Polymeric Prodrugs using Dynamic Covalent Chemistry for Prolonged Local Anesthesia
Dr. Tianrui Xue
Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115 United States
Search for more papers by this authorDr. Yang Li
Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115 United States
Search for more papers by this authorDr. Matthew Torre
Department of Pathology Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115 United States
Search for more papers by this authorRachelle Shao
Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115 United States
Search for more papers by this authorDr. Yiyuan Han
Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115 United States
Search for more papers by this authorShuanglong Chen
Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115 United States
Search for more papers by this authorDaniel Lee
Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115 United States
Search for more papers by this authorCorresponding Author
Prof. Dr. Daniel S. Kohane
Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115 United States
Search for more papers by this authorDr. Tianrui Xue
Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115 United States
Search for more papers by this authorDr. Yang Li
Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115 United States
Search for more papers by this authorDr. Matthew Torre
Department of Pathology Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115 United States
Search for more papers by this authorRachelle Shao
Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115 United States
Search for more papers by this authorDr. Yiyuan Han
Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115 United States
Search for more papers by this authorShuanglong Chen
Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115 United States
Search for more papers by this authorDaniel Lee
Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115 United States
Search for more papers by this authorCorresponding Author
Prof. Dr. Daniel S. Kohane
Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115 United States
Search for more papers by this authorAbstract
Depot-type drug delivery systems are designed to deliver drugs at an effective rate over an extended period. Minimizing initial “burst” can also be important, especially with drugs causing systemic toxicity. Both goals are challenging with small hydrophilic molecules. The delivery of molecules such as the ultrapotent local anesthetic tetrodotoxin (TTX) exemplifies both challenges. Toxicity can be mitigated by conjugating TTX to polymers with ester bonds, but the slow ester hydrolysis can result in subtherapeutic TTX release. Here, we developed a prodrug strategy, based on dynamic covalent chemistry utilizing a reversible reaction between the diol TTX and phenylboronic acids. These polymeric prodrugs exhibited TTX encapsulation efficiencies exceeding 90 % and the resulting polymeric nanoparticles showed a range of TTX release rates. In vivo injection of the TTX polymeric prodrugs at the sciatic nerve reduced TTX systemic toxicity and produced nerve block lasting 9.7±2.0 h, in comparison to 1.6±0.6 h from free TTX. This approach could also be used to co-deliver the diol dexamethasone, which prolonged nerve block to 21.8±5.1 h. This work emphasized the usefulness of dynamic covalent chemistry for depot-type drug delivery systems with slow and effective drug release kinetics.
Conflict of interests
The authors declare no conflict of interest.
Open Research
Data Availability Statement
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