Pain - particularly chronic pain - is a major cause of morbidity, especially in patients with cancer or neuropathic pain. The goal of this research is to develop prolonged duration local anesthetics (PDLA) that would provide local anesthesia lasting days to weeks from a single injection, depending on the clinical context (perioperative vs. chronic pain). Our strategy has been to use a variety of sustained release vehicles to deliver site 1 sodium channel blockers (S1SCBs) such as saxitoxin (STX) and tetrodotoxin (TTX) in combination with compounds that are known to have synergistic or adjunctive effects on the duration of nerve blockade, such as conventional local anesthetics and steroids. To date, this line of inquiry has been very productive; since the current R01 began 3.5 years ago, we have produced 29 publications, and met or exceeded the goals of our Specific Aims. Our base formulation is a liposome containing S1SCBs and other drugs, where we have shown we can obtain sciatic nerve blocks in the rat lasting a week with minimal systemic and local toxicity. We propose a spectrum of potential modifications to produce yet longer blocks while maintaining safety. An equally important aim will be the in vivo assessment of the efficacy and systemic toxicity of these new formulations by neurobehavioral tests in rats and rabbits, by following serum drug levels. Another crucial aspect of the research, which has not received sufficient attention, will be to study the development of inflammation, myotoxicity, and neurotoxicity with these formulations, using histological and toxicogenomic approaches.

Public Health Relevance

Prolonged pain after surgery and chronic pain afflict millions of people in the U.S. and across the globe. The purpose of this application is to develop means of treating such localized pain with a single injection that would last for days to weeks without patients having to take pain medications that would cloud their minds.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM073626-14
Application #
9477674
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2006-02-01
Project End
2019-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
14
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
Rwei, Alina Y; Sherburne, Robert T; Zurakowski, David et al. (2018) Prolonged Duration Local Anesthesia Using Liposomal Bupivacaine Combined With Liposomal Dexamethasone and Dexmedetomidine. Anesth Analg 126:1170-1175
Santamaria, Claudia M; Woodruff, Alan; Yang, Rong et al. (2017) Drug delivery systems for prolonged duration local anesthesia. Mater Today (Kidlington) 20:22-31
Rwei, Alina Y; Paris, Juan L; Wang, Bruce et al. (2017) Ultrasound-triggered local anaesthesia. Nat Biomed Eng 1:644-653
Santamaria, Claudia M; Zhan, Changyou; McAlvin, J Brian et al. (2017) Tetrodotoxin, Epinephrine, and Chemical Permeation Enhancer Combinations in Peripheral Nerve Blockade. Anesth Analg 124:1804-1812
Li, Mengyuan; Li, Lele; Zhan, Changyou et al. (2016) Core-Shell Nanostars for Multimodal Therapy and Imaging. Theranostics 6:2306-2313
Salvador-Culla, Borja; Jeong, Kyung Jae; Kolovou, Paraskevi Evi et al. (2016) Titanium Coating of the Boston Keratoprosthesis. Transl Vis Sci Technol 5:17
Li, Lele; Tong, Rong; Li, Mengyuan et al. (2016) Self-assembled gemcitabine-gadolinium nanoparticles for magnetic resonance imaging and cancer therapy. Acta Biomater 33:34-9
Zhan, Changyou; Wang, Weiping; McAlvin, James B et al. (2016) Phototriggered Local Anesthesia. Nano Lett 16:177-81
Lim, Dong-Kwon; Wylie, Ryan G; Langer, Robert et al. (2016) Selective binding of C-6 OH sulfated hyaluronic acid to the angiogenic isoform of VEGF(165). Biomaterials 77:130-138
Rwei, Alina Y; Lee, Jung-Jae; Zhan, Changyou et al. (2015) Repeatable and adjustable on-demand sciatic nerve block with phototriggerable liposomes. Proc Natl Acad Sci U S A 112:15719-24

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