We report a phototriggerable formulation enabling in vivo repeated and on-demand anesthesia with minimal toxicity. Gold nanorods (GNRs) that can convert near-infrared (NIR) light into heat were attached to liposomes (Lip-GNRs), enabling light-triggered phase transition of their lipid bilayers with a consequent release of payload. Lip-GNRs containing the site 1 sodium channel blocker tetrodotoxin and the α2-adrenergic agonist dexmedetomidine (Lip-GNR-TD) were injected subcutaneously in the rat footpad. Irradiation with an 808 nm continuous wave NIR laser produced on-demand and repeated infiltration anesthesia in the rat footpad in proportion to the irradiance, with minimal toxicity. The ability to achieve on-demand and repeated local anesthesia could be very beneficial in the management of pain.

Numerous drug delivery systems have been applied to the problem of providing prolonged duration local anesthesia (PDLA). Here we review the rationale for PDLA, the desirable features for and important attributes of such systems, and specific examples that have been developed.

There is clinical and scientific interest in developing local anesthetics with prolonged durations of effect from single injections. The need for such is highlighted by the current opioid epidemic. Site 1 sodium channel blockers such as tetrodotoxin (TTX) are extremely potent, and can provide very long nerve blocks but the duration is limited by the associated systemic toxicity. Here we report a system where slow release of TTX conjugated to a biocompatible and biodegradable polymer, poly(triol dicarboxylic acid)-co-poly(ethylene glycol) (TDP), is achieved by hydrolysis of ester linkages. Nerve block by the released TTX is enhanced by administration in a carrier with chemical permeation enhancer (CPE) properties. TTX release can be adjusted by tuning the hydrophilicity of the TDP polymer backbone. In vivo, 1.0–80.0 µg of TTX released from these polymers produced a range of durations of nerve block, from several hours to 3 days, with minimal systemic or local toxicity.

An injectable local anesthetic producing repeatable on-demand nerve block would be desirable for pain management. Here we present a phototriggerable device to achieve repeatable and adjustable on-demand local anesthesia in superficial or deep tissues, consisting of gold nanorods attached to low temperature sensitive liposomes (LTSL). The particles were loaded with tetrodotoxin and dexmedetomidine. Near infrared light (NIR, 808 nm, continuous wave) could heat GNRs at low fluence (short duration and low irradiance), leading to rapid release of payload. In vivo, 1–2 minutes of irradiation at ≤ 272 mW/cm2 produced repeatable and adjustable on-demand infiltration anesthesia or sciatic nerve blockade with minimal toxicity. The nerve block intensity and duration correlated with the irradiance and duration of the applied light.

Shear-thinning and self-healing steroid-drug-based hydrogels are presented, which exhibit rapid and complete recovery of their mechanical properties within seconds following stress-induced flow. The hydrogels release steroid drug in vivo with no visible residue when release is complete.

The efficacy of tetrodotoxin (TTX), a very potent local anesthetic, is limited by its poor penetration through barriers to axonal surfaces. To address this issue, we encapsulated TTX in hollow silica nanoparticles (TTX-HSN) and injected them at the sciatic nerve in rats. TTX-HSN achieved an increased frequency of successful blocks, prolonged the duration of the block, and decreased the toxicity compared to free TTX. In animals injected with fluorescently labeled HSN, the imaging of frozen sections of nerve demonstrated that HSN could penetrate into nerve and that the penetrating ability of silica nanoparticles was highly size-dependent. These results demonstrated that HSN could deliver TTX into the nerve, enhancing efficacy while improving safety.

Background Chemical permeation enhancers (CPEs) have the potential to improve nerve blockade by site 1 sodium channels blockers such as tetrodotoxin (TTX). Here we investigated the efficacy and toxicity of CPE-enhanced nerve blockade across a range of TTX concentrations, using two CPEs (sodium octyl sulfate and octyl trimethyl ammonium bromide). We also tested the hypotheses that CPEs could be used to reduce the concentrations of TTX and/or of a second adjuvant drug (in this case epinephrine) needed to achieve prolonged local anesthesia Methods Sprague-Dawley rats were injected at the sciatic nerve with combinations of TTX and CPEs, with and without epinephrine. Sensory and motor nerve blockade were assessed using a modified hot plate test and a weight-bearing test, respectively. Systemic and local toxicities of the different combinations were assessed. Results Addition of increasing concentrations of TTX to fixed concentrations of CPEs produced a marked concentration-dependent improvement in the rate of successful nerve blocks and in nerve block duration. CPEs did not affect systemic toxicity. At some concentrations, the addition of sodium octyl sulfate increased the duration of block from TTX plus epinephrine, and epinephrine increased that from TTX plus CPEs. The addition of epinephrine did not cause an increase in local toxicity, and markedly reduced systemic toxicity. Conclusions CPEs can prolong the duration of nerve blockade across a range of concentrations of TTX. CPEs could also be used to reduce the concentration of epinephrine needed to achieve a given degree of nerve block. CPEs may be useful in enhancing nerve blockade from site 1 sodium channel blockers.

Polyketals, which can be biodegradable, have good biocompatibility, and are pH-sensitive, could have broad applicability in drug delivery and other biomedical applications. However, facile synthesis of high molecular weight polyketals is challenging, and short durations of drug release from polyketal particulate formulations limit their application in drug delivery. Here we report the synthesis of a di-isopropenyl ether monomer and its use to synthesize high molecular weight estradiol-polyketal conjugates by addition polymerization. Microparticles were prepared from the estradiol-polyketal conjugate, where estradiol was incorporated into the polymer backbone. The particles had high drug loading and significantly prolonged drug release. Release of estradiol from the drug-polyketal conjugate microparticles was acid-responsive, as evidenced by faster drug release at low pH and with co-incorporation of PLGA. Tissue reaction to the microparticles was benign in vivo. Polyketal drug conjugates are promising candidates for long-acting drug delivery systems to treat chronic diseases.