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Contributed by Robert Langer, September 24, 2015 (sent for review July 20, 2015)
Significance
We demonstrate an injectable drug-delivery system that would allow patients to adjust the timing, duration, and intensity of local anesthesia in painful parts of the body. Such on-demand analgesia could greatly enhance the management of a variety of pain states. Light-sensitive liposomes containing the potent local anesthetic tetrodotoxin induced sensory and motor nerve block in vivo upon irradiation with a 730-nm laser. The timing, duration, and intensity of the nerve blockade were adjustable by the timing, irradiance, and duration of irradiation. Tissue reaction to the formulation and associated irradiation was benign.
Abstract
Pain management would be greatly enhanced by a formulation that would provide local anesthesia at the time desired by patients and with the desired intensity and duration. To this end, we have developed near-infrared (NIR) light-triggered liposomes to provide on-demand adjustable local anesthesia. The liposomes contained tetrodotoxin (TTX), which has ultrapotent local anesthetic properties. They were made photo-labile by encapsulation of a NIR-triggerable photosensitizer; irradiation at 730 nm led to peroxidation of liposomal lipids, allowing drug release. In vitro, 5.6% of TTX was released upon NIR irradiation, which could be repeated a second time. The formulations were not cytotoxic in cell culture. In vivo, injection of liposomes containing TTX and the photosensitizer caused an initial nerve block lasting 13.5 ± 3.1 h. Additional periods of nerve block could be induced by irradiation at 730 nm. The timing, intensity, and duration of nerve blockade could be controlled by adjusting the timing, irradiance, and duration of irradiation. Tissue reaction to this formulation and the associated irradiation was benign.
Footnotes
- ↵1To whom correspondence may be addressed. Email: rlanger{at}mit.edu or daniel.kohane{at}childrens.harvard.edu.
Author contributions: A.Y.R., J.-J.L., C.Z., R.L., and D.S.K. designed research; A.Y.R., J.-J.L., C.Z., Q.L., and M.T.O. performed research; A.Y.R., J.-J.L., and Q.L. contributed new reagents/analytic tools; A.Y.R., J.-J.L., C.Z., Q.L., M.T.O., S.A.S., R.L., and D.S.K. analyzed data; and A.Y.R., J.-J.L., C.Z., Q.L., M.T.O., S.A.S., R.L., and D.S.K. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1518791112/-/DCSupplemental.
- Alina Y. Rweia,b,
- Jung-Jae Leea,c,
- Changyou Zhana,c,
- Qian Liua,c,
- Meryem T. Oka,d,
- Sahadev A. Shankarappae,
- Robert Langerc,f,1, and
- Daniel S. Kohanea,c,1
- aLaboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115;
- bDepartment of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;
- cDavid H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
- dDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;
- eAmrita Centre for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India;
- fDepartment of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
Contributed by Robert Langer, September 24, 2015 (sent for review July 20, 2015)
Significance
We demonstrate an injectable drug-delivery system that would allow patients to adjust the timing, duration, and intensity of local anesthesia in painful parts of the body. Such on-demand analgesia could greatly enhance the management of a variety of pain states. Light-sensitive liposomes containing the potent local anesthetic tetrodotoxin induced sensory and motor nerve block in vivo upon irradiation with a 730-nm laser. The timing, duration, and intensity of the nerve blockade were adjustable by the timing, irradiance, and duration of irradiation. Tissue reaction to the formulation and associated irradiation was benign.
Abstract
Pain management would be greatly enhanced by a formulation that would provide local anesthesia at the time desired by patients and with the desired intensity and duration. To this end, we have developed near-infrared (NIR) light-triggered liposomes to provide on-demand adjustable local anesthesia. The liposomes contained tetrodotoxin (TTX), which has ultrapotent local anesthetic properties. They were made photo-labile by encapsulation of a NIR-triggerable photosensitizer; irradiation at 730 nm led to peroxidation of liposomal lipids, allowing drug release. In vitro, 5.6% of TTX was released upon NIR irradiation, which could be repeated a second time. The formulations were not cytotoxic in cell culture. In vivo, injection of liposomes containing TTX and the photosensitizer caused an initial nerve block lasting 13.5 ± 3.1 h. Additional periods of nerve block could be induced by irradiation at 730 nm. The timing, intensity, and duration of nerve blockade could be controlled by adjusting the timing, irradiance, and duration of irradiation. Tissue reaction to this formulation and the associated irradiation was benign.
- pain
- site 1 sodium-channel blocker
- photosensitizer
- light
- near infrared
Footnotes
- ↵1To whom correspondence may be addressed. Email: rlanger{at}mit.edu or daniel.kohane{at}childrens.harvard.edu.
Author contributions: A.Y.R., J.-J.L., C.Z., R.L., and D.S.K. designed research; A.Y.R., J.-J.L., C.Z., Q.L., and M.T.O. performed research; A.Y.R., J.-J.L., and Q.L. contributed new reagents/analytic tools; A.Y.R., J.-J.L., C.Z., Q.L., M.T.O., S.A.S., R.L., and D.S.K. analyzed data; and A.Y.R., J.-J.L., C.Z., Q.L., M.T.O., S.A.S., R.L., and D.S.K. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1518791112/-/DCSupplemental.
Repeatable and adjustable on-demand nerve block
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