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Challenges and Opportunities for Cleavable Linkers Used in Polymer-Drug Conjugates
Fatemeh Karimi1, Katherine E S Locock1,2,3, John Chiefari1
1Commonwealth Scientific and Industrial Research Organisation, Clayton, Victoria 3168, Australia.
Journal of the American Chemical Society
|May 14, 2026
Summary
Polymer-drug conjugates offer controlled drug release but face challenges in linker specificity and clinical translation. New strategies are proposed to overcome these barriers for wider therapeutic adoption.
Area of Science:
- Polymer Chemistry
- Drug Delivery Systems
- Biomaterials Science
Background:
- Polymer-drug conjugates with cleavable linkers are promising for controlled drug release.
- Current linker strategies often lack specificity or introduce complexity, hindering clinical use.
Purpose of the Study:
- To review linker types in polymer-drug conjugates based on their cleavage stimuli responsiveness.
- To discuss challenges and opportunities for clinical translation of these therapeutics.
Main Methods:
- Literature review of linker cleavage strategies.
- Analysis of responsiveness to target stimuli.
- Discussion of clinical developments and translation barriers.
Main Results:
- Various linker types have distinct advantages and disadvantages regarding cleavage specificity and responsiveness.
- Efficacy, biocompatibility, and manufacturing complexity are key translation hurdles.
Conclusions:
- Overcoming linker specificity and translation challenges is crucial for clinical adoption.
- Novel approaches inspired by prodrug chemistry and polymer science can advance this field.
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