Quantitative metal-encoded approaches for targeted drug delivery
Embargo Date
2025-09-27
OA Version
Citation
Abstract
In modern drug discovery, the clinical success of new therapies is often hindered by physiological barriers that impact their toxicity, efficacy, and biodistribution. One approach to overcome these barriers is to implement tissue-targeted formulations that utilize ligands to enable drug accumulation at pathogenic sites and limit toxic off-target effects in healthy tissues. Currently, only a small number of known targeting ligands or formulations are being evaluated clinically, and no systematic approaches to the discovery of new targeting modalities have been reported. To address this need, we have developed quantitative metal-encoded strategies utilizing lanthanide metals for facile identification of new targeting modalities with unique biodistributions.
We have successfully completed proof-of-concept studies for a quantitative metal-encoded conjugate (Q-MEC) platform and validated its utility in vivo. We synthesized three organometallic-DNA conjugates with targeting ligands that have known biodistribution profiles: triantennary N-acetylgalactosamine (GalNAc), folic acid, and gambogic acid. The organometallic complexes enabled each targeting ligand to be encoded by complexation with different lanthanide (Gd, Eu, and Tm) metals. Metal quantitation both in vitro and in vivo determined that our targeted DNA conjugates matched the expected biodistribution profiles of known targeting ligands in target-positive cell lines and target organs in healthy
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or diseased mouse models. Next, we applied this platform to discover novel tissue-targeting ligands from a collection of small molecules evaluated for unique serum protein-binding profiles on small-molecule microarrays (SMMs). We showed that the molecule P2_12 displayed dose-dependent binding with mouse serum and demonstrated a targeting preference to bone marrow and muscle utilizing our metal-encoded conjugate platform.
Finally, nanotechnology plays an important role to support agricultural development however no systematic approach to screen targeted nanoparticles for plants has been reported. We encapsulated lanthanide metals into lipid nanoparticles and successfully determined the biodistribution of these nanoparticles in plant tissues. These results show the utility of our metal-encoded approach in determining biodistribution in both plants and animals and can also be successfully adapted to nanoparticle formulations.
In summary, we have successfully deployed a metal-encoded approach to screen small-molecule targeting ligands directly in vivo, identified novel serum proteins, and have established its role in screening nanoparticles for agriculture. This concept will form the basis of a platform to discover more targeting modalities for drug delivery in various medical and agricultural scenarios.