PSMA-Targeted Conjugates With Cleavable Linkers for Tumor-Selective Imaging

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Solution Overview

Problem

Existing PSMA-targeted cancer therapies and imaging modalities face challenges with significant accumulation and uptake in non-cancer tissues such as salivary glands, lacrimal glands, and kidneys, leading to dose-limiting toxicity and interference in imaging.

Innovation Solution

Development of PSMA targeted conjugate compounds with specific selectivity for PSMA-expressing cancer tissues, minimizing accumulation in non-cancer tissues, and incorporating detectable moieties, therapeutic agents, or theranostic agents, such as radiolabels, chelating agents, and photosensitizers, linked via protease-cleavable or acid-labile linkers.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If PSMA-targeted compounds are administered to treat or image prostate cancer, then therapeutic efficacy and imaging accuracy improve, but accumulation and uptake in non-cancer tissues such as salivary glands, lacrimal glands, and kidneys increase causing dose-limiting toxicity and imaging interference

Engineering Contradiction:

Improvetherapeutic efficacy and imaging accuracyVSAvoidtoxicity and imaging interference in non-cancer tissues

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention segments the PSMA-targeting function from the therapeutic/imaging function by using a conjugate structure where a PSMA-targeting moiety is linked to a therapeutic agent or detectable moiety via a cleavable linker. This segmentation allows the targeting component to guide the compound to cancer cells while the therapeutic/imaging component remains separated until activation at the target site, reducing off-target effects in normal tissues expressing PSMA

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The cleavable linker serves as an intermediary between the PSMA-targeting moiety and the therapeutic/imaging agent. This intermediary is designed to be stable in circulation but cleave specifically at the target site (via protease or acid conditions), mediating the transition from a stable conjugate that minimizes off-target accumulation to an activated state that releases the therapeutic/imaging payload only at cancer cells

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If existing PSMA-targeted therapies are used, then cancer treatment is achieved, but significant accumulation in non-PSMA targets in non-cancer tissue occurs leading to dose-limiting toxicity

Engineering Contradiction:

Improvecancer treatment effectivenessVSAvoidaccumulation in non-cancer tissues

Core Design Contradiction:

ProductivityVSQuantity of substance

Solution Approach 1:

The invention changes the chemical parameters of the compound by incorporating a cleavable linker that undergoes specific chemical transformation (cleavage) under conditions present at the cancer cell site (protease activity or acidic endosomal/lysosomal environment). This parameter change transforms the compound from a stable, non-cleaved conjugate with minimal off-target accumulation to an activated state with released therapeutic agent, thereby treating cancer effectively while limiting toxicity in normal tissues

Inventive Principle:

Principle #35Parameter changes

3Measurement precision

If PSMA-targeted compounds accumulate in non-cancer tissues, then imaging can be performed, but interference from non-PSMA targets reduces imaging accuracy

Engineering Contradiction:

Improveimaging accuracyVSAvoidimaging interference from non-PSMA targets

Core Design Contradiction:

Measurement precisionVSObject-generated harmful factors

Solution Approach 1:

The invention applies preliminary action by designing the conjugate to remain intact and stable during circulation, preventing premature release of the detectable moiety in non-cancer tissues. The cleavable linker is engineered to maintain structural integrity until it encounters the specific biochemical conditions at the cancer cell site, ensuring that imaging signals are generated only from true PSMA-expressing tumor cells and not from normal tissues with lower PSMA expression

Inventive Principle:

Principle #10Preliminary action

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 compounds demonstrate selective targeting of PSMA-expressing cancer tissues with minimal uptake in non-cancer tissues, enhancing therapeutic efficacy and imaging accuracy while reducing toxicity and interference.

Implementation Method 1

Y1 and Y2 are each independently a H of B or can include at least one detectable moiety, therapeutic agent, or theranostic agent

Methodology Applied

Scientific EffectRadioactive decay: Radioactive Decay

Implementation Method 2

incorporating detectable moieties, therapeutic agents, or theranostic agents, such as radiolabels, chelating agents, and photosensitizers

Methodology Applied

Scientific EffectChelation:

Implementation Method 3

linked via protease-cleavable or acid-labile linkers

Methodology Applied

Scientific EffectEnzymatic hydrolysis: Enzyme

Implementation Method 4

linked via protease-cleavable or acid-labile linkers

Methodology Applied

Scientific EffectAcid hydrolysis: Hydrolysis

Data Source

PatentUS20250332265A1PSMA targeted conjugate compounds and uses thereof

Publication Date: 2025.10.30 CASE WESTERN RESERVE UNIV

AI summary

PSMA targeted conjugate compounds, pharmaceutical compositions comprising these compounds, methods for treating and detecting cancers in a subject, methods for identifying cancer cells in a sample are described herein.