Systemic Dbait Molecules for Resistant Cancer Treatment
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Solution Overview
Problem
Current treatments for triple-negative breast cancer (TNBC) and other chemoresistant cancers are limited due to resistance to standard therapies, and there is a need for improved methods to enhance the efficacy of cancer treatments, especially without the use of quinoline endosomolytic agents like chloroquine.
Innovation Solution
The use of DBait molecules, specifically coDBait conjugated to cholesterol, administered systemically via intraperitoneal or intravenous routes without chloroquine, which target DNA repair pathways to induce false DNA damage signaling in cancer cells, potentially enhancing the effectiveness of chemotherapy and radiotherapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If DBait molecules are administered locally by intra-tumoral injection, then tumor treatment efficacy is improved, but treatment complexity and patient burden increase
Solution Approach 1:
The treatment approach is segmented into two distinct administration routes: local intra-tumoral injection for targeted high-dose delivery and systemic intraperitoneal injection for broader distribution. This segmentation allows optimization of each route's advantages while mitigating their respective disadvantages.
Solution Approach 2:
Chloroquine serves as an intermediary substance that enhances DBait molecule uptake and efficacy. By co-administering this endosomolytic agent, the patent achieves improved tumor treatment efficacy through facilitated cellular uptake of DBait molecules, while enabling the use of lower DBait doses that reduce toxicity.
2Reliability
If higher doses of DBait molecules are administered to achieve similar efficacy to local administration, then treatment efficacy is maintained, but toxicity increases
Solution Approach 1:
The patent applies local quality by concentrating the therapeutic effect specifically in tumor tissue through targeted uptake mechanisms. DBait molecules administered systemically achieve tumor-selective accumulation via enhanced permeability and retention effects and active uptake by tumor cells, allowing lower overall doses that reduce systemic toxicity while maintaining efficacy.
Solution Approach 2:
Chloroquine acts as a mediator that amplifies the effectiveness of DBait molecules at lower concentrations. By facilitating endosomal release and cellular uptake of DBait, chloroquine enables reduced dosing that maintains tumor treatment efficacy while minimizing toxic side effects.
3Reliability
If quinoline endosomolytic agents like chloroquine are used to enhance DBait uptake, then cellular uptake and efficacy are improved, but treatment complexity and potential side effects increase
Solution Approach 1:
Chloroquine is employed as an intermediary substance that bridges the gap between DBait administration and cellular uptake. This well-characterized endosomolytic agent facilitates DBait release from endosomes into the cytosol, thereby enhancing efficacy while leveraging existing knowledge about chloroquine's safety and pharmacokinetics.
Solution Approach 2:
The patent optimizes treatment parameters by determining specific dosing regimens for DBait and chloroquine that maximize efficacy while minimizing complexity. By establishing standardized dosage ranges and administration schedules, the patent simplifies the treatment protocol despite involving multiple substances.
4Ease of operation
If systemic administration is used instead of local injection, then treatment simplicity is improved, but drug distribution and uptake efficiency may be reduced
Solution Approach 1:
The patent achieves universality by demonstrating that the DBait-chloroquine combination protocol can be effectively administered through multiple routes (intraperitoneal and intravenous). This multi-functional approach allows the treatment to achieve both simplicity of systemic administration and effectiveness of targeted delivery.
Solution Approach 2:
Chloroquine serves as a universal intermediary that enhances DBait uptake regardless of the administration route. Whether DBait is delivered systemically or locally, chloroquine facilitates cellular uptake and endosomal release, ensuring consistent efficacy across different administration methods.
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 systemic administration of coDBait molecules achieves similar efficacy to local administration without chloroquine, with reduced toxicity and at a 2-5 fold lower dose, effectively treating resistant cancers by impairing DNA repair pathways and increasing tumor sensitivity to chemotherapy and radiotherapy.
Implementation Method 1
C is the molecule facilitating endocytosis selected from a lipophilic molecule or a ligand which targets cell receptor enabling receptor mediated endocytosis
Implementation Method 2
These molecules are short double-stranded DNA with a free double strand blunt end, which target key damage signal transducers such as DNA dependent protein kinase (DNA-PK) and Poly-ADP-Ribo-Polymerase, triggering their activation
Implementation Method 3
Consequently, the recruitment of downstream DNA repair enzymes is impaired, inhibiting several DNA repair pathways such as homologous recombination, non-homologous end joining, base excision repair and single-strand break repair leading to an accumulation of unrepaired damage causing cell death
Data Source
AI summary
The present invention relates to the use of a DBait molecules by systemic routes without any combination with an endosomolytic agent.