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Peer-reviewedCC BY-NC-NDJournal of the American Chemical Society

Challenges and Opportunities for Cleavable Linkers Used in Polymer–Drug Conjugates

  • Fatemeh Karimi1
  • Katherine E. S. Locock1,2,3
  • John Chiefari1
  • Charlotte C. Williams1
  • Lewis D. Blackman1
  1. 1Commonwealth Scientific and Industrial Research Organisation , , ,
  2. 2Monash University , , , ,
  3. 3Southern Cross University , , , ,
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Abstract

Polymer-drug conjugates with cleavable linkers show excellent promise as controlled-release drug delivery systems for a range of diseases; however, several cleavage strategies fall short in their specificity or require additional complexities that pose significant challenges for clinical adoption. This Perspective outlines the advantages and pitfalls of various linker types in terms of their responsiveness to their target cleavage stimuli. Aside from overcoming efficacy and biocompatibility challenges, we critically discuss other key challenges in the translation of these materials and highlight the latest clinical developments. Taking inspiration from other areas of prodrug chemistry and polymer science, new opportunities for this field are proposed, which aim to overcome the current barriers and may be the key to the clinical adoption of this exciting class of therapeutics.

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Cite

BibTeXRIS
BibTeX
@article{karimi2026challenges,
  title = {{Challenges and Opportunities for Cleavable Linkers Used in Polymer–Drug Conjugates}},
  author = {Fatemeh Karimi and Katherine E. S. Locock and John Chiefari and Charlotte C. Williams and Lewis D. Blackman},
  journal = {Journal of the American Chemical Society},
  year = {2026},
  month = may,
  doi = {10.1021/jacs.6c03661},
  url = {https://doi.org/10.1021/jacs.6c03661},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Challenges and Opportunities for Cleavable Linkers Used in Polymer–Drug Conjugates
AU  - Fatemeh Karimi
AU  - Katherine E. S. Locock
AU  - John Chiefari
AU  - Charlotte C. Williams
AU  - Lewis D. Blackman
PY  - 2026
DA  - 2026/05/14
JO  - Journal of the American Chemical Society
DO  - 10.1021/jacs.6c03661
UR  - https://doi.org/10.1021/jacs.6c03661
AB  - Polymer-drug conjugates with cleavable linkers show excellent promise as controlled-release drug delivery systems for a range of diseases; however, several cleavage strategies fall short in their specificity or require additional complexities that pose significant challenges for clinical adoption. This Perspective outlines the advantages and pitfalls of various linker types in terms of their responsiveness to their target cleavage stimuli. Aside from overcoming efficacy and biocompatibility challenges, we critically discuss other key challenges in the translation of these materials and highlight the latest clinical developments. Taking inspiration from other areas of prodrug chemistry and polymer science, new opportunities for this field are proposed, which aim to overcome the current barriers and may be the key to the clinical adoption of this exciting class of therapeutics.
SN  - 0002-7863
SN  - 1520-5126
SN  - 1943-2984
ER  -