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  • Review Article
  • Published:

Self-assembled lipid–prodrug nanoparticles

Nature Reviews Bioengineering volume 1, pages 749–768 (2023)Cite this article

Abstract

Nanomedicines suffer from poor drug loading and uncontrolled ‘burst release’ after administration. Combining prodrug strategies with nanostructured carriers can help to overcome these limitations by improving diffusion through biological barriers, enzymatic activation of the lipid conjugate in the diseased area, drug protection, pharmacokinetics and biodistribution, intracellular delivery and/or targeting properties. Owing to fundamental advances in supramolecular chemistry and the fine-tuning of drug, lipid and drug–lipid chemical link modifications, it is now possible to develop lipid–prodrug conjugates that can spontaneously self-assemble into nanoparticles in aqueous media with unique supramolecular organizations and without additional excipients. In this Review, we describe the chemical synthesis, physicochemical properties, structure and pharmacological activity of lipid–prodrug-based nanomedicines and discuss the path towards clinical translation for the treatment of severe diseases.

Key points

  • Lipid–prodrug nanomedicines combine the benefits of nanoparticles and prodrugs by modulating drug release, reducing drug metabolism, improving pharmacokinetic and biodistribution and enhancing intracellular delivery.

  • A typical lipid–drug bioconjugate is composed of a lipid carrier molecule, a drug and, if required, a chemical spacer, which can be stimulus responsive.

  • The supramolecular architectures of lipid–prodrug nanomedicines is a key factor for bioactivation of the prodrug and its pharmacological activity.

  • Lipid–prodrug nanomedicines exhibit higher in vitro and in vivo pharmacological activity than their parent drugs in experimental models of cancer, neurological disorders, infectious diseases or uncontrolled inflammation.

  • Clinical translation of lipid–prodrug nanomedicines remains limited owing to difficulties in prodrug chemical synthesis, control of drug release, the lack of predictive preclinical models and the need to improve patient selection.

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Fig. 1: Schematic representation of nanomedicines.
Fig. 2: Building blocks of lipid–prodrug conjugates.
Fig. 3: Structure of lipid–prodrug conjugates that can self-assemble into nanoparticles.
Fig. 4: Relationship between the structure of squalene-based nanoparticles and their pharmacological activity.
Fig. 5: Schematic illustration of a visible-light-triggered prodrug nanoparticles.

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Authors and Affiliations

  1. Institut Galien Paris-Sud, UMR CNRS 8612, Université Paris-Saclay, Orsay Cedex, France

    Patrick Couvreur & Sinda Lepetre-Mouelhi

  2. Chemistry and Pharmaceutical Technology Department, Universidad de Navarra, Pamplona, Spain

    Elisa Garbayo & Maria J. Blanco-Prieto

  3. Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain

    Elisa Garbayo & Maria J. Blanco-Prieto

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  1. Patrick Couvreur
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  4. Maria J. Blanco-Prieto
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Contributions

P.C. organized the writing of the Review, provided the first drafts of the text and the boxes, drew some figures, discussed with the co-authors and answered the reviewer and editor queries. S.L.-M. collected the data and wrote the lipid–prodrug chemical synthesis and drew the figures with the chemical structures and was involved in replying to the reviewers. E.G. and M.J.B.-P. collected data and wrote parts of the Review, drew some figures and tables, and were involved in replying to the reviewers.

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Correspondence to Patrick Couvreur.

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Competing interests

S.L.-M. and P.C. have non-financial competing interests as inventors of patents related to squalene-based nanoparticles; M.J.B.-P. and E.G. declare no competing interests.

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Nature Reviews Bioengineering thanks Natalie Trevaskis and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Couvreur, P., Lepetre-Mouelhi, S., Garbayo, E. et al. Self-assembled lipid–prodrug nanoparticles. Nat Rev Bioeng 1, 749–768 (2023). https://doi.org/10.1038/s44222-023-00082-0

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