DNP Prodrug Formulation for Sustained Mitochondrial Modulation
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Solution Overview
Problem
Current treatments for neurodegenerative, neuromuscular, autoimmune, developmental, and metabolic diseases are inadequate in altering the disease progression towards early death, with no effective disease-modifying therapies available.
Innovation Solution
Development of 2,4-dinitrophenol (DNP) prodrugs in the form of depot nanoparticle formulations that release DNP in a slow, sustained fashion at low doses, targeting mitochondrial dysfunction and oxidative stress to induce BDNF expression and increase energy expenditure.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional chemotherapeutic agents are used to treat cancer, then tumor growth is inhibited, but severe side effects occur including immunosuppression and neurotoxicity
Solution Approach 1:
The patent segments the therapeutic approach by using different compounds (DNP and its prodrugs) for different purposes: DNP for metabolic modulation and cancer treatment, while prodrugs are designed to selectively activate in tumor tissues. This segmentation allows the treatment to target cancer cells specifically while sparing healthy tissues, thereby reducing side effects like immunosuppression and neurotoxicity while maintaining treatment efficacy.
Solution Approach 2:
The patent employs prodrugs as intermediaries that are converted to active DNP compounds within tumor tissues. These prodrugs act as mediators that deliver the therapeutic agent selectively to cancer cells through enzymatic conversion by beta-glucuronidase, which is overexpressed in tumor tissues. This intermediary approach enables targeted delivery, reducing exposure of healthy tissues to the active compound and thereby minimizing harmful side effects.
2Reliability
If DNP is used to treat cancer and metabolic diseases, then metabolic regulation and tumor growth inhibition are achieved, but the compound may cause toxicity due to its mechanism of action
Solution Approach 1:
The patent applies preliminary action by administering prodrugs that are converted to active DNP compounds in situ within tumor tissues. This preliminary formulation as a prodrug allows the compound to be safely administered and stored, then activated only when and where needed (in tumor tissues expressing beta-glucuronidase). This preliminary preparation reduces the risk of systemic toxicity while maintaining the metabolic regulation and anti-cancer efficacy of DNP.
Solution Approach 2:
The patent implements local quality by designing prodrugs with selective activation in tumor tissues through the enzyme beta-glucuronidase, which is overexpressed in cancer cells. This creates a localized conversion of the prodrug to active DNP specifically at the tumor site, ensuring that the metabolic regulation and anti-cancer effects occur locally where needed, while minimizing systemic exposure and potential toxicity to healthy organs.
3Area of stationary object
If traditional chemotherapy is administered systemically, then widespread tumor coverage is achieved, but healthy tissues are damaged causing immunosuppression and neurotoxicity
Solution Approach 1:
The patent uses prodrugs as intermediaries that are selectively activated in tumor tissues by beta-glucuronidase. This intermediary mechanism allows the therapeutic compound to reach and cover widespread tumor areas through systemic administration, while the selective enzymatic activation ensures that the active compound is generated primarily in tumor tissues, thereby minimizing damage to healthy tissues and reducing side effects like immunosuppression and neurotoxicity.
Solution Approach 2:
The patent applies parameter changes by utilizing the differential expression of beta-glucuronidase between tumor and healthy tissues. This enzymatic parameter difference is exploited to achieve selective activation of the prodrug in tumor areas, allowing widespread tumor coverage through systemic administration while limiting active compound formation in healthy tissues, thus reducing tissue damage and side effects.
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 DNP prodrugs demonstrate potential in reversing, slowing, or preventing disease progression by improving cognitive function, reducing muscle wasting, and managing metabolic disorders without significant adverse effects, offering a disease-modifying approach.
Implementation Method 1
DNP and related compounds have long been known to uncouple oxidative phosphorylation, a process by which cells generate adenosine triphosphate (ATP), the primary energy currency of life.
Implementation Method 2
In one embodiment, the prodrug is converted to the active DNP compound by beta-glucuronidase, an enzyme that is overexpressed in many tumor types.
Data Source
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AI summary
A composition and method of treatment of neuromuscular, neuromuscular degenerative, neurodegenerative, autoimmune, developmental, traumatic, hearing loss related, and/or metabolic diseases, including spinal muscular atrophy (SMA) syndrome (SMAI, SMA2, SMA3, and SMA4, also called Type I, II, III and IV), traumatic brain injury (TBI), concussion, keratoconjunctivitis sicca (Dry Eye Disease), glaucoma, Sjogren's syndrome, rheumatoid arthritis, post-LASIK surgery, anti-depressants use, Wolfram Syndrome, and Wolcott-Rallison syndrome. The composition is selected from the group consisting of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP, bipartite 2,3-dinitrophenol, 2,4-dinitrophenol, 2,5-dinitrophenol, 2,6-dinitrophenol, 3,4- dinitrophenol, or 3,5-dinitrophenol (2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP) prodrugs; Gemini prodrugs, bioprecursor molecules, and combinations thereof.