Salicylic Acid Polymeric CEST Agents for PSMA Imaging

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Solution Overview

Problem

Current organic chemical exchange saturation transfer (CEST) MRI contrast agents suffer from low sensitivity and challenges in detecting prostate-specific membrane antigen (PSMA) due to small chemical shift differences between exchangeable protons and water, leading to low spatial/temporal resolution and artifacts.

Innovation Solution

Development of salicylic acid-based polymeric CEST contrast agents that incorporate salicylic acid as a CEST probe, which resonates at a frequency far removed from water, enhancing contrast sensitivity and retaining binding affinity for PSMA when grafted onto a polymeric platform.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If conventional CEST contrast agents are used, then MRI contrast can be achieved, but sensitivity is low due to small chemical shift differences between exchangeable protons and water

Engineering Contradiction:

Improvedetection sensitivityVSAvoidchemical shift difference

Core Design Contradiction:

Measurement precisionVSLoss of information

Solution Approach 1:

The patent changes the chemical structure parameter of the CEST agent by incorporating salicylic acid moieties, which shift the resonance frequency of exchangeable protons far from water frequency. This parameter change directly resolves the contradiction by increasing chemical shift difference while maintaining MRI contrast capability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a composite polymeric structure combining salicylic acid units with PSMA-targeting moieties. This composite approach simultaneously achieves large chemical shift difference (improving detection sensitivity) and specific target binding (maintaining contrast functionality)

Inventive Principle:

Principle #40Composite materials

2Measurement precision

If conventional CEST agents are used, then PSMA targeting can be achieved, but spatial and temporal resolution is low leading to artifacts

Engineering Contradiction:

Improvespatial and temporal resolutionVSAvoidartifacts

Core Design Contradiction:

Measurement precisionVSObject-affected harmful factors

Solution Approach 1:

By changing the resonance frequency parameter through salicylic acid incorporation, the patent enables higher spatial and temporal resolution imaging while reducing artifacts that plague conventional CEST agents with small chemical shift differences

Inventive Principle:

Principle #35Parameter changes

3Measurement precision

If salicylic acid is grafted onto polymeric platform, then CEST contrast sensitivity is enhanced, but binding affinity for PSMA must be retained

Engineering Contradiction:

ImproveCEST contrast sensitivityVSAvoidbinding affinity

Core Design Contradiction:

Measurement precisionVSReliability

Solution Approach 1:

The patent segments the molecule into distinct functional modules: salicylic acid units for CEST contrast enhancement and separate PSMA-targeting moieties for maintaining binding affinity. This segmentation allows each component to optimize its function independently while working together as a unified agent

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The polymeric platform serves multiple functions simultaneously: it provides the salicylic acid units for CEST contrast, incorporates PSMA-targeting moieties for specific binding, and offers a structural framework that integrates these functions. This multi-functionality resolves the contradiction by achieving both enhanced contrast sensitivity and retained binding affinity

Inventive Principle:

Principle #6Universality (Multi-functionality)

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 salicylic acid-based polymeric CEST agents provide significantly enhanced MRI contrast and retain high binding affinity for PSMA, offering improved sensitivity and clarity in imaging PSMA-expressing tumors, overcoming the limitations of existing CEST agents.

Implementation Method 1

a new type of MRI contrast that relies on direct chemical exchange of protons with bulk water has been developed and is referred to as chemical exchange saturation transfer (CEST) MRI

Methodology Applied

Scientific EffectChemical exchange saturation transfer (CEST):

Implementation Method 2

concentration marker molecules are labeled by either saturating or labeling their exchangeable proton spins by radio-frequency (RF) irradiation

Methodology Applied

Scientific EffectRadio-frequency saturation:

Implementation Method 3

salicylic acid as a CEST probe, which resonates at a frequency far removed from water, enhancing contrast sensitivity

Methodology Applied

Scientific EffectMagnetic resonance:

Data Source

PatentUS10688198B2Salicylic acid-based polymeric CEST contrast agents targeting prostate-specific membrane antigen and uses thereof

Publication Date: 2020.06.23 JOHNS HOPKINS UNIVERSITY

AI summary

Salicylic acid-based polymeric CEST contrast agents targeting prostate-specific membrane antigen, pharmaceutical composition comprising the same and methods of use thereof are disclosed.