ArticleBioconjugate chemistry2025
Impact of Conjugation Chemistry on the Pharmacokinetics of Peptide-Polymer Conjugates in a Model of Traumatic Brain Injury.
Article in Bioconjugate chemistry, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- AI-Designed TREM1-Targeted LYTAC Nanoparticles Reprogram the Neuroimmune Microenvironment in Traumatic Brain Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Phage Display as a Promising Platform for Peptide Drug Discovery.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Recent advances in multimodal foundation model-enabled peptide screening and optimization for smart biomaterials and functional tissue engineering.Frontiers in bioengineering and biotechnology · 2026Review
- 3D-Printed Oral Disintegrating Films of Brain-Targeted Acetyl Salicylic Acid Nanoparticles for Enhanced CNS Delivery in Ischemic Stroke.Pharmaceutics · 2025Article
- Review
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Authors and funding
4 authors.
Funding
Abstract
Traumatic brain injury (TBI) remains a leading cause of long-term disability and mortality; however, there are no effective therapies to mitigate secondary injury and long-term neurological impairments. After the initial mechanical insult, there is a secondary injury that leads to neuroinflammation and blood-brain barrier (BBB) disruption, both of which are linked to changes in the extracellular matrix (ECM). A short peptide sequence, CAQK (Cys-Ala-Gln-Lys), targets upregulated ECM proteoglycans after TBI and has exhibited therapeutic properties in preclinical TBI studies. However, like many peptides, CAQK has poor pharmacokinetics, with rapid systemic clearance limiting its therapeutic potential. To overcome these limitations, we investigated a peptide-polymer conjugate using a poly(ethylene glycol) (PEG) scaffold to improve the peptide pharmacokinetics of CAQK. We synthesized materials using two conjugation chemistries, maleimide-thiol Michael-type addition and dibenzocyclooctyne (DBCO)-azide strain-promoted azide-alkyne cycloaddition. The impact of linker selection on biodistribution and clearance was distinct. We first showed that conjugation of CAQK to PEG, irrespective of linkers, significantly extended the peptide's blood half-life by 90-fold and increased brain accumulation. In the analysis of off-target organs, we observed longer retention of DBCO conjugates in the liver, kidney, and spleen compared to maleimide conjugates. Given the high incidence of TBI in populations such as military personnel and athletes, we explored whether our long-circulating material could be given as a prophylaxis. We demonstrated the accumulation of 4.5%ID/g CAQK in the injured brain when the conjugate was delivered prophylactically 24 h before injury. Our work underscores the advantage of long-circulating peptide-polymer conjugates in the context of TBI and the impact of conjugation chemistry on pharmacokinetics.
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