It has been a long-standing goal to develop local anesthetic formulations producing prolonged duration local anesthesia (PDLA) with minimal side effects. Tetrodotoxin (TTX), a site 1 sodium-channel blocker, which blocks the sodium channel at site 1 on the cell surface, is a naturally occurring compound with extremely potent local anesthetic properties. Besides, TTX does not cause myo- or neurotoxicity. However, the principal reason that TTX has not achieved clinical use despite its great potency is concern over its associated systemic toxicity. The TTX overdose causes neural blockade and muscular weakness resulting in diaphragmatic paralysis leading to respiratory arrest and death. The primary objective of this research is to use the drug controlled release technology to address the limitations imposed by the toxicity of TTX and to provide PDLA lasting 2-4 weeks from a single injection. To achieve this goal, we propose to 1) covalently conjugate TTX onto polymer backbones through ester bonds, hydrolysis of which can achieve the slow release of TTX; 2) make the polymer backbone to be liquid, viscous and hydrophobic, where the enhanced local material retention can be accomplished. Once we fabricated the formulation, the duration of nerve blockade and systemic toxicity will be assessed using the rat sciatic nerve block model and neurobehavioral testing. Pharmacokinetics (PK)-pharmacodynamics (PD) models of the sustained-release TTX and the tissue toxicity following the PDLA will also be investigated. If successful, this research could have a substantial clinical impact. Sustained-release formulations of TTX would increase the safety margin of TTX, improve patient compliance due to less frequent anesthetic administration, reduce and possibly eliminate the need for opioids in pain treatment to avoid complications and to lessen the risk of addiction.