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Published on: June 13, 2014
Small Organic Carbonic Anhydrase IX Ligands from DNA-Encoded Chemical Libraries for Tumor-Targeted Delivery of
Marco Müller1, Tony Georgiev1, Jacqueline Mock1
1Philochem AG, 8112 Otelfingen, Switzerland.
Abstract:
Carbonic anhydrase IX (CAIX) is a membrane protein that is highly expressed in clear cell renal cell carcinoma (ccRCC) and in hypoxic tumors. Being virtually absent in most healthy tissues, CAIX became an attractive target for the selective delivery of diagnostic and therapeutic payloads. Here, we report the discovery and characterization of DNA-encoded chemical library (DEL)-derived CAIX ligands for radionuclide-based imaging applications.
Methods:
DELs were screened against CAIX and CAII to prioritize hits based on their selectivity and enrichment against CAIX. In vitro characterization of hits was performed by fluorescence polarization (FP), surface plasmon resonance (SPR), and flow cytometry. In vivo biodistribution studies of Lutetium-177 and Gallium-68-radiolabeled compounds were performed in SK-RC-52 tumor-bearing mice.
Results:
DEL-based CAIX ligands with different affinities and selectivities could be identified. Selectivity and high affinity toward the target correlated with higher tumor-to-organ ratios and improved tumor retention. The best candidate, named OncoCAIX, reached up to ∼55% injected dose per gram in SK-RC-52 lesions at early time points with very low healthy organ uptake (tumor-to-kidney ratio of >23).
Conclusion:
OncoCAIX demonstrated rapid and selective tumor uptake, which is a key feature for the development of radionuclide-based imaging agents for early and late-stage ccRCC and hypoxic tumors.
Insights
New DNA-encoded chemical library ligands targeting carbonic anhydrase IX (CAIX) show high tumor uptake and selectivity. These CAIX ligands are promising for developing advanced imaging agents for clear cell renal cell carcinoma (ccRCC) and hypoxic tumors.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Carbonic anhydrase IX (CAIX) is a tumor-associated protein overexpressed in clear cell renal cell carcinoma (ccRCC) and hypoxic tumors.
- Its limited expression in healthy tissues makes CAIX an attractive target for selective cancer imaging and therapy.
- DNA-encoded chemical libraries (DELs) offer a powerful platform for discovering novel molecular ligands.
Purpose of the Study:
- To discover and characterize novel CAIX ligands using DEL technology.
- To evaluate the potential of these ligands for radionuclide-based imaging of ccRCC and hypoxic tumors.
- To identify selective CAIX-targeting agents with high tumor uptake and retention.
Main Methods:
- Screening of DELs against CAIX and carbonic anhydrase II (CAII) to ensure target selectivity.
- In vitro characterization using fluorescence polarization (FP), surface plasmon resonance (SPR), and flow cytometry.
- In vivo biodistribution studies using Lutetium-177 and Gallium-68 labeled compounds in a ccRCC mouse model.
Main Results:
- Identification of DEL-derived CAIX ligands with varying affinities and selectivities.
- Demonstrated correlation between ligand selectivity/affinity and improved tumor-to-organ ratios and retention.
- The lead candidate, OncoCAIX, achieved significant tumor uptake (∼55% injected dose/gram) with high tumor-to-kidney ratios (>23) in vivo.
Conclusions:
- OncoCAIX exhibits rapid and selective tumor accumulation, validating its potential as an imaging agent.
- These findings support the development of OncoCAIX for early and late-stage ccRCC and hypoxic tumor imaging.
- DEL technology is effective for discovering targeted diagnostic and therapeutic agents.
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