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Published on: July 7, 2014
In vivo optical imaging of integrin alphaV-beta3 in mice using multivalent or monovalent cRGD targeting vectors
Zhao-Hui Jin1, Véronique Josserand, Stéphanie Foillard
1INSERM, U823, Cibles Diagnostiques ou Thérapeutiques et Vectorisation des Drogues dans le Cancer du Poumon, Institut Albert Bonniot, La Tronche Cedex, France. jinzhaohui67@yahoo.com
Background:
The cRGD peptide is a promising probe for early non-invasive detection of tumors. This study aimed to demonstrate how RAFT-c(-RGDfK-)4, a molecule allowing a tetrameric presentation of cRGD, improved cRGD-targeting potential using in vivo models of alphaVbeta3-positive or negative tumors.
Results:
We chose the human embryonic kidney cells HEK293(beta3) (high levels of alphaVbeta3) or HEK293(beta1) (alphaVbeta3-negative but expressing alphaV and beta1) engrafted subcutaneously (s.c.) in mice. Non-invasive in vivo optical imaging demonstrated that as compared to its monomeric cRGD analogue, Cy5-RAFT-c(-RGDfK-)4 injected intravenously had higher uptake, prolonged retention and markedly enhanced contrast in HEK293(beta3) than in the HEK293(beta1) tumors. Blocking studies further demonstrated the targeting specificity and competitive binding ability of the tetramer.
Conclusion:
In conclusion, we demonstrated that Cy5-RAFT-c(-RGDfK-)4 was indeed binding to the alphaVbeta3 receptor and with an improved activity as compared to its monomeric analog, confirming the interest of using multivalent ligands. Intravenous injection of Cy5-RAFT-c(-RGDfK-)4 in this novel pair of HEK293(beta3) and HEK293(beta1) tumors, provided tumor/skin ratio above 15. Such an important contrast plus the opportunity to use the HEK293(beta1) negative control cell line are major assets for the community of researchers working on the design and amelioration of RGD-targeted vectors or on RGD-antagonists.
Insights
Tetrameric cRGD peptide probes show enhanced tumor targeting and retention compared to monomeric versions. This improved activity in alphaVbeta3-positive tumors offers better non-invasive detection potential.
Area of Science:
- Biomedical Imaging
- Molecular Imaging
- Drug Delivery
Background:
- The cyclic Arginine-Glycine-Aspartic acid (cRGD) peptide is a promising probe for early non-invasive tumor detection.
- This study investigates RAFT-c(-RGDfK-)4, a tetrameric cRGD molecule, for improved targeting potential.
Purpose of the Study:
- To evaluate the enhanced cRGD-targeting potential of the tetrameric RAFT-c(-RGDfK-)4 molecule.
- To compare the in vivo performance of the tetrameric cRGD probe against its monomeric analog.
Main Methods:
- Utilized human embryonic kidney cells (HEK293) with high alphaVbeta3 (HEK293(beta3)) or negative alphaVbeta3 (HEK293(beta1)) expression, engrafted subcutaneously in mice.
- Employed non-invasive in vivo optical imaging and blocking studies to assess probe uptake, retention, and specificity.
Main Results:
- Cy5-RAFT-c(-RGDfK-)4 demonstrated higher uptake, prolonged retention, and enhanced contrast in alphaVbeta3-positive tumors compared to monomeric cRGD.
- Blocking studies confirmed the tetramer's specific targeting and competitive binding to the alphaVbeta3 receptor.
- Achieved a tumor/skin contrast ratio above 15 with intravenous injection of Cy5-RAFT-c(-RGDfK-)4.
Conclusions:
- Cy5-RAFT-c(-RGDfK-)4 effectively binds to the alphaVbeta3 receptor with improved activity over monomeric analogs, validating multivalent ligand strategies.
- The tetrameric cRGD probe offers significant advantages for non-invasive tumor detection and research on RGD-targeted vectors and antagonists.
- The developed HEK293(beta3)/HEK293(beta1) tumor model provides a valuable tool for evaluating RGD-targeted agents.
