An injectable, nanostructured implant for the delivery of adenosine triphosphate: towards long-acting formulations of small, hydrophilic drugs

While long-acting injectable treatments are gaining increasing interest in managing chronic diseases, the available drug delivery systems almost exclusively rely on hydrophobic matrixes, limiting their application to either hydrophobic drugs or large and hydrophilic molecules such as peptides. To ad...

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Bibliographic Details
Published in:	Drug delivery and translational research Vol. 14; no. 8; pp. 2146 - 2157
Main Authors:	Giacalone, Giovanna, Quaillet, Marion, Huang, Nicolas, Nicolas, Valérie, Boulogne, Claire, Gillet, Cynthia, Fattal, Elias, Bochot, Amélie, Hillaireau, Hervé
Format:	Journal Article
Language:	English
Published:	New York Springer US 01-08-2024
Subjects:	Biomedical and Life Sciences Biomedicine Original Article Pharmaceutical Sciences/Technology In situ-forming implant PLGA In vivo drug release Chitosan Nanogel Adenosine triphosphate
Online Access:	Get full text
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Summary:	While long-acting injectable treatments are gaining increasing interest in managing chronic diseases, the available drug delivery systems almost exclusively rely on hydrophobic matrixes, limiting their application to either hydrophobic drugs or large and hydrophilic molecules such as peptides. To address the technological lock for long-acting delivery systems tailored to small, hydrophilic drugs such as anticancer and antiviral nucleoside/nucleotide analogues, we have synthesized and characterized an original approach with a multi-scale structure: (i) a nucleotide (adenosine triphosphate, ATP) is first incorporated in hydrophilic chitosan-Fe(III) nanogels; (ii) these nanogels are then transferred by freeze-drying and resuspension into a water-free, hydrophobic medium containing PLGA and an organic solvent, N-methyl-2-pyrrolidone. We show that this specific association allows an injectable and homogeneous dispersion, able to form in situ implants upon injection in physiological or aqueous environments. This system releases ATP in vitro without any burst effect in a two-step mechanism, first as nanogels acting as an intermediate reservoir over a week, then as free drug over several weeks. In vivo studies confirmed the potential of such nanostructured implants for sustained drug release following subcutaneous injection to mice hock, opening perspectives for sustained and targeted delivery through the lymphatic system. Graphical abstract
ISSN:	2190-393X 2190-3948
DOI:	10.1007/s13346-024-01631-9