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[Design of New Cancer Nanotherapeutics Which Controls Active Gaseous Molecules in Vivo]
1Faculty of Pure and Applied Sciences, University of Tsukuba.
Abstract:
Reactive oxygen species (ROS) are known to play a variety of roles in many important events in vivo. However, the overproduction of ROS causes serious adverse effects to living beings. Numerous drugs have been developed and applied to reduce overproduced ROS, but these have failed to be clinically approved. Since most of these antioxidants are low molecular weight (LMW) compounds, they not only eliminate ROS related to diseases, but also destroy the essential redox reactions necessary for basic energy production in living bodies. In the mitochondria of normal cells, ATP production by electron transport chain is carried out, and a large amount of ROS is thus generated; however, LMW antioxidants also nonspecifically enter normal cells and affect essential oxidation. To improve selective antioxidant properties without damage to these normal redox reactions, we designed new polymer antioxidants. These polymers have self-assembling properties and form nanoparticles (RNPs) in which nitroxide radicals covalently attach as a side chain of the hydrophobic segment in the amphiphilic block copolymers, which are then compartmentalized into the solid core of the nanoparticles. Unlike LMW antioxidants, RNPs have extremely poor in vivo toxicity, as they are less likely to be taken up by healthy cells. Since one of RNPs, RNPN has pH-sensitive disintegration properties, it disintegrates at pH lower than 7.0 such as solid tumors and inflammation. It can therefore be used in pH responsive bioimaging and therapy. We have used RNPs experimentally in the treatment of several diseases and confirmed their effectiveness.
Insights
New polymer nanoparticles (RNPs) selectively target and neutralize harmful reactive oxygen species (ROS) without affecting essential cellular functions. These advanced antioxidants show low toxicity and potential for targeted therapy and bioimaging in diseases.
Area of Science:
- Biomedical Engineering
- Materials Science
- Nanotechnology
Background:
- Reactive oxygen species (ROS) play crucial roles in vivo but overproduction causes adverse effects.
- Existing low molecular weight (LMW) antioxidants lack specificity, harming essential redox reactions and leading to clinical trial failures.
- Mitochondria generate ROS during ATP production, and LMW antioxidants disrupt this vital process.
Purpose of the Study:
- To design novel polymer antioxidants with improved selectivity and reduced toxicity.
- To develop self-assembling nanoparticles (RNPs) encapsulating nitroxide radicals for targeted ROS scavenging.
- To investigate the potential of pH-sensitive RNPs for targeted therapy and bioimaging in disease states.
Main Methods:
- Amphiphilic block copolymers were synthesized with covalently attached nitroxide radicals.
- Self-assembly of copolymers formed nanoparticles (RNPs) with a solid core containing the radicals.
- pH-sensitive RNP variant (RNPN) was designed for targeted disintegration in acidic environments.
- In vivo toxicity and therapeutic efficacy of RNPs were evaluated in disease models.
Main Results:
- RNPs demonstrated significantly lower in vivo toxicity compared to LMW antioxidants due to poor uptake by healthy cells.
- RNPN showed pH-sensitive disintegration at pH < 7.0, characteristic of tumor microenvironments and inflammation.
- Experimental use of RNPs in various diseases confirmed their therapeutic effectiveness.
Conclusions:
- Polymer nanoparticles (RNPs) offer a promising strategy for selective ROS neutralization, overcoming limitations of LMW antioxidants.
- RNPs exhibit excellent biocompatibility and can be engineered for targeted delivery and therapeutic applications.
- pH-responsive RNPs hold potential for advanced bioimaging and localized treatment of diseases like cancer and inflammation.
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