Cyclized NGR Peptides for CD13 Targeting
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Solution Overview
Problem
Current NGR peptides used for targeting cancer cells are not stable under physiological conditions, limiting their effectiveness in targeting aminopeptidase N isoform CD13 expressed on tumor vasculature.
Innovation Solution
Development of permanently cyclized compounds containing the NGR peptide motif, combined with a lipid-bilayer and optional polyethylene glycol, for selective targeting of cancerous tissue expressing CD13, enhancing stability and delivery efficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If disulfide-bridged cyclic peptides containing the NGR motif are used to target tumor vasculature, then anti-tumor activity is enhanced, but stability under physiological conditions deteriorates
Solution Approach 1:
The patent changes the chemical structure parameter from disulfide bridges to alternative cyclization methods (amide bonds, ester bonds, or other stable linkages) that maintain the cyclic conformation while improving stability under physiological conditions. This allows the peptide to retain its tumor-targeting ability while resisting breakdown in the cellular environment.
Solution Approach 2:
The patent employs composite peptide structures that combine the NGR motif with stable cyclic frameworks, creating a hybrid molecule that integrates the tumor-targeting functionality of NGR with the enhanced stability of alternative cyclic structures, thereby achieving both high anti-tumor activity and physiological stability.
2Ease of manufacture
If linear NGR peptides are used for delivering therapeutic agents, then ease of manufacture is improved, but anti-tumor activity is reduced
Solution Approach 1:
The patent incorporates the cyclization step into the synthesis process itself, performing the cyclic structure formation during peptide assembly rather than as a separate post-synthesis modification. This preliminary action maintains manufacturing simplicity while ensuring the peptide adopts the required cyclic conformation for high anti-tumor activity.
Solution Approach 2:
The patent modifies the structural parameter from linear to cyclic configuration, which enhances the peptide's ability to bind to CD13 on tumor vasculature and deliver therapeutic agents effectively, while maintaining compatibility with standard peptide synthesis methodologies.
3Productivity
If disulfide-bridged cyclic NGR peptides are used to target CD13, then delivery efficiency is enhanced, but stability in cellular environments deteriorates
Solution Approach 1:
The patent changes the chemical linkage parameter from disulfide bonds (which are labile in cellular environments) to stable amide or ester bonds that maintain the cyclic structure intact during intracellular delivery, thereby preserving both delivery efficiency and stability in cellular environments.
Solution Approach 2:
The patent designs the cyclic peptide to be stable enough to reach the target and perform its function, but not necessarily permanent, allowing for controlled degradation after delivering its therapeutic payload, thus optimizing both delivery efficiency and environmental stability.
Data Source
AI summary
Cyclized peptide compounds containing the NGR motif of formula (I) or a pharmaceutically-acceptable salt thereof are disclosed. Compositions comprising the cyclized peptide compounds and methods of their use are also disclosed.