Making treatment for malignant tumours better for the kidneys  

Making treatment for malignant tumours better for the kidneys

Researchers at the Paul Scherrer Institute have optimised treatment for malignant tumours using radionuclides. Potential side effects to the kidneys can now be significantly reduced through a molecular process. 

New developments in radiopharmaceuticals have allowed researchers to address the issue of radioactive substances remaining in the kidneys for a long time. The new approach relies on an additional protein that can be split apart in the kidneys. This process means drugs can detach radioactive substances from the kidney and move them to the urinary tract where they can be excreted.  

The findings have been published in the journal Bioorganic & Medicinal Chemistry. 

What are Radiopharmaceuticals?

Radiopharmaceuticals are medicines that can be used to detect and attack malignant tumours and can be administered by injection. Typically, they consist of a radionuclide and a biomolecule. 

The biomolecule, usually an antibody or a peptide, attaches itself to certain surface structures of tissues. The radionuclide emits radiation, which can help detect malignant tumours and destroy them. 

Researchers understand the principles of radiopharmaceuticals, however, there are issues that still need to be overcome before the drugs can be used. 

“If the molecule is too specific, there is a danger that malignant tumours will not be detected. However, if it is too general, it could possibly bind to healthy tissue, leading to false positive diagnoses,” explained Martin Béhé, head of the Pharmacology Group in the Centre for Radiopharmaceutical Sciences at the Paul Scherrer Institute.  

However, for suitable molecules, there are other targets besides malignant tumours. The suitable molecules could be used to target the extracellular matrix, the part of the tissue situated between the cells. 

Research has indicated that proteins present in the extracellular matrix can promote the viability of cancer cells. It has been proven that malignant tumour growth is accompanied by a remodelling of the extracellular matrix. 

The researchers wanted to use this remodelling to bring the radionuclide to the tissue of malignant tumours. They focused specifically on the fibronectin protein. In healthy tissue fibronectin exhibits an extended, taut structure, this will relax as the disease progresses. 

“You can think of it as being like a mechanical spring. When the spring is tense, there are large gaps between the individual coils where the medicine can’t bind. If on the other hand, the spring relaxes, the gaps are closed and the binding affinity increases,” explained Béhé.  

Fibronectin can change structurally while maintaining its chemical composition. This change can significantly increase the binding affinity with certain peptides. 

In earlier studies, Béhé and his team showed that fibronectin-binding peptides (FnBPs) could be used to carry the radionuclides into the extracellular matrix of a tumour. The researchers combined the fibronectin-binding peptide FnBP5 with the radioactive isotope indium-111 

Radiopharmaceuticals can successfully attack malignant tumours

It was found that this radiopharmaceutical could successfully detect and attack prostate cancer. However, the radionuclide accumulates not only in the tumour but also in the kidneys which can have adverse effects. 

Radioactive deposits in the kidneys can damage the organ as well as interfere with imaging. This happens as proteins and peptides are filtered out by the kidneys before they are excreted. This process means radionuclides can linger in the kidney for long periods of time.  

To find a resolution to this problem, the researchers modified the FnBP5 peptide with a protein that could be split apart in the kidneys. This protein allows the FnBP5 to dock onto the fibronectin and make the tumour visible. However, as soon the modified drug gets into the kidneys, the extracted protein is cut and directed into the urinary tract.  

Through his molecular process, the researchers were able to maintain the effectiveness of the original medicine while efficiently reducing radioactive damage to the kidneys. 

We hope that our findings can also be used for other radiopharmaceuticals that are associated with similar side effects,” concluded Béhé. 

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