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Targeting Ligands Deliver Model Drug Cargo into the Central Nervous System along Autonomic Neurons
Drew L Sellers1,2, James-Kevin Y Tan1, Julio Marco B Pineda1
1Department of Bioengineering , University of Washington , Seattle , Washington 98195 , United States.
ACS Nano
|October 8, 2019
Summary
Researchers developed targeted ANS-to-CNS uptake ligands (TACL) peptides to deliver biologic drugs across the blood-brain barrier. These peptides successfully delivered a model enzyme into the brain and spinal cord, bypassing traditional delivery challenges.
Area of Science:
- Neuroscience
- Drug Delivery
- Biotechnology
Background:
- The blood-brain barrier (BBB) restricts systemic delivery of biologic drugs (proteins, peptides, nucleic acids) to the central nervous system (CNS).
- This limitation hinders the clinical application of promising neurodegenerative disease therapeutics.
- Targeting specific neuronal pathways is a potential strategy to overcome BBB drug delivery challenges.
Purpose of the Study:
- To identify peptides capable of targeting drug uptake by autonomic nervous system (ANS) neurons for enhanced CNS delivery.
- To evaluate the efficacy of these identified peptides in delivering therapeutic cargo across the BBB.
- To optimize peptide stability and delivery efficiency for potential therapeutic applications.
Main Methods:
- An in vivo phage display screen was employed to identify ANS-targeting peptides.
- Next-generation sequencing identified 21 candidate targeted ANS-to-CNS uptake ligands (TACL).
- Synthesized TACL peptides were tested for their ability to deliver a model enzyme (NeutrAvidin-horseradish peroxidase fusion) into the CNS after intraperitoneal administration; peptide cyclization was explored to enhance stability.
Main Results:
- Three TACL peptides demonstrated significant active enzyme delivery into the CNS with minimal off-target organ accumulation.
- Cyclization of TACL peptides via perfluoroarylation with decafluorobiphenyl enhanced serum stability and CNS delivery.
- TACL-peptides localized in parasympathetic ganglia neurons and neuronal structures within the hindbrain and spinal cord.
Conclusions:
- Targeted uptake into ANS neurons provides a viable strategy to bypass the blood-brain barrier.
- TACL-peptides show potential as a novel platform for delivering therapeutic payloads to the brain and spinal cord.
- This approach could overcome major hurdles in developing biologic drugs for neurological disorders.
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