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Bottlebrush Polymers with Sequence-Controlled Backbones for Enhanced Oligonucleotide Delivery.

Yun Wei¹, Peiru Chen¹, Mengqi Ren¹

¹Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States.

Journal of the American Chemical Society

|November 27, 2024

Summary

This summary is machine-generated.

Researchers developed novel polymer-drug delivery vehicles for oligonucleotides. An optimized design enhanced cellular uptake, pharmacokinetics, and in vivo antisense activity, improving therapeutic potential.

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Area of Science:

Biomaterials Science
Polymer Chemistry
Drug Delivery Systems

Background:

Clinical translation of oligonucleotide therapeutics is hindered by delivery challenges.
Existing delivery vehicles often lack precise control over structure-property relationships.

Purpose of the Study:

To introduce a novel class of poly(ethylene glycol) (PEG) bottlebrush polymers as oligonucleotide delivery vehicles.
To investigate the impact of incorporating specific chemical modifiers (C18) into sequence-defined polymer backbones on delivery performance.
To optimize the polymer backbone structure for enhanced oligonucleotide delivery.

Main Methods:

Solid-phase synthesis utilizing bespoke phosphoramidites to assemble oligonucleotide and polymer backbone.
Incorporation of carbon 18 (C18) chemical modifiers into the polymer backbone in specific patterns.
Grafting of PEG side chains to create bottlebrush polymer-oligonucleotide conjugates.
Evaluation of cellular uptake, pharmacokinetics, biodistribution, and in vivo antisense activity.

Main Results:

An optimal pattern of C18 incorporation was identified.
This optimized pattern significantly improved cellular uptake, plasma pharmacokinetics, and biodistribution.
Enhanced in vivo antisense activity was observed with the optimized bottlebrush polymer-oligonucleotide conjugates.

Conclusions:

The study demonstrates the successful development of sequence-defined PEG bottlebrush polymers for oligonucleotide delivery.
Structure-property relationships were elucidated, highlighting the importance of backbone modification.
This platform offers tunable polymer backbones for tailored oligonucleotide delivery for various diseases.