Modulating Lysosomal pH through Innovative Multimerized Succinic Acid-Based Nucleolipid Derivatives.
Mathias Brouillard1, Rémi Kinet2, Marie Joyeux1
1University of Bordeaux, INSERM U1212, UMR CNRS 5320, Bordeaux 33405, France.
Bioconjugate Chemistry
|February 28, 2023
Summary
Researchers developed multimeric nucleolipids (NLs) as prodrugs to treat lysosomal acidification defects. These tetrameric NLs effectively deliver four active succinic acid units, restoring lysosomal pH in Parkinson
Area of Science:
- Drug delivery and nanomedicine
- Nucleic acid chemistry
- Biochemistry and molecular biology
Background:
- Multimerization of active compounds enhances drug delivery and therapeutic efficiency.
- Nucleic acid derivatives are underexplored for multimeric drug development.
- Lysosomal acidification defects are implicated in diseases like Parkinson's.
Purpose of the Study:
- To synthesize tetrameric nucleolipids (NLs) as prodrugs for lysosomal acidification defects.
- To evaluate the efficacy of multimeric NLs in restoring lysosomal pH in a Parkinson's disease model.
- To compare the therapeutic potential and tolerance of multimeric compounds versus monomers.
Main Methods:
- Straightforward synthesis of tetrameric NLs.
- Development of lipid nanosystems using oil-in-water nanoemulsions.
- In vitro cell membrane crossing studies using human neuroblastoma cells.
- Biological evaluation in a genetic and cellular model of Parkinson's disease.
Main Results:
- Successfully synthesized tetrameric NLs releasing four succinic acid units.
- Demonstrated effective release of succinic acid within lysosomes, restoring optimal pH.
- Achieved therapeutic efficacy at a fourfold lower concentration compared to monomeric compounds.
- Showcased enhanced in vivo stability and therapeutic efficiency of multimeric NLs.
Conclusions:
- Multimeric NLs represent a feasible and therapeutically promising approach for treating lysosomal acidification defects.
- Multimeric compounds offer potential for improved drug delivery, sustained action, and better patient tolerance.
- This strategy holds significant potential for developing novel nanocarriers for various therapeutic applications.
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