Cytotoxic Fluoropyrimidine Polymers for Colorectal Cancer

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Solution Overview

Problem

Current fluoropyrimidine (FP) drugs, such as 5-fluorouracil (5-FU), have limitations including rapid degradation and excretion, gastrointestinal toxicities, and limited efficacy in treating advanced colorectal cancer (CRC).

Innovation Solution

Development of novel cytotoxic fluoropyrimidine polymers, specifically nucleic acid molecules with 5-fluoro-2′deoxyuridine monophosphate (FdUMP) appended with a polyethylene glycol (PEG) spacer and a cytarabine (AraC) nucleotide, exemplified by CF10, which enhances internalization into malignant cells and reduces gastrointestinal toxicity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If 5-fluorouracil (5-FU) is used to treat colorectal cancer, then it shows therapeutic efficacy against cancer cells, but it causes gastrointestinal toxicities and is rapidly degraded and excreted

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidgastrointestinal toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent segments the fluoropyrimidine molecule into a polymer structure consisting of multiple FdUMP units linked together. This polymerization approach modifies the pharmacokinetic and pharmacodynamic properties of the drug, reducing its rapid degradation and excretion while maintaining anticancer efficacy. The segmented polymer structure allows for controlled release and reduced gastrointestinal toxicity compared to monomeric 5-FU.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention creates a composite molecular structure by combining FdUMP units with specific linkers to form a polymeric fluoropyrimidine compound. This composite material approach integrates multiple functional units that work together to achieve both therapeutic efficacy and reduced toxicity, representing a fundamental shift from simple small-molecule chemotherapy to complex polymeric therapeutics.

Inventive Principle:

Principle #40Composite materials

2Reliability

If 5-fluorouracil (5-FU) is used to treat colorectal cancer, then it affects RNA function through misincorporation, but this causes dose-limiting gastrointestinal toxicities

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoiddose-limiting toxicity

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by designing the FdUMP polymer to specifically target DNA synthesis pathways in cancer cells through thymidylate synthase inhibition. The polymer structure ensures that the cytotoxic effect is localized to DNA replication processes rather than affecting RNA function systemically. This selective mechanism of action maintains therapeutic efficacy while avoiding the dose-limiting gastrointestinal toxicities associated with RNA misincorporation.

Inventive Principle:

Principle #3Local quality

3Reliability

If conventional fluoropyrimidine drugs are used, then they treat cancer cells, but they have rapid degradation and short half-life

Engineering Contradiction:

Improvecancer treatment efficacyVSAvoidhalf-life

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent employs preliminary action by pre-assembling multiple FdUMP units into a stable polymeric structure before administration. This pre-organized polymer form protects the active fluoropyrimidine moieties from premature degradation in circulation. The polymer structure serves as a protected reservoir that releases active drug at the target site, thereby extending the effective half-life and maintaining therapeutic concentrations for longer periods.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The polymeric structure acts as an intermediary carrier that transports multiple FdUMP units through the bloodstream to the tumor site. This intermediary polymer protects the labile FdUMP units from rapid degradation by plasma nucleases and other degradative enzymes, effectively extending their circulating half-life while maintaining the ability to deliver therapeutic doses to cancer cells.

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

CF10 demonstrates significant therapeutic advantages by being well-tolerated, rapidly internalized by cancer cells, and highly effective in reducing tumor burden and metastasis in orthotopic models of CRC, while minimizing gastrointestinal toxicity.

Implementation Method 1

more rapid internalization into malignant cells than previous FPs

Methodology Applied

Scientific EffectCellular internalization:

Implementation Method 2

CF10 potency correlates with enhanced thymidylate synthase (TS) inhibition

Methodology Applied

Scientific EffectEnzyme inhibition: Enzyme

Implementation Method 3

increased DNA topoisomerase 1 (Top1)-mediated DNA damage

Methodology Applied

Scientific EffectDNA damage:

Data Source

PatentUS12319915B2Cytotoxic fluoropyrimidine polymers and methods of use thereof

Publication Date: 2025.06.03 WAKE FOREST UNIVERSITY HEALTH SCIENCES INC

AI summary

Novel cytotoxic fluoropyrimidine polymers for treating cancer (e.g., colorectal cancer (CRC)) in a subject (e.g., a subject having cancer) are nucleic acid molecules including 5-fluoro-2′deoxyuridine monophosphate (FdUMP)[10] having a polyethylene glycol (PEG) spacer appended to the 5′ terminus and a cytarabine (AraC) nucleotide appended to 3′termius. These novel cytotoxic fluoropyrimidine polymers may be used in compositions, kits and methods for treating advanced and high-risk cancers, including CRC.