Research overview

My research interestes can broadly be divided in the following topics. Please click on the topic of your interest for further information.

For the complete list of my publications, click here 

 

Isotope production

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The use of targeted radionuclides for diagnostics and therapy has focused on a few specific radionuclides for decades, but massive improvements in cancer therapy are possible by selecting radionuclides with specific half-lives, emitted nuclides and gamma energies for different applications. A recent trend finds global interest in other, potentially better, radionuclides steadily increasing. Where 99mTc was once practically the only diagnostic radionuclide in use, focus is shifting to including a large range of 'new' diagnostic and therapeutic isotopes. However, a current lack of supply in many medically relevant radionuclides limits the research and development into the use of these, and hence halting clinical trials. In addition, one of the main challenges in radiopharmaceutical development is presented by the highly variable specific activities of the used radionuclides which are generally far below the theoretical values. This is especially true for the large number of medical radionuclides which are predominantly or exclusively produced via (n,γ) reactions in nuclear reactors. To support the use of new radionuclides, it is important that they are abundantly available, and in sufficiently high specific activity. My research focusses on the (pre)clinical development of radionuclides which can be used to design new, patient-specific, radiotracers and therapeutics, using electrochemistry, liquid-liquid or solvent extraction, microfluidics, and ion exchange chromatography. I explore principles based on hot atom chemistry to achieve high specific activity of the produced radionuclides.

 

Radionuclide production and separation

To facilitate the development of novel radiopharmaceutical, radionuclides with specific properties need to be abundantly available. I work on the development of production and separation pathways for a number of different radionuclides, including 47Sc, 68Ga, 99mTc, 161Tb and 166Ho. With our on-site nuclear reactor (the Hoger Onderwijs Reactor of the TU Delft) we are able to make most radionuclides following (n,y) and (n.p) reactions. Separation and recovery is performed based on e.g. ion exchange chromatography, electrochemistry, as well as liquid-liquid or solvent extraction using microfluidics.

Liquid-liquid extraction is a very effective way to separate radioactive isotopes intended for medical applications, but up to now it is not commonly used. The big drawback of these extraction systems is the large size of the installation, determined, as a rule, by the extractor size; need for using heavy protection in operation, high skill required of the staff and lack of convenient automated systems. All of these make it not applicable for the daily use in hospitals. This is why we are working on the development of microfluidic devices for radionuclide separation, which would take away these drawbacks by miniaturising the extraction system and making them easy to automate. Our final goal will be an automated system for the purification of medically applied isotopes.

 

Publications and theses:

Microfluidic solvent extraction for an automated 68Ga cyclotron production loop, S. Trapp, E. Paulssen, R.M. de Kruijff, 19th Radiochemical Conference, Marianske Lazne, Czech Republic, 2022

 

Nanomaterials for radionuclide generators

99mTc is one of the most often used radionuclides in nuclear medicine, good for about 20 million procedures worldwide annually. At the hospital, it is eluted from a generator containing both 99Mo (the mother isotope) and 99mTc. Most of the 99Mo is currently  produced from the fission of 235U in reactors worldwide, which results in about 6% 99Mo, and 94% radioactive waste products. There is an alternative method of producing 99Mo, namely through a neutron capture reaction from 98Mo: 98Mo(n,y)99Mo. However, through this method the target and product nuclides are the same element and cannot be separated using conventional chemical methods, resulting in a large amount of molybdenum in the generator. Using the conventional alumina-based column for the 99Mo/99mTc generator therefore means that the column needs to be very large to be able to contain enough molybdenum for the generator. 

 

We are working on the development of a new type of target material based on Mo-containing nanoparticles, which will function both as target as well as generator material. Advantages of this method include not requiring fissile 235U target material, small generators as no column material is needed, and reusable targets. However, this puts some very strict constraints on the target material options. Obviously, the target material needs to consist to a large degree of molybdenum, but it must also be very stable in e.g. aqueous solutions for extractions of the 99mTc, and under increased temperatures during irradiation. The final aim will be to develop a nanoparticle-based generator which can be returned to the irradiation facility after use in the hospital to make it radioactive again for re-use as generator. 

Publications and theses:

RID ontwikkelt recyclebare technetium generator, Kernvisie, 2022, pg 16-17

 

Continuous radionuclide production using liquid targets

Improvements in tumor-specific targeting vectors are realizing significant enhancements in radiopharmaceutical efficacy using a number of different radionuclides with characteristics matching patient-specific requirements. Depending on the nature of the molecular targeting agent, a high specific activity of the radiolabel is critical to exploit the highly tumor-specific but low-abundance targets. One of the main challenges in radiopharmaceutical development is presented by the highly variable specific activities of the used radionuclides.

 

I am working on the development of a loop-based irradiation system, where the target nuclei are continuously flowing through the reactor core, with an on-line extraction system of the produced radionuclides. This system will allow for rapid extraction of produced radionuclides. Separation of the produced radioisotopes can be performed using e.g. ion exchange columns, or liquid-liquid extraction. Furthermore, the system could enable the recycling of the (sometimes costly isotopically enriched) target nuclides. Use of the proposed loop system in research reactors worldwide could increase the availability and specific activity of these isotopes and stimulate further research. 

 

Tracers to study dietary supplements and mineral metabolism

Stable elements play a large role in our daily lives. A number of these metals are essential for the proper functioning of the human body, or even essential to our survival. However, there exists a delicate balance, with excesses or deficits often resulting in toxicity. For example, dietary supplements are becoming increasingly popular, both prescribed by the hospital as well as self-medicated. In fact, it is estimated that about 75% of all US adults take supplements. In many instances the underlying biochemical mechanisms and health effects are not well understood. My research focusses on the safety and effectiveness of these supplements, as well as interactions of the supplements and nanomaterials with the metabolism and their retention into the body. The use of radiotracers as well as enriched stable tracers allows for very precise study of the uptake and biodistribution of minerals such as calcium and iron. We use analytical methods like instrumental neutron activation analysis (INAA),  mass spectrometry (ICP-MS), and Mossbauer spectroscopy.

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Bioaccessibility of calcium and iron in milk

​Globally, it is estimated that more than two billion people suffer from micronutrient deficiencies, such as calcium and iron. Calcium stimulates healthy bone growth and prevents osteoporosis, and with anemia affecting a third of the women in reproductive age worldwide increasing dietary iron uptake is now more important than ever. Nutrient-rich foods are clearly at the center of creating healthy and sustainable diets, but most supplements only look at the amount of nutrients and do not consider the bioaccessibility (uptake potential by the body) of these nutrients. And although dairy products can be an excellent source of many minerals, the body is not always able to absorb them. We therefore aim to assess the bioaccessibility and exchangeability of calcium naturally present in skim milk, as well as the usefulness of fortifiers and supplements. We use radiotracers such as radioactive 45Ca and 55Fe to very selectively track the supplemented nutrients in in vitro systems. In this way, a better understanding of the exchange behavior of Ca and Fe in milk can be obtained, which is essential to develop effective milk products containing bioaccessible nutrients to combat micronutrient deficiencies.

Publications and theses:

Use of radiotracers to evaluate the bioaccessibility of essential minerals from dairy products, R.M. de Kruijff, M. de Vos, L. Kloosterboer, S. Sewrattan, B. Terpstra, E. van der Horst, T. Huppertz, 19th Radiochemical Conference, Marianske Lazne, Czech Republic, 2022

 

 
 

The effect of Fe supplementation on human gut bacteria

Stable elements play a large role in our daily lives. A number of these metals are important for the proper functioning of the human body, or even essential to our survival. Dietary supplements are becoming increasingly popular, both prescribed by the hospital as well as self-medicated. However, there is a delicate balance, where too much or too little can often be toxic. The microbiome of an individual plays an important role in human’s health. The majority of the microbiome is made up of mico-organisms present in the gut. Metals are known to play a role in the survival and reproduction of bacteria. Iron (Fe) supplementation can be necessary in the treatment of iron deficient anaemia and mostly oral supplements are used to restore iron stocks. However the intestinal uptake of this iron is low, which results in an exposure of the human micriobiome in the gut to an excess of iron. Little is known about the effect of such an exposure on the various strains of bacteria. There are indications that such an excess of iron may be detrimental to the balance between favorable and pathological bacteria. In handling metals by bacteria, metalloproteins play a vital role in cell metabolism. The MIRAGE technique, studying metalloproteomics in bacteria by using radioactive metal isotopes as tracers, provides information on the effect of overexposure as well as deficiency of metals on cell metabolism of bacteria. We use this technique to study the effect over overexposure to iron on various micro-organisms that play a crucial role in the maintenance of the human microbiome. This will help us understand how Fe supplementation may affect the human microbiome, and therefore human health, down to the molecular level.    

Publications and theses:

The Role of Iron in Staphylococcus aureus Infection and Human Disease: A Metal Tug of War at the Host-Microbe Interface, M.C. van Dijk, R.M. de Kruijff, P. Hagedoorn, Frontiers in Cell and Developmental Biology, 2022, 10, 1-7