Labeled biomolecules in diagnosis/treatment of primary and metastatic cancer

Radiopharmacy is now in its fortieth year of existence, and in its rather short scientific life it has greatly contributed in the development and evolution of another modern science, Nuclear Medicine. Its contribution is basically focused on the development of specialized radiopharmaceuticals to be used in the diagnosis and/or therapeutic intervention of cancer.

During the last few years, the development of novel, highly specific radiopharmaceuticals on an international level is based on the radiolabeling of bioactive molecules (biomolecules) with radionuclides, which emit gamma or beta radiation. Biomolecules are biologically active molecules usually of a natural origin, which are comprised of a combination of amino acids. They exercise their pharmacological action via their specific interaction with specific receptors, which are found either on the surface of these cell-targets, or internally. The major categories of biomolecules, currently applied in Nuclear Medicine under radiolabeled form, are Monoclonal Antibodies (ÌoAbs) and Peptides, which are used in the following fields:

• Radioimmunoscintigraphy, for the localization and imaging of primary and metastatic tumors
• Radioimmunotherapy, for the inhibition of the development of tumors, and
• Molecular Nuclear Medicine, for the depiction of a variety of pathological situations and of the accompanying molecular abnormalities.

The application of MoAbs in the diagnosis and therapy of cancer is based on their ability to bind, in a specific way, to antigens, which are found on the surface of tumors. The localization of these radiolabeled biomolecules on tumors allows their scintigraphic imaging (Radioimmunoscintigraphy - RIS) and/or their therapeutic intervention (Radioimmunotherapy - RIT). The differences between the scintigraphic and therapeutic techniques refer to:

• The type of radiation emitted by the radionuclide
• The applied radiation dose
• The applied antibody dose
• The dose which is uptaken by the tumor

• Because of their large molecular weight, MoAbs have slow blood clearance and high background radiation
• During Radioimmunoscintigraphy, there is delayed imaging, as a result of which short-lived isotopes cannot be used
• During Radioimmunotherapy, the irradiation of healthy tissue is inevitable
• The binding of MoAbs with tumor antigens is not always specific and is usually weak
• Monoclonal Antibodies do not penetrate into the cancerous tissue, but remain on the surface of the tumor
• Initially, the antibodies which had been developed were of animal origin, therefore their intravenous injection resulted in immunological response (HAMA)

• RIS, in the pre-operative stage, allows the exact localization of the tumor, and the specific determination of its dimensions, while it also assists in the prompt detection of distant metastases
• The isolation and labeling of small molecular weight antibody "fragments" increases the blood clearance rate, thus increasing the rate of uptake of the biomolecule by the tumor.
• The elimination of the Fc fragment leads to a decrease in allergic reactions
• The use of "chimeric" antibodies, or antibodies of human origin, facilitates the administration of larger doses of the protein, thus opening new horizons in RIT
• The use of radiolabeled antibodies in the detection and imaging of newly-formed blood vessels around the developing tumor, opens new horizons in tumor diagnosis

The above mentioned disadvantages of radiolabeled monoclonal antibodies have led international research to the study and application of lower-molecular-weight protein compounds. Thus, while the molecules of ÌïÁbs are comprised of a combination of over 50 amino-acids, radiolabeled peptides have recently started to be applied in Niclear Medicine, the molecules of which are a combination of fewer than 50 amino-acids, and specifically small peptides, whose molecules have fewer than 30 amino-acids. The advantages of peptides, as compared to monoclonal antibodies, are as follows:

• Peptides are easily synthesized
• Because of their small size, after their application they are quickly excreted from the organism
• Their structure can easily be modified, so that their ability to bind to receptors is optimized
• Because of their small size, they do not cause allergic reactions
• The labeled peptide derivatives are almost exclusively excreted via the urinary tract

In order to fully exploit the advantages of peptides, in comparison to larger protein molecules, during their labeling, certain things must be kept in mind:

• The labeling conditions must be carefully monitored, so as to avoid altering the biological activity of the peptide
• The radionuclide must bind with the bioactive molecule in a stable fashion
• The labeling site must not be too close to the receptor binding site, or it must not obstruct this

The peptide derivatives used today in Nuclear Medicine are labeled with Tc-99m and radioisotopes of Indium (In-111 In-113) for diagnosis, Iodine (É-131, É-123) for diagnosis and therapy, and Rhenium (Re-186, Re-188) for therapy.

Fields of application of radiolabeled peptides - Prospectives

Oncology

• Radiolabeled Somatostatin Derivatives (¹¹¹In-Octreotide, ^99mTc- Octreotate, ^99mTc-Lanreotide, ¹⁸⁶Re-Lanreotide, ¹⁵³Sm-Lanreotide, ¹²³I-VIP) are used in the detection of a variety of tumor types, such as tumors of the hypophysis, the thyroid, neuroendocrine tumors, as well as tumors of the GastroEnteroPancreatic (GEP) system
• Radiolabeled Bombesin Derivatives are used in the diagnosis/therapy of tumors of the lung, the prostate, the breast, as well as tumors of the GastroEnteroPancreatic system

• Peptides connected to endogenous molecules, such as transferrin, are able to cross the Blood Brain Barrier (BBB), thus imaging CNS receptors.

• The peptide Annexin, labeled with I-131 or Tc-99m, binds to phosphatidylserine, thus allowing the imaging of:
  • Myocardial infarct
  • Atheromatic plaques
  • Endocarditis
  • Rejected transplant
• ¹¹¹In-octreotide is also mentioned for such studies

• Investigation of the imaging of inflammation with labeled cytokines, chemotactic peptides, leucine and isoleucine, as well as antimicrobial peptides

• Radiolabeled biomolecules are a very important imaging and therapeutic tool for modern Nuclear Medicine
• These molecules are also a very important "tool" to be used for the development of a new research field, Molecular Nuclear Medicine

Speaker: Alexandra D. Varvarigou, Radiobiological Studies Laboratory, Institute of Radioisotopes and Radiodiagnostic Products, N.C.S.R. "Demokritos"
Time: Monday, 27 January 2003, 13:00