Rhenium(I) Complexes for Platinum-Resistant Cancer Treatment

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Solution Overview

Problem

Platinum-based chemotherapeutic agents, such as cisplatin, are limited by toxicity, side effects, and resistance in treating ovarian cancer, particularly in relapsed cases, and lack effective imaging modalities for drug distribution and response evaluation.

Innovation Solution

Development of rhenium(I) complexes coordinated with neutral ligands, including isonitrile and bidentate ligands, which are stable, water-soluble, and cytotoxic, allowing for ER stress induction and potential as theragnostic agents for cancer treatment, particularly platinum-resistant cancers.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If platinum-based chemotherapeutic agents (e.g., cisplatin) are used to treat cancer, then cancer treatment efficacy is improved, but toxicity and side effects increase

Engineering Contradiction:

Improvecancer treatment efficacyVSAvoidtoxicity and side effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the central metal atom from platinum to rhenium and modifies the ligand environment to create rhenium(I) complexes with different pharmacological properties. This parameter change allows maintaining cancer cell targeting while reducing off-target toxicity, as rhenium complexes exhibit selective cytotoxicity toward cancer cells with reduced harm to normal tissues

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite rhenium(I) complexes combining multiple ligands (isonitrile, bidentate ligands, and other neutral ligands) to achieve optimal balance between efficacy and toxicity. The composite structure allows fine-tuning of the complex's biological activity and selective cytotoxicity

Inventive Principle:

Principle #40Composite materials

2Adaptability or versatility

If platinum-based chemotherapeutic agents are used to treat relapsed ovarian cancer, then treatment coverage is expanded, but resistance develops

Engineering Contradiction:

Improvetreatment coverageVSAvoiddrug resistance

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

Instead of modifying platinum-based drugs to overcome resistance, the patent inverts the approach by using a completely different metal center (rhenium) with distinct mechanism of action. This inversion bypasses platinum resistance mechanisms while maintaining effectiveness against relapsed ovarian cancer

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent changes the fundamental chemical and biological parameters of the chemotherapeutic agent by substituting platinum with rhenium and adjusting ligand configurations, thereby creating a drug that does not share the resistance mechanisms of platinum-based agents

Inventive Principle:

Principle #35Parameter changes

3Reliability

If platinum-based drugs are administered, then cancer cell cytotoxicity is achieved, but water solubility and stability in aqueous solution are poor

Engineering Contradiction:

ImprovecytotoxicityVSAvoidwater solubility and stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent changes the metal center and ligand composition to create rhenium(I) complexes with improved aqueous stability. The specific ligand choices and rhenium coordination chemistry enable better water solubility and resistance to degradation in physiological conditions while maintaining cytotoxic activity

Inventive Principle:

Principle #35Parameter changes

4Measurement precision

If conventional imaging methods are used to evaluate platinum drug distribution, then drug distribution can be assessed, but imaging capability is insufficient for real-time evaluation

Engineering Contradiction:

Improvedrug distribution imagingVSAvoidreal-time evaluation capability

Core Design Contradiction:

Measurement precisionVSDifficulty of detecting and measuring

Solution Approach 1:

The patent incorporates imaging-active ligands or metal centers with characteristic optical properties that enable detection. The rhenium(I) complexes can be designed with ligands that provide detectable signals for real-time imaging of drug distribution and accumulation in tumor tissues

Inventive Principle:

Principle #32Color changes

Solution Approach 2:

The patent creates theragnostic agents that simultaneously provide therapeutic cytotoxicity and diagnostic imaging capability. The rhenium(I) complexes serve both as cancer treatment agents and as probes for real-time monitoring of drug distribution and response

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS11884685B2Rhenium complexes and methods of use for treating cancer

Publication Date: 2024.01.30 CORNELL UNIVERSITY

AI summary

A composition comprising the following structure: (1) wherein Re represents a rhenium ion having a +1 charge; (I) represents an uncharged bidentate ligand containing at least one ring containing a ring nitrogen atom bound to the rhenium (Re), and the bidentate ligand containing another nitrogen atom, either in a ring or not in a ring, bound to the rhenium (Re); and L1, L2, L3, and L4 are neutral ligands with at least one neutral ligand being an isonitrile ligand of the formula —CN—R, wherein R is an aliphatic or aromatic hydrocarbon group containing 1-20 carbon atoms; and X− represents a non-coordinating monovalent anion; wherein the bidentate ligand and R are optionally substituted by one or more groups selected from (i)-(xi) as further discussed above. Methods for treating a condition that benefits from ER stress induction, such as cancer, by administering the above rhenium complex are also disclosed.