Affibody Molecules as Targeting Vectors for PET Imaging
Abstract
:1. Introduction
2. Engineered Scaffold Protein-Based Imaging Probes: Affibody Molecules
- Their small size ensures rapid extravasation and diffusion in the extracellular space, providing efficient localization in tumors. Unbound affibody molecules are rapidly excreted from blood via glomerular filtration, and this reduces the background.
- Affibody molecules can be selected to have a high affinity and specificity to a desirable molecular target.These Features Together Safeguard the Rapid Acquisition of a High Imaging Contrast and Determine the High Sensitivity of Molecular Imaging
- Small proteins (less than 45 kDa) do not accumulate in tumors by the EPR effect [30]. This reduces the risk of false-positive diagnostics.
- Affibody molecules are proteolytically, chemically, and thermally stable and refold within 3 µs with a high fidelity after thermal or chemical denaturation [31]. This permits the use of high temperatures (up to 90–95 °C), which enables rapid labeling using macrocyclic chelators [32,33], a broad range of pH values (from 3.6 to 11.0) [32,33,34,35], and lipophilic organic solvents for intermediate purifications [36], without losing specificity and affinity.
- Affibody molecules do not contain cysteines, and their folding is independent of disulphide bridges. This allows the use of large amounts of oxidants (e.g., during electrophilic iodination) or reductants (e.g., during labeling with 99mTc or 186/188Re), without the risk of denaturation.
3. Biodistribution and Targeting Features of Radiolabeled Affibody Molecules
- Small size;
- Slow internalization after specific binding to a molecular target;
- High reabsorption in proximal tubules;
- Elevated hepatic uptake and/or hepatobiliary exertion after modifications, increasing the overall or local lipophilicity.
4. Affinity and Dimerization
5. Injected Mass and Molar Activity
6. Labeling of Affibody Molecules with Positron-Emitting Radionuclides
6.1. Fluorine-18
6.2. Gallium-68
6.3. Long-Lived Positron Emitters
7. Conclusions
- Affinity should be in the low nanomolar range for targets with a high expression, and a subnanomolar affinity is necessary in the case of low expression;
- A desirable affinity should be achieved by affinity maturation, not by dimerization;
- Meticulous dose-finding studies should be performed in the case of the physiological expression of a target in normal tissues. Conventional microdosing studies might be misleading due to a much higher normal tissue uptake when compared to imaging using optimal doses;
- The molecular design of affibody-based tracers should aim to minimize off-target interactions. Labeling approaches resulting in an increased lipophilicity are undesirable, but their negative effect might be compensated for by adding a negatively charged linker (e.g., a triglutamyl linker).
- The combination of a radiometal and chelator has an appreciable influence on off-target interactions and thus on the imaging contrast. Several alternative approaches should be tested to select the best one.
Funding
Conflicts of Interest
References
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Tolmachev, V.; Orlova, A. Affibody Molecules as Targeting Vectors for PET Imaging. Cancers 2020, 12, 651. https://doi.org/10.3390/cancers12030651
Tolmachev V, Orlova A. Affibody Molecules as Targeting Vectors for PET Imaging. Cancers. 2020; 12(3):651. https://doi.org/10.3390/cancers12030651
Chicago/Turabian StyleTolmachev, Vladimir, and Anna Orlova. 2020. "Affibody Molecules as Targeting Vectors for PET Imaging" Cancers 12, no. 3: 651. https://doi.org/10.3390/cancers12030651