Pain - particularly chronic pain - is a major cause of morbidity, especially in patients with cancer or neuropathic pain. These conditions are often refractory to treatment. The purpose of this research is to develop microparticle based prolonged duration local anesthetics (PDLA) employing site 1 sodium channel blockers such as tetrodotoxin (TTX). The underlying hypothesis - which was validated in preceding research - is that TTX, encapsulated in combination with compounds such as conventional local anesthetics and steroids, can produce extremely long nerve blocks. As envisioned here, PDLA could last weeks to months for chronic pain, or could be tailored to shorter durations for other (e.g. perioperative) applications. The research could potentially be applicable to any excitable tissue (brain, muscle, heart, uterus), and in fact to any environment where controlled release could be useful.
One specific aim of this research is to resolve difficult formulation problems such as burst release, which arise in encapsulating potentially toxic hydrophilic molecules. Microspheres of a-hydroxy ester polymers such as PLGA, containing TTX, bupivacaine, and dexamethasone will be modified sequentially as needed to minimize burst release and extend release in vitro. The spectrum of potential modifications includes constructing secondary polymeric shells, use of cross- linkable hyaluronic acids inside or outside of the particles, using alternative polymers such as polyanhydrides, and devising TTX-only systems, since TTX - unlike conventional local anesthetics - is not believed to cause myo- or neurotoxicity. An equally important aim will be the in vivo assessment of the efficacy and toxicity of these new formulations by neurobehavioral tests in rats and rabbits, and by following serum levels. Another crucial aspect of the research, which has not received sufficient attention, will be to understand of factors that contribute to the development of inflammation, myotoxicity, and neurotoxicity with PLDA formulations, and perhaps mitigating or avoiding those. ? ?
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| 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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