PSMA-Targeting Multivalent Scaffold for Enhanced Binding Affinity
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Solution Overview
Problem
Current methods for creating multivalent scaffolds for prostate-specific membrane antigen (PSMA) targeting are complex and have not successfully imaged PSMA in vivo, lacking efficient methods for multimeric presentation of PSMA and other targeting species.
Innovation Solution
Development of compounds with a lysine-based multimeric urea dendron structure, utilizing a DOTA chelating agent for radiometal incorporation, enabling the generation of bivalent and higher valent forms for improved PSMA targeting, which can be used with various radiometals and imaging isotopes for both imaging and therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multivalent scaffolds are constructed using various approaches, then binding affinity to PSMA is improved, but the chemistry used to produce them becomes complicated
Solution Approach 1:
The multivalent scaffold is constructed by segmenting the molecule into distinct functional modules: a dendron core structure, multiple PSMA-targeting ligand arms, and a radionuclide chelator. This segmentation allows each module to be optimized and synthesized separately, then assembled through well-defined coupling reactions, reducing overall chemical complexity while maintaining high binding affinity through the multivalent architecture
Solution Approach 2:
The dendron scaffold is designed with universal coupling sites that can accommodate different PSMA-targeting ligands and radionuclide chelators. This multi-functionality allows the same core structure to be used for creating various multivalent conjugates with different therapeutic or diagnostic payloads, simplifying the chemical synthesis pathway across different applications
2Adaptability or versatility
If a bifunctional chelator is attached to a separately multimerized construct, then radionuclide incorporation is enabled, but the chemistry becomes even more complicated
Solution Approach 1:
The bifunctional chelator is merged into the dendron scaffold structure itself during the multimerization process, rather than being attached as a separate post-processing step. This integration means the chelator is positioned optimally within the multivalent construct and reduces the number of separate chemical operations required, simplifying the overall synthesis while maintaining radionuclide incorporation capability
Solution Approach 2:
The chelator functionality is built into the dendron structure in advance during scaffold construction, before the final conjugation with PSMA-targeting ligands. This preliminary action ensures the chelator is already in place and properly oriented when the multivalent construct is completed, eliminating the need for separate chelator attachment steps and reducing chemical complexity
3Device complexity
If monovalent forms are used, then the structure is simpler, but binding affinity and in vivo retention are reduced
Solution Approach 1:
The multivalent scaffold employs a nested dendron architecture where multiple PSMA-targeting ligand arms are arranged in a hierarchical structure around a central core. This nested arrangement maximizes the local concentration of binding sites, enhancing binding affinity through avidity effects while maintaining a compact overall structure that is more manageable than fully extended multivalent configurations
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The multivalent scaffold allows for enhanced PSMA targeting with increased binding affinity and retention in vivo, enabling effective imaging and potential therapeutic applications by facilitating prolonged tumor retention and reduced non-target tissue clearance.
Implementation Method 1
utilizing a DOTA chelating agent for radiometal incorporation
Data Source
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AI summary
The present invention provides a compound contains a PSMA binding Lys-Glu urea moiety linked to DOTA in complex with 111In3+ and its use in imaging PSMA cells.