Brush-Arm Star Polymer MRI Contrast Agents for Toxicity Reduction

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current MRI contrast agents, particularly metal-based ones, face limitations such as toxicity concerns, especially in patients with kidney issues and newborns, and rapid bioreduction of nitroxide-based agents, which reduces their effectiveness for long-term imaging applications like tumor imaging.

Innovation Solution

Development of Brush-Arm Star Polymer Organic Radical Contrast Agents (BASP-ORCAs) that utilize a poly(nitroxide) macromolecule structure to enhance relaxivity and stability, allowing for prolonged in vivo imaging without toxicity concerns.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If metal-based contrast agents (Gd, Mn, Fe-oxide) are used to achieve high relaxivity and good image contrast, then imaging quality is improved, but toxicity concerns arise especially in patients with kidney issues and newborns

Engineering Contradiction:

Improveimage contrastVSAvoidtoxicity

Core Design Contradiction:

Measurement precisionVSObject-affected harmful factors

Solution Approach 1:

The patent transitions from metal-based contrast agents to organic radical-based contrast agents, fundamentally changing the chemical composition parameter. This substitution eliminates toxic metal ions (Gd3+, Mn2+, Fe-oxide) while maintaining contrast functionality through organic nitroxide radicals, directly resolving the toxicity issue while preserving image contrast quality

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs biocompatible organic materials that are naturally metabolizable and excretable, replacing persistent metal-based agents. The organic radical contrast agents are designed to be temporarily functional in the body and then safely eliminated, reducing long-term toxicity concerns associated with metal accumulation

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

2Object-affected harmful factors

If nitroxide-based contrast agents are used to eliminate toxicity concerns, then safety is improved, but rapid bioreduction occurs which reduces effectiveness for long-term imaging

Engineering Contradiction:

ImprovetoxicityVSAvoidimaging duration

Core Design Contradiction:

Object-affected harmful factorsVSDuration of action of stationary object

Solution Approach 1:

The patent creates a composite structure where nitroxide radicals are incorporated into a polymer matrix (such as polyacrylamide or polyethylene glycol). This composite approach protects the labile nitroxide radicals from rapid bioreduction by the biological environment while maintaining their MRI contrast functionality, thereby extending the effective imaging duration

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The patent modifies the local chemical environment of the nitroxide radicals by embedding them within a polymer structure. This local modification creates a protective microenvironment that reduces exposure to biological reducing agents, thereby slowing bioreduction rates and extending the functional lifetime of the contrast agent in vivo

Inventive Principle:

Principle #3Local quality

3Measurement precision

If poly(nitroxide) macromolecule structure is used to enhance relaxivity, then contrast performance is improved, but structural complexity increases

Engineering Contradiction:

ImproverelaxivityVSAvoidmolecular structure

Core Design Contradiction:

Measurement precisionVSDevice complexity

Solution Approach 1:

The patent divides the contrast agent into modular segments: a polymer backbone structure and multiple attached nitroxide radical units. This segmentation allows systematic design where the polymer provides structural stability and the nitroxide units provide contrast functionality, making the complex structure more manageable and designable through modular assembly

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent designs polymer backbones with universal functional groups that can accommodate different nitroxide radical configurations. This universality allows the same polymer framework to support various contrast agent designs, reducing overall system complexity while maintaining high relaxivity through multiple nitroxide units

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

BASP-ORCAs provide stable, high-relaxivity MRI contrast for extended periods, enabling effective tumor imaging and potential applications in image-guided drug delivery strategies without the toxicity issues associated with metal-based agents.

Implementation Method 1

nitroxide ORCAs rely on standard water relaxation mechanisms to achieve MRI contrast... the nitroxide radical only possesses one unpaired electron... compared to metal-based contrast agents such as Gd3+ (7 unpaired electrons) or Mn2+ (5 unpaired electrons), nitroxide ORCAs inherently suffer from much lower 1H water relaxivity

Methodology Applied

Scientific EffectParamagnetic relaxation enhancement:

Data Source

PatentUS11752221B2Brush-arm star polymer imaging agents and uses thereof

Publication Date: 2023.09.12 MASSACHUSETTS INST OF TECH

AI summary

Disclosed are methods, compositions, reagents, systems, and kits to prepare nitroxide-functionalized brush-arm star polymer organic radical contrast agent (BASP-ORCA) as well as compositions and uses thereof. Various embodiments show that BASP-ORCA display unprecedented per-nitroxide and per-molecule transverse relaxivities for organic radical contrast agents, exceptional stability, high water solubility, low in vitro and in vivo toxicity, and long blood compartment half-life. These materials have the potential to be adopted for tumor imaging using clinical high-field 1H MRI techniques.