Dual-Target TATE-RGD Molecular Probe for Enhanced Tumor Uptake

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Solution Overview

Problem

Current radioactive probes for tumor diagnosis and treatment often target single receptors, limiting their binding affinity and tumor uptake, and existing chelating agents like DOTA have stability issues.

Innovation Solution

A TATE-RGD dual-target radioactive molecular probe linked by a PEG molecule, utilizing a NOTA chelating agent for radionuclide labeling, allowing simultaneous binding to SSTR2 and integrin αvβ3 receptors, improving pharmacokinetic properties and stability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If single-target molecular probes are used, then the probe structure is simple, but the tumor uptake and binding affinity are limited

Engineering Contradiction:

Improvetumor uptakeVSAvoidprobe structure

Core Design Contradiction:

Quantity of substanceVSDevice complexity

Solution Approach 1:

The patent combines two targeting peptides (TATE for SSTR2 and RGD for integrin αvβ3) into a single dual-target molecular probe. This merging of multiple targeting functions into one probe structure enables simultaneous binding to both SSTR2 and integrin αvβ3 receptors on tumor cells, significantly enhancing tumor uptake and binding affinity compared to single-target probes.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The dual-target probe is constructed as a composite molecular structure incorporating both TATE and RGD peptides linked by a PEG spacer, with a NOTA chelating agent for radionuclide attachment. This composite design integrates multiple functional components into a unified probe that achieves superior tumor targeting capability.

Inventive Principle:

Principle #40Composite materials

2Reliability

If DOTA chelating agent is used, then the radionuclide labeling is achieved, but the in vivo stability is insufficient

Engineering Contradiction:

Improvein vivo stabilityVSAvoidlabeling process

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent changes the chelating agent from DOTA to NOTA, altering the chemical parameters of the labeling system. NOTA provides enhanced in vivo stability due to its smaller molecular size and higher thermodynamic stability constant with radionuclides like 68Ga, while maintaining ease of labeling through similar coordination chemistry mechanisms.

Inventive Principle:

Principle #35Parameter changes

3Quantity of substance

If dual-target probe is designed, then the tumor uptake is enhanced, but the pharmacokinetic properties need optimization

Engineering Contradiction:

Improvetumor uptakeVSAvoidpharmacokinetic properties

Core Design Contradiction:

Quantity of substanceVSDuration of action of moving object

Solution Approach 1:

The patent introduces a PEG (polyethylene glycol) spacer as an intermediary component linking the TATE and RGD peptides. This PEG mediator optimizes the spatial arrangement between the two targeting moieties, improving the probe's pharmacokinetic properties by enhancing circulation time and reducing renal clearance, while maintaining the enhanced tumor uptake capability.

Inventive Principle:

Principle #24Intermediary (Mediator)

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

Enhances tumor uptake and imaging effectiveness, with improved stability and pharmacokinetic properties, achieving better diagnostic and therapeutic outcomes compared to single-target probes.

Implementation Method 1

In vivo, the radiolabeled probe is concentrated to the lesion by TATE and/or RGD polypeptide tumor cell receptor targeting

Methodology Applied

Scientific EffectReceptor targeting:

Implementation Method 2

The molecule can be radiolabeled by a bifunctional chelating agent NOTA-labeled radionuclide

Methodology Applied

Scientific EffectChelation:

Data Source

PatentEP3613441B1Dual-target imaging molecular probe, preparation method therefor, and application thereof

Publication Date: 2023.05.31 PEKING UNION MEDICAL COLLEGE HOSPITAL

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AI summary

The present invention discloses a targeting polypeptide compound having dual targets, comprising a TATE cyclic peptide structure, an RGD cyclic peptide structure and a NOTA chelating group, wherein the TATE cyclic peptide structure, the RGD cyclic peptide structure and the NOTA chelating group are respectively linked by a PEG segment having a polymerization degree of 1 to 5 or directly linked to a same glutamic acid molecule; the structure of the polypeptide compound can be simplified represented as NOTA-PEGn-Glu{PEGm-TATE}-PEGP-RGD, where m, n and p are an integer from 0 to 5 respectively. The prresent invention further discloses a TATE-RGD dual-target radioactive molecular probe based on the polypeptide compound. The TATE-RGD dual-target polypeptide drug of the present invention may simultaneously bind to SSTR, integrin αvβ3, has higher receptor binding affinity and uptake, more excellent non-target tissue clearance rate, and better in vivo and in vitro stability. The invention further discloses a method for preparing the compound and radioactive probe and applications thereof.