Learning Nuclear Chemistry through Practice: A High School Student

Article pubs.acs.org/jchemeduc

Learning Nuclear Chemistry through Practice: A High School Student Project Using PET in a Clinical Setting Lucia Liguori*,† and Tom Christian Holm Adamsen‡,§ †

Nordahl Grieg High School, Bergen N-5239, Norway Department of Radiology, Centre for Nuclear Medicine and PET, Haukeland University Hospital, Bergen N-5021, Norway § Department of Chemistry, University of Bergen, Bergen N-5007, Norway ‡

ABSTRACT: Practical experience is vital for promoting interest in science. Several aspects of chemistry are rarely taught in the secondary school curriculum, especially nuclear and radiochemistry. Therefore, we introduced radiochemistry to secondary school students through positron emission tomography (PET) associated with computer tomography (CT). PET−CT technology, radiochemistry, and clinical practice were introduced through five steps comprising fundamental aspects of nuclear chemistry, organic synthesis, diagnostic nuclear medicine, evaluation of medical results, and final presentation of their exposure through posters and oral presentations.

KEYWORDS: High School/Introductory Chemistry, Collaborative/Cooperative Learning, Communication/Writing, Hands-On Learning/Manipulatives, Medicinal Chemistry, Organic Chemistry, Safety/Hazards

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ENGAGING STUDENT INTEREST IN SCIENCE THROUGH COLLABORATIVE FIELD EXPERIENCE In recent years, the Ministry of Education and Research in Norway has developed a strategic plan1 to encourage the study of natural sciences and technology at educational levels from primary to secondary school. Financial support has contributed to the building of interactive science and technological centers in several cities with the aim of encouraging young people to develop an interest in science and the comprehension of natural phenomena. The program has been motivated by two important factors: the first is a future strong demand for specialists and engineers in several industrial sectors, such as in sustainable energy, petroleum, medicine, and nanotechnology; the second is the insufficient number of students entering science and technology fields. In fact, during the last six years (2005−2011)2 scientific disciplines such as chemistry, mathematics, and biology suffered from a loss of interest among secondary school students, causing a significant decrease in student enrollment at natural science faculties. Due to the active and continuous expansion of the Norwegian oil industry, the discipline of physics1 has registered a recruitment increase. According to the Ministry of Education and Research strategy plan,1 early schooling has to actively promote and awaken the interest of young people in science, beyond just using spectacular science shows. Against this background many high schools have initiated collaboration with universities, research institutes, and companies in order to institute short-term projects. In this direction research institutes, university hospitals, and companies in any field have always been receptive to including © XXXX American Chemical Society and Division of Chemical Education, Inc.

students in their activities. The outcome is beneficial to all parties: high school students get a practical insight into science by interacting with researchers and graduate and undergraduate students sharing similar career interests and goals. Companies and institutes promote their field of work to ensure future employees. Herein we report the results from a short-term project in chemistry, which was promoted through the collaboration between Nordahl Grieg High School and the Center for Nuclear Medicine and PET at Haukeland University Hospital in Bergen, Norway.

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REPRESENTATIONS AND MISCONCEPTIONS IN HIGH SCHOOL CHEMISTRY High school students often consider chemistry a difficult and demanding subject due to a language based on symbols (formulas, chemical equations, etc.) and concepts not simply linkable to a visual reality. Some pedagogues describe the learning process in chemistry with a triangle,3 in which the three vertices represent the three knowledge levels: macroscale, microscale, and representational. The macroscale level is the description of chemical substances and phenomena. The microscale level is explanation of chemistry by means of atoms and molecules. Finally, the representational level indicates the summary of concepts through formulas, chemical equations, and computation. One of the first concepts students meet in chemistry is the atom described through associations to visual models such as the solar system (macroscale level). Other concepts strongly linked to the atom

A

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are isotopes, stability of the nucleus, and radioactivity (microscale level). Teaching at the microscale level is not in itself simple; educators have to also face students’ misconceptions about scientific facts and, at the same time, find learning strategies to ensure sound knowledge based on understanding and not mechanical memorization. Misconceptions about nuclear chemistry, such as “Irradiated food is radioactive”, “All radiation is harmful”, “Once a material is radioactive it is radioactive forever”,4 are quite common and completely independent of students’ country of origin. Nuclear and radiochemistry have never had a special place in the high school curricula and in most of the schools this subject is still taught, just with abstract theory. Lack of training in this subject for some teachers or lack of nuclear-related equipment in the school can be the reason for this kind of negligence. Classical teaching approaches start from the middle of the triangle regarding isotopes, α- and βprocesses, the properties of α, β, γ-radiation to penetrate different materials, and nuclear equations. These concepts have to be accepted on trust, which often requires significant intellectual endeavors and creates misconceptions. Due to its social impact in healthcare, energy sustainability, and global security,5 nuclear chemistry has gained attention and has become a significant topic. Fortunately, literature reports6 from the past decade offer teachers alternative methods to make nuclear chemistry more understandable. Schools have easy access to technology and new equipment in order to perform experiments on radioisotopes and learn how to plot decay data.7 This work describes how radiochemistry, in combination with clinical PET, can be used to introduce several interdisciplinary subjects, namely, the atom both at a microscale and representational level, the physics of positron emission and annihilation, the synthesis of radioactive compounds and their clinical application, and the collection of clinical data and their interpretation in order to furnish a diagnosis. We believe that a practical experience, whenever possible, is useful to awaken interest in a particular subject and make it easier to understand difficult aspects of the scientific theories related to that specific subject.

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Figure 1. The PET trace (GE Healthcare, Waukesha, WI) cyclotron at the PET Center, Haukeland University Hospital in Bergen, Norway.

The positron (e+) has the same charge of the electron but with a positive electric charge of +1.6 × 10−19 C. The β+ emission, typical for atoms with low atomic number, is also accompanied by a neutrino (ν) emission (eq 1): 18 9F

→ 188O + e+ + υ

(1)

Several radionuclides that undergo β+-emission can be used in PET-diagnostics, such as 18F (t1/2 = 109.8 min), 11C (t1/2 = 20.4 min),10 124I (t1/2 = 4.17 days) and 15O (t1/2 = 122 s). The positron emitted through β+ decay has a short lifetime as it reacts rapidly with an atomic electron in the tissue. This process, known as annihilation,9 converts the mass of the electron and the positron into electromagnetic energy according to Einstein’s mass-energy relation (eq 2) 9

E = mc 2 = mec 2 + mpc 2 = 1.022 MeV

(2)

−1

where c (3 × 10 ms ) is the speed of light, and mp, me are the mass of the positron (1.67 × 10−27 kg) and the electron (9.1 × 10−31 kg), respectively. This energy is released in form of two photons each having energy of 511 keV (equal to one-half of 1.022 MeV) and a net momentum close to zero owing to a simultaneous and opposite emission direction of 180° (Figure 2). 8

RADIOCHEMISTRY AND POSITRON EMISSION TOMOGRAPHY

Background

Positron emission tomography (PET) is a technique from the 1960s8 based on the positron emission decay of short-lived radionuclides mainly produced in a cyclotron (Figure 1). The radionuclides are successively employed in the synthesis of radiolabeled compounds destined for in vivo applications. These compounds, administered to the patient intravenously, have the ability to interact with various cells or organs, depending on their biochemical properties. The radioactive atom in the labeled compounds is unstable, and decays by emission of a positron from the nucleus resulting in two annihilation photons (511 keV) escaping the body. These are registered by a PET scanner and converted to electrical signals, which are successively corrected and converted by mathematical algorithms to furnish a three-dimensional tomographic image of the body. In this context, students learned that a nucleus is composed of the nucleons, protons (p) and neutrons (n), and its stability is strongly related to the balance of repulsive and attractive nuclear forces. In case of excess or lack either of protons or neutrons, respectively, the nucleus becomes unstable and tries to reach a more stable configuration by emission of positrons, known as beta-plus decay (β+), or through electron capture.

Figure 2. The annihilation process.

Annihilation photons exit the body owing to their high energy and are detected by the PET scanner via collinearly aligned detectors.11 Because the positron emission and annihilation occur spatially quite close it is possible to localize where the radioactive atom was in the body. An accurate reconstruction of the body image is done through the computed tomography by registering the total amount of radioactivity passing through several angles in the analyzed organ. The acquired data are converted by mathematical logarithms to three-dimensional PET images. Two limits to spatial resolution achieved with PET are due to the uncertain positron range (the scanner detects the annihilation photons and not exactly where the decaying positron B

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school students who were studying their first year of advanced chemistry. The working plan consisted of five steps: 1. Basic course in radiochemistry, radiopharmacy, and nuclear medicine. 2. Preparation and quality control of the radioactive compound [18F]FDG 3. Clinical application of this compound in patient examination (PET scanning) 4. Evaluation and discussion of the results of the medical examination 5. Summary in the form of a poster and oral presentation Students attended a full day of lectures during which they were introduced to different aspects of nuclear physics, radiochemistry, radiopharmacy, and clinical nuclear medicine by the staff at the PET center. These lectures were aimed at giving an overview of the variety of scientific disciplines at the PET center, along with sufficient knowledge to benefit from the hands-on session the day after. This included theory about the atom and its subatomic particles, radiation and radiation protection, the cyclotron (Figure 1), isotope production and radioactive decay, and different uses of nuclear radiation in chemistry and basic radiochemistry with special emphasis on its application to organic and medicinal chemistry. Relevant analytical techniques with regard to radiopharmaceutical quality control, radiopharmacy, and regulations governing parenterals (products administrated to the body by injection or infusion) were presented. A session on radiation working techniques, including contamination and monitoring, was included. Finally, the clinical basis of nuclear medicine was covered using actual patient data as examples. Students were then divided into two groups: the radiopharmacy group and the clinical group. The radiopharmacy group was involved in radiosynthesis and quality control, while the clinical group mainly focused on injection, scanning, and image analysis.

is emitted) and the noncollinearity owing to angle variations of the annihilation momentum ∼180°. Clinical Application of PET

Most of the clinical PET studies and investigations are based10 on fluoride-18 labeled 2-deoxy-2-[18F]-fluoroglucose ([18F]FDG, 1, Figure 3), which exhibits biochemical properties similar to

Figure 3. [18F]FDG, 2-deoxy-2-[18F]-fluoroglucose, 1.

glucose. In fact, [18F]FDG is taken up by the cells as glucose but is not completely metabolized, thus being trapped inside the uptaking cells. The more active tumor cells reveal an increased uptake of glucose compared to normal cells and [18F]FDG is thus used as a glucose metabolism marker. The radionuclide F-18 thereafter decays by positron emission with a half-life of approximately 110 min. This means that the production of the radiolabeled compound must be carried out on the same day of the patient examination. The synthesis of [18F]FDG, 1,12 is still the object of numerous studies aimed to increase the yield and the selectivity of the entire synthetic process. The most used protocol13 in PET centers throughout the world is based on a two-step synthesis and gives an approximate 60% isolated yield of the desired radiolabeled product. The [18F]fluoride ion is produced using enriched [18O] water in the cyclotron, in which hydride (H−) ions are accelerated, extracted through a carbon foil, and converted into protons. The collision between the protons and the enriched water [18O]H2O promotes a nuclear reaction (eq 3) with formation of the radioactive isotope 18F and a neutron, n: 18

O + p → 18F + n

The Radiopharmacy Group

(3)

The radiopharmacy group assisted in the chemical synthesis of the radiolabeled compound [18F]FDG, 1. This was performed on an automated synthesis platform, a Tracerlab MXFDG module (GE Healthcare, Waukesha, WI), according to good manufacturing practice and based on slightly modified synthetic methods from the chemical literature.15 Quality controls were conducted according to the [18F]FDG-monograph entry of the European Pharmacopoeia.16 At the synthesis phase of the project, the students were substantially observers because the procedure is totally automated. Due to the amount of radiation involved, the synthesis module is situated inside a so-called “hotcell”, which is a closed lead cabinet (with walls that are 7.5 cm or 2.95 in. thick) and the reaction cannot be performed in a standard laboratory, much less in a school lab. The students were instead actively involved in the quality control tests. These are fundamental to ensure that the final formulation is compliant with regulations concerning parenterals. This included measurement of pH and isotonicity, determination of residual aminopolyether, radionuclidic purity, radiochemical purity, radionuclidic identification, and determination of endotoxins. The laboratory work showed students that it is possible to handle harmful chemicals and work in a radiation environment by taking appropriate security measures. Students encountered several chemical concepts (Table 1), learning about nucleophilic substitution, the use of phase transfer catalysts, the selection of acetonitrile as a suitable solvent to enhance the nucleophilic

The first synthesis step is the nucleophilic substitution of the triflate group in the tetra-O-acetyl-2-O-trifluoromethansulfonyl 18 D-mannose (2) by the [ F]fluoride ion in the presence of Kryptofix (4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane) as a phase transfer catalyst. The reaction occurs using acetonitrile as the solvent (Scheme 1). Scheme 1. Synthesis of [18F]FDG, 1, by Nucleophilic Substitution of the Mannose Triflate, 2

The second step is the deprotection of the acetyl protecting groups under basic or acidic conditions13,14 (Scheme 1). One important drawback of this synthetic method is that the final product is obtained in mixture with a large excess of D-glucose and some other byproducts not considered harmful to the patient. The presence of byproducts is not negligible using other tracers.13

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THE PET PROJECT

Incorporating the Project in the Curriculum

Radiochemistry associated with PET diagnostics was useful as an interdisciplinary subject, and the project involved high C

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Table 1. Topics Related to PET−CT Investigation Nuclear Chemistry Atom, subatomic particles, nucleus stability, isotopes, radioactivity, annihilation, β+ decay

Organic Chemistry

Medicine

Literacy

[18F]FDG synthesis, nucleophilic substitution, solvent choice, leaving group, yield, selectivity, purification techniques, anion exchange columns, TLC, HPLC, GC, GC−MS, CMC protocol

Medical protocol, patient investigation, image analysis, anatomy, diagnosis

Bibliographic research, teamwork, discussion, poster, oral presentation

Figure 4. Images obtained from CT and CT−PET scans of a patient affected by tumor in the lungs (green area). Coronal CT image of the chest (A) combined with a PET scan (B) revealing the lung tumor. Sagittal CT image (C) combined with a PET scan (D), which also reveals natural uptake in the bladder.

nature of [18F]F-ion, and the nature of triflate as a suitable leaving group. They discussed the reaction yield and selectivity, the influence of byproducts and use of different purification techniques,14 such as anion exchange column, C-18 reverse phase column, and alumina column. Students learned about TLC, GC, and GC−MS as fast techniques to check the quality of the final product. The radionuclidic identity and purity could be confirmed by gamma spectroscopy, half-life measurement, HPLC, and TLC. During the laboratory work it was emphasized that a highly pure final labeled tracer is necessary for patient safety. Furthermore the laboratory has to provide a product that meets the standards described by several pharmacopoeia and the Chemistry, Manufacturing and Controls document (CMC) relative to [18F]FDG, 1.14,17

the clinical group acquainted each other with the work performed by short electronic presentations. Students discussed together to better understand, define, and formulate the different concepts into words. This ensured that everybody had a complete picture of the entire process starting from the radiolabeled-compound chemical synthesis to the patients’ medical diagnoses. The project results, including nuclear chemistry theory, comparison among different radiolabeled compounds, challenges related to the synthesis and purification of these compounds, clinical investigation, evaluation of the medical data, and patients’ privacy, were presented in oral presentations and posters at an annual conference of the school where students from several educational programs (media and communication, health and social science, service and transport, and subjects of studies at Nordahl Grieg school) were in attendance. In general, posters and oral presentations of students participating in a practical hands-on project showed a higher quality in the content selection and presentation when compared to other students’ works based only on chemical literature information. These did not show similar reasoning in nuclear chemistry and PET technique but were often a faithf ul reproduction of the literature. In our opinion, the hands-on training and on-site experience increased students’ learning outcomes and interest in the field. Practical work, related to the theoretical background, added another dimension to the teaching experience and helped put difficult or abstract subjects into perspective. There is no doubt that nuclear chemistry is considered as a difficult subject. However, it becomes more engaging and approachable when it is studied in a real context accompanied by a practical experience. If we related the students’ learning to the knowledge triangle,3 we can say that they moved from the macro corner, that is, the practical experience, toward the micro level consisting of nuclear chemistry concepts, organic chemistry, technical aspects of PET technique and medical interpretation, and evaluation of PET data. The representational level is composed of students’ efforts in transferring their acquired knowledge into scientific words, schemes, and chemical equations. This was the poster and oral presentation phase. It is of course difficult to ascertain for each student the depth of knowledge acquired. The learning process is individual and proceeds in a personal way. It could be that some students just were moving along the shared edges among the triangle corners, never touching the inside of the triangle. This is a question that requires further study.

The Clinical Group

The clinical group participated in the entire hospital procedure for the PET investigation: patient interviews about their medical history, medical preparation of the patient for the radioactivecompound injection, and registration of image analysis data with the help of specialized hospital staff. At this stage of the project students were observing and asking questions about the PET scanner and the patients’ data. The discussion and comparison of the image analyses were performed with the help of a medical doctor. Students learned that PET analysis is always associated with another modality, computed tomography (CT), hence the name PET−CT. In fact, CT provides detailed morphological information of the human body in the form of black and white images, much like X-ray images, where it would be difficult to distinguish a small tumor volume. Clinical PET analysis highlights the human body parts that accumulate a strong radioactive emission caused by an increased up-take of [18F]FDG, 1, due to the tumor (Figure 4). Figure 4 (A and C) shows the CT image of a patient’s chest in which it is not evident that a tumor is present. However, the fused PET−CT images (Figure 4B, D) clearly show a bright-green-colored spot where a tumor is located. The red-colored spot is due to normal up-take by urine in the bladder. Student Assessment

Student assessment is crucial to any educational program because it shows what degree of success the program has achieved. After their experience at the hospital, students conducted further literature searches on the Internet and through textbooks and scientific articles in order to find more information. Reading new material required several skills, among them analysis and comprehension of advanced texts, and evaluation and validity of the information. Students worked in teams to help each other through dialogue and discussion. The radiopharmacy group and

Participating Students’ Evaluation of the Project

To determine the value of the project, a poll among students was conducted. Students were asked to express their opinion D

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proposed in Table 1 offers a guide to choosing different issues students could study under an educator’s supervision. The educator could guide students throughout the entire project. This approach would help avoid a situation in which the project results summarized in form of posters and oral presentations become a trivial reproduction of information reported in the literature. The main goal of the project would be to provide students with a satisfactory knowledge of nuclear chemistry and PET technique. Students, especially those interested in going into the healthcare professions, will learn about a modern medical technique while also being engaged in learning a difficult subject, nuclear chemistry, in a meaningful way.

about the project, underlining positive and negative aspects suggesting what it should be improved. Of the students polled, 100% reported enthusiasm toward and appreciation for the project. Theory and practice combination was described as a smart way to motivate study of a difficult subject such as nuclear chemistry. All of the students affirmed that the most difficult moment was the results evaluation and their presentation in form of posters and oral presentations. Teamwork was considered helpful in this situation. Most of the students, 85%, considered the short duration of the project as a negative aspect. A longer working period at the hospital was desired to allow all the students to participate both in the chemical synthesis of the radiolabeled compound [18F]FDG and in its application in the clinical phase. Students understood that this request could not be easily satisfied because of the limited availability of the hospital staff. Finally, 95% of the students suggested including this project as a permanent part of teaching nuclear chemistry. From this unique experience, we observe that the learning process happens through practice, dialogue, and teamwork in line with Dewey’s18 pedagogical theory. The project was certainly interdisciplinary, involving physics (the cyclotron and accelerations of particles for the synthesis of [18F]F ion), chemistry (synthesis, purification, and quality control), and medicine (anatomy and diagnosis). Considering that chemistry was the focal point of this project, students acquired significant knowledge about several chemistry topics (Table 1) that would have required many hours with traditional “teaching by telling”. Learning occurred in a quite natural way because all of the steps were meaningful and directed toward a highly pure labeled compound and a correct diagnosis. Some of the misconceptions about radioactive compounds such as “All radiation is harmful”, and “Once a material is radioactive, it is radioactive forever” were seen as incorrect by students after this experience.

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CONCLUSION PET−CT technology in a clinical setting was chosen as a tool to introduce advanced level high school students to nuclear chemistry and radiochemistry. The project was initiated in response to a major campaign of the Norwegian government to promote students’ interest in science and technology fields. The project was a success from several pedagogical points of view. New topics, such as nuclear chemistry and nuclear pharmacy, were naturally linked to the traditional high school curriculum in chemistry. The idea of teaching nuclear chemistry starting from PET− CT is still of great value when a practical experience is not possible. Chemical topics such as isotopes, radioactivity, challenges in radiolabeled-compound synthesis, purification techniques, and quality control of the final compound are closely related to PET−CT. Students learn about medical protocols, patient investigation, image analysis, anatomy, and diagnosis. They gain experience with teamwork and discussion in order to present the acquired knowledge in a concise and clear way. The PET−CT project results were presented in the form of posters and oral presentations. Students positively evaluated the project because the subject concerned a new and advanced technique used in cancer diagnosis. Students liked the experience of being not just students, but hospital employees in contact with several categories of working professionals: synthetic chemists, pharmacologists, radiologists, nurses, doctors, as well as the patients. Chemistry appeared in a different light and lost the image of being only a pure collection of sterile theory and laws. For these students, chemistry became participation in experimentation to acquire practical skills and knowledge, which will be relevant for a later working life and useful for the community.

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OTHER CONCERNS Nuclear chemistry, as any other fields of chemistry, involves some risk. In this project, the students operated under the same safety conditions and working rules used daily by hospital employees. During the time at the hospital, the students never worked alone for safety and quality control reasons. Therefore, they did not need special training before starting the project. For privacy regarding patients’ medical data, students signed a confidentiality agreement. Moreover, the presence of students during the medical investigation was always approved by the patient. Discussion of medical data and diagnosis was performed with the doctor in full respect of patient anonymity. Another concern is about PET technique. PET is quite expensive, and not all locations have this kind of equipment. This means it would be difficult for some schools to organize a similar practical experience. Nevertheless, we do not consider this as an obstacle for introducing students to the PET technique. In this case, educators can approach nuclear chemistry using PET technique as a concrete application of nuclear chemistry in healthcare. The Internet has many short videos on PET investigation, especially for the clinical part. These videos can be used to enrich lessons and teaching. Students could start the project investigating about PET−CT facilities in their area. Next, they could approach topics such as: basic nuclear chemistry theory; state of the art for radiolabeled compounds, including type of radionuclides; challenges in synthesis; purification and isolation of these compounds; image analysis; patient investigation; evaluation of medical data; and patients’ privacy. The list of topics

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors like to sincerely thank Boel Johnsen, Odd Harald Odland, and Andreas Drangevåg at the Center for Nuclear Medicine and PET center for excellent support during the practical work of the project. Maartin Biermann is acknowledged for PET and CT images, and Hans-René Bjørsvik for linguistics assistance and discussion.

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