V., Cecchetti R., et al. A long journey into aging, brain aging, and Alzheimer’s disease following the oxidative stress tracks. J Alzheimers Dis. 2018;62(3):1319–1335. doi:10.3233/JAD-170732.

6.     Swerdlow R.H., Khan S.M. A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Med Hypotheses. 2004;63(1):8–20. doi:10.1016/j.mehy.2003.12.045.

7.      Swerdlow R.H. Alzheimer’s disease pathologic cascades: who comes first, what drives what. Neurotox Res. 2012;22(3):182–194. doi:10.1007/s12640-011-9272-9.

8.     Mosconi L., Pupi A., De Leon, M.J. Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann NY Acad Sci. 2008;1147(1):180–195. doi:10.1196/annals.1427.007.

9.     Zuo L., Zhou T., Pannell B.K., Ziegler A.C., Best T.M. Biological and physiological role of reactive oxygen species–the good, the bad and the ugly. Acta Physiol. 2015;214(3):329–348. doi:10.1111/apha.2015.214.issue-3.

10.  Feng Y., Wang X. Antioxidant therapies for Alzheimer’s disease. Oxid Med Cell Longev. 2012;2012:472932. doi:10.1155/2012/472932.

11.  Zandi P.P., Anthony J.C., Khachaturian A.S., et al. Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Arch Neurol. 2004;61(1):82–88.

12.  Kryscio R.J., Abner E.L., Caban-Holt A., et al. Association of antioxidant supplement use and dementia in the prevention of Alzheimer’s disease by vitamin E and selenium trial (PREADViSE). JAMA Neurol. 2017;74(5):567–573. doi:10.1001/jamaneurol.2016.5778.

13.  “Vitamin E.” Accessed September 17, 2020. https://www.hsph.harvard.edu/nutritionsource/vitamin-e/.

14.  “Office of Dietary Supplements - Vitamin E.” NIH Office of Dietary Supplements. U.S. Department of Health and Human Services. Accessed September 17, 2020. https://ods.od.nih.gov/factsheets/VitaminE-HealthProfessional/.  

15.  “Vitamin E: 7 Amazing Benefits That You Need to Be Aware Of,” July 5, 2019. https://www.healthifyme.com/blog/vitamin-e-benefits/.

16.  Patel, HH. “Is Alzheimer's Disease Transmissible?” News, June 28, 2019. https://www.news-medical.net/health/Is-Alzheimers-Disease-Transmissible.aspx.

17.  “Chapter 7 Vitamins. - Ppt Video Online Download.” SlidePlayer. Accessed September 10, 2020. https://slideplayer.com/slide/2757474/.