Modulating Lysosomal pH through Innovative Multimerized Succinic Acid-Based Nucleolipid Derivatives

Mathias Brouillard, Rémi Kinet, Marie Joyeux, Benjamin Dehay, Sylvie Crauste-Manciet, Valérie Desvergnes
Bioconjugate Chem.. 2023-02-28; :
DOI: 10.1021/acs.bioconjchem.3c00041

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Brouillard M(1), Kinet R(2), Joyeux M(1), Dehay B(2), Crauste-Manciet S(1)(3), Desvergnes V(1).

Author information:
(1)University of Bordeaux, INSERM U1212, UMR CNRS 5320, Bordeaux 33405, France.
(2)Univ. de Bordeaux, CNRS, IMN, UMR 5293, Bordeaux F-33000, France.
(3)Univ. Angers, CHU Angers, INSERM, CNRS, MINT, SFR ICAT, F-49000 Angers,

The multimerization of active compounds has emerged as a successful approach,
mainly to address the multivalency of numerous biological targets. Regarding the
pharmaceutical prospect, carrying several active ingredient units on the same
synthetic scaffold was a practical approach to enhance drug delivery or
biological activity with a lower global concentration. Various examples have
highlighted better in vivo stability and therapeutic efficiency through
sustained action over monomeric molecules. The synthesis strategy aims to
covalently connect biologically active monomers to a central core using simple
and efficient reaction steps. Despite extensive studies reporting carbohydrate
or even peptide multimerization developed for therapeutic activities, very few
are concerned with nucleic acid derivatives. In the context of our efforts to
build non-viral nucleolipid (NL)-based nanocarriers to restore lysosomal
acidification defects, we report here a straightforward synthesis of tetrameric
NLs, designed as prodrugs that are able to release no more than one but four
biocompatible succinic acid units. The use of oil-in-water nanoemulsion-type
vehicles allowed the development of lipid nanosystems crossing the membranes of
human neuroblastoma cells. Biological evaluations have proved the effective
release of the acid within the lysosome of a genetic and cellular model of
Parkinson’s disease through the recovery of an optimal lysosomal pH associated
with a remarkably fourfold lower concentration of active ingredients than with
the corresponding monomers. Overall, these results suggest the feasibility, the
therapeutic opportunity, and the better tolerance of multimeric compounds
compared to only monomer molecules.


Auteurs Bordeaux Neurocampus