Bismuth(III) Complexes Reduce Cisplatin Nephrotoxicity

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Solution Overview

Problem

Cisplatin-based cancer treatments suffer from significant side effects such as nephrotoxicity, neurotoxicity, and ototoxicity, with nephrotoxicity being the most severe and dose-limiting factor, despite its effectiveness in treating various cancers.

Innovation Solution

The use of bismuth(III) complexes, specifically bismuth(III) zinc(II) citrate complexes like BicitZ, is administered prior to cisplatin to reduce host organ toxicity by inducing metallothionein, which binds to cisplatin, mitigating renal toxicity and oxidative damage without interfering with cisplatin's antitumor activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If cisplatin is administered at high dosage to treat cancer effectively, then antitumor activity is improved, but nephrotoxicity increases and becomes dose-limiting

Engineering Contradiction:

Improveantitumor activityVSAvoidnephrotoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies preliminary action by pre-administering bismuth(III) complexes before cisplatin treatment. The bismuth complex is given at least one day prior to cisplatin administration, allowing metallothionein induction and protective mechanisms to be established before the toxic cisplatin dose is delivered, thereby protecting renal tissue while maintaining antitumor efficacy

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent uses metallothionein as an intermediary substance that mediates between cisplatin and renal tissue. The bismuth(III) complex induces metallothionein production, which then acts as a protective intermediary that binds to cisplatin and prevents direct toxic interaction with kidney cells, reducing nephrotoxicity while allowing therapeutic dosing

Inventive Principle:

Principle #24Intermediary (Mediator)

2Object-affected harmful factors

If bismuth inorganic salts are used to reduce cisplatin toxicity, then nephrotoxicity is reduced, but solubility and absorption are poor limiting activity

Engineering Contradiction:

ImprovenephrotoxicityVSAvoidsolubility and absorption

Core Design Contradiction:

Object-affected harmful factorsVSEase of operation

Solution Approach 1:

The patent applies parameter changes by modifying the chemical form of bismuth from simple inorganic salts to coordinated complexes with specific ligands (such as amino acids, peptides, or small molecules). This coordination chemistry modification changes the solubility and bioavailability parameters of bismuth, making it sufficiently absorbable while maintaining its ability to induce metallothionein and protect against cisplatin toxicity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses composite materials by creating bismuth(III) complexes that combine bismuth ions with organic ligands. These composite molecular structures integrate the toxicological benefits of bismuth with the solubility and bioavailability characteristics of the ligand, achieving both improved absorption and maintained protective activity

Inventive Principle:

Principle #40Composite materials

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

Pre-administration of bismuth(III) complexes significantly reduces cisplatin-induced nephrotoxicity and maintains the efficacy of cisplatin in treating cancer, as demonstrated by increased survival rates and reduced blood urea nitrogen levels in mice, with no interference in tumor growth or metastasis.

Implementation Method 1

an inorganic bismuth salt was able to selectively reduce cisplatin-induced nephrotoxicity without compromising its antitumor activity in animal models, and such an effect is positively correlated to the renal expression level of metallothionein

Methodology Applied

Scientific EffectMetallothionein induction and binding:

Implementation Method 2

the ability of MT to sequestrate cisplatin as well as to protect against cisplatin-induced oxidative damage

Methodology Applied

Scientific EffectSequestration of cisplatin by metallothionein:

Implementation Method 3

Bismuth-based complexes have been utilized clinically for the treatment of Helicobacter pylori infection for decades and are also preferentially accumulated in proximal tubular cells of kidney, which are found to be a good MT inducer

Methodology Applied

Scientific EffectPreferential accumulation in renal cells:

Implementation Method 4

Metallothionein is a cysteine-rich small protein with the function of protection of toxicity of heavy metals, oxidative stress as well as chemical and radiation carcinogenesis

Methodology Applied

Scientific EffectProtection against oxidative damage:

Data Source

PatentUS11554138B2Bismuth(III) complexes as adjuvants in the treatment of cancer using platinum-based chemotherapy

Publication Date: 2023.01.17 THE UNIVERSITY OF HONG KONG

AI summary

The present disclosure relates to methods of using cisplatin active agents in which reduced organ toxicity is observed are provided. In the subject methods, an effective amount is administrated to the host before administration of an effective amount of cisplatin active agents. The cisplatin toxicity reducing agent comprising of stable bismuth(III) complexes or pharmaceutically acceptable salts reduces the levels of undesired toxicity of cisplatin active agents without compromising their anticancer activity. Also provided are methods for use in practicing the subject methods in the treatment of different disease conditions.