Polymeric Prodrugs using Dynamic Covalent Chemistry for Prolonged Local Anesthesia

Area of Science:

• Polymer chemistry
• Drug delivery systems
• Nanotechnology

Background:

• Depot-type drug delivery systems aim for sustained drug release, which is challenging for small hydrophilic molecules like tetrodotoxin (TTX).
• Minimizing initial drug burst is crucial for potent drugs like TTX to mitigate systemic toxicity.
• Existing methods, such as ester conjugation, can lead to slow hydrolysis and subtherapeutic release rates.

Purpose of the Study:

• To develop a prodrug strategy for controlled release of tetrodotoxin (TTX) using dynamic covalent chemistry.
• To create polymeric nanoparticles that encapsulate TTX with high efficiency and tunable release rates.
• To evaluate the in vivo efficacy and safety of TTX polymeric prodrugs for prolonged nerve block.

Main Methods:

• Developed polymeric prodrugs utilizing the reversible reaction between diol-containing TTX and phenylboronic acids.
• Achieved high TTX encapsulation efficiencies (>90%) in polymeric nanoparticles.
• Administered TTX polymeric prodrugs via injection at the sciatic nerve in vivo.

Main Results:

• Polymeric prodrugs demonstrated tunable TTX release rates.
• In vivo administration reduced TTX systemic toxicity compared to free TTX.
• Achieved a nerve block duration of 9.7±2.0 hours with TTX prodrugs, significantly longer than free TTX (1.6±0.6 hours).
• Co-delivery with dexamethasone further extended nerve block to 21.8±5.1 hours.

Conclusions:

• Dynamic covalent chemistry offers a versatile approach for designing depot-type drug delivery systems.
• This strategy enables controlled, sustained release of drugs like TTX, mitigating toxicity and enhancing therapeutic efficacy.
• The developed prodrug system shows promise for long-acting local anesthesia and potential co-delivery applications.