Releasable PARP Inhibitor Conjugates for Lower Systemic Toxicity
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Solution Overview
Problem
Existing cancer treatments using PARP inhibitors and DNA damaging chemotherapeutic agents suffer from undesired systemic toxicity due to simultaneous exposure in normal tissues, limiting their effectiveness.
Innovation Solution
Development of releasable conjugates of DNA damage response inhibitors, such as PARP inhibitors, which accumulate in tumor tissues using the enhanced permeability and retention effect, minimizing systemic exposure and maximizing local concentrations in tumors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PARP inhibitors and DNA damaging chemotherapeutic agents are administered simultaneously, then treatment efficacy is improved through synergistic effects, but systemic toxicity increases due to exposure of normal tissues
Solution Approach 1:
The patent divides the treatment approach into two separate components: (1) a DNA damaging agent administered first to induce DNA damage in tumor cells, and (2) a PARP inhibitor administered subsequently to block repair mechanisms. This temporal segmentation allows the DNA damage to accumulate in tumor cells before PARP inhibition, maximizing synergistic efficacy while reducing simultaneous exposure of normal tissues to both agents, thereby reducing systemic toxicity.
Solution Approach 2:
The patent applies preliminary action by administering the DNA damaging chemotherapeutic agent first to create DNA damage and trigger the DNA damage response pathway. This preliminary damage sets the stage for subsequent PARP inhibitor administration, which then blocks the repair of this pre-induced damage. This sequence ensures that tumor cells have already incurred damage before repair pathways are inhibited, enhancing treatment efficacy while allowing normal tissues time to recover between exposures.
2Reliability
If high doses of DNA damage response inhibitors are used to maximize tumor cell killing, then treatment efficacy improves, but systemic toxicities increase in normal tissues
Solution Approach 1:
The patent implements local quality by creating a treatment sequence where tumor tissues receive the full benefit of both DNA damaging agents and PARP inhibitors, while normal tissues are exposed to reduced cumulative doses. The DNA damaging agent selectively accumulates in tumor cells due to their higher metabolic activity and defective DNA repair mechanisms, and subsequent PARP inhibition then selectively kills these pre-damaged cells. This spatial and temporal differentiation allows high local concentrations in tumors without proportionally increasing systemic toxicity in normal tissues.
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 conjugates provide high local concentrations of DNA damage response inhibitors in tumors while reducing systemic toxicities, enhancing treatment efficacy and minimizing side effects.
Implementation Method 1
accumulate in tumor tissues using the enhanced permeability and retention effect
Data Source
AI summary
Provided herein are releasable conjugates of inhibitors of DNA damage response suitable for use as therapeutic agents in the treatment of disease.