Repeatable and adjustable on-demand sciatic nerve block with phototriggerable liposomes

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.National Institutes of Health (U.S.) (GM073626

Repeatable and adjustable on-demand local anesthesia using externally-triggerable liposomes

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Materials Science and Engineering, 2017."June 2017." Cataloged from PDF version of thesis.Includes bibliographical references.Pain management would be greatly enhanced by a formulation that would provide local anesthesia at the time desired by patients, with the desired intensity and duration. Current treatment for many pain states - including localized pain - often involves systemic medications such as opioids that have significant side effects. Externally triggerable drug delivery systems provide a strategy for the delivery of therapeutic agents preferentially to the target site at the desired timing, dosage, and duration, presenting the ability to enhance therapeutic efficacy while reducing side effects. Here we have developed light- and ultrasound- triggerable liposomes that provide on-demand nerve block at the desired timing, intensity and duration. The responsiveness of the liposomes towards the external triggering was studied in vitro, where the light triggerable system showed 5.6% drug release upon irradiation with 730 nm light and the ultrasound triggerable system showed 5.4% drug release upon insonation 1 MHz, 3W/cm² ultrasound. Sciatic nerve blockades for up to a duration of 2h was successfully achieved with safe dosage of light (730 nm, 75 mW/cm², 15 min) or ultrasound (1 MHz, 3W/cm², 10 min). Sciatic nerve block could be triggered repeatedly with light or ultrasound for more than 5 times upon a single injection. The duration of nerve block showed a linear relationship with the energy density of the triggering event, which was controlled by duration and intensity of the external energy source. Tissue reaction was benign. Such on-demand nerve block systems have promising potential to provide personalized and effective local anesthesia that will enhance pain management.by Alina Yu-Hsin Rwei.Ph. D

Photoresponsive nanoparticles for drug delivery

© 2015 Elsevier Ltd.Summary Externally triggerable drug delivery systems provide a strategy for the delivery of therapeutic agents preferentially to a target site, presenting the ability to enhance therapeutic efficacy while reducing side effects. Light is a versatile and easily tuned external stimulus that can provide spatiotemporal control. Here we will review the use of nanoparticles in which light triggers drug release or induces particle binding to tissues (phototargeting).Link_to_subscribed_fulltex

Enhanced Triggering of Local Anesthetic Particles by Photosensitization and Photothermal Effect Using a Common Wavelength

On-demand pain relief systems would be very helpful additions to the armamentarium of pain management. Near-infrared triggered drug delivery systems have demonstrated the potential to provide such care. However, challenges remain in making such systems as stimulus-sensitive as possible, to enhance depth of tissue penetration, repeatability of triggering, and safety. Here we developed liposomes containing the local anesthetic tetrodotoxin and also containing a photosensitizer and gold nanorods that were excitable at the same near-infrared wavelength. The combination of triggering mechanisms enhanced the photosensitivity and repeatability of the system in vitro when compared with liposomes with a single photoresponsive component. In vivo, on-demand local anesthesia could be induced with a low irradiance and short irradiation duration, and liposomes containing both photosensitizer and gold nanorods were more effective than those containing just one photoresponsive component. Tissue reaction was benign

Ultrasensitive Phototriggered Local Anesthesia

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 gold nanorods at low fluence (short duration and low irradiance), leading to rapid release of payload. In vivo, 1–2 min 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

An optical aptasensor for real-time quantification of endotoxin: From ensemble to single-molecule resolution

Endotoxin is a deadly pyrogen, rendering it crucial to monitor with high accuracy and efficiency. However, current endotoxin detection relies on multistep processes that are labor-intensive, time-consuming, and unsustainable. Here, we report an aptamer-based biosensor for the real-time optical detection of endotoxin. The endotoxin sensor exploits the distance-dependent scattering of gold nanoparticles (AuNPs) coupled to a gold nanofilm. This is enabled by the conformational changes of an endotoxin-specific aptamer upon target binding. The sensor can be used in an ensemble mode and single-particle mode under dark-field illumination. In the ensemble mode, the sensor is coupled with a microspectrometer and exhibits high specificity, reliability (i.e., linear concentration to signal profile in logarithmic scale), and reusability for repeated endotoxin measurements. Individual endotoxins can be detected by monitoring the color of single AuNPs via a color camera, achieving single-molecule resolution. This platform can potentially advance endotoxin detection to safeguard medical, food, and pharmaceutical products.</p

An optical aptasensor for real-time quantification of endotoxin: From ensemble to single-molecule resolution

Endotoxin is a deadly pyrogen, rendering it crucial to monitor with high accuracy and efficiency. However, current endotoxin detection relies on multistep processes that are labor-intensive, time-consuming, and unsustainable. Here, we report an aptamer-based biosensor for the real-time optical detection of endotoxin. The endotoxin sensor exploits the distance-dependent scattering of gold nanoparticles (AuNPs) coupled to a gold nanofilm. This is enabled by the conformational changes of an endotoxin-specific aptamer upon target binding. The sensor can be used in an ensemble mode and single-particle mode under dark-field illumination. In the ensemble mode, the sensor is coupled with a microspectrometer and exhibits high specificity, reliability (i.e., linear concentration to signal profile in logarithmic scale), and reusability for repeated endotoxin measurements. Individual endotoxins can be detected by monitoring the color of single AuNPs via a color camera, achieving single-molecule resolution. This platform can potentially advance endotoxin detection to safeguard medical, food, and pharmaceutical products

Single Molecule Detection of Nitric Oxide Enabled by d(AT)15 DNA Adsorbed to Near Infrared Fluorescent Single-Walled Carbon Nanotubes

We report the selective detection of single nitric oxide (NO) mols. using a specific DNA sequence of d(AT)15 oligonucleotides, adsorbed to an array of near-IR fluorescent semiconducting single-walled carbon nanotubes (AT15-SWNT). While SWNT suspended with eight other variant DNA sequences show fluorescence quenching or enhancement from analytes such as dopamine, NADH, L-ascorbic acid, and riboflavin, d(AT)15 imparts SWNT with a distinct selectivity toward NO. In contrast, the electrostatically neutral polyvinyl alc. enables no response to nitric oxide, but exhibits fluorescent enhancement to other mols. in the tested library. For AT15-SWNT, a stepwise fluorescence decrease is obsd. when the nanotubes are exposed to NO, reporting the dynamics of single-mol. NO adsorption via SWNT exciton quenching. We describe these quenching traces using a birth-and-death Markov model, and the max. likelihood estimator of adsorption and desorption rates of NO is derived. Applying the method to simulated traces indicates that the resulting error in the estd. rate consts. is less than 5% under our exptl. conditions, allowing for calibration using a series of NO concns. As expected, the adsorption rate is found to be linearly proportional to NO concn., and the intrinsic single-site NO adsorption rate const. is 0.001 s-1 μM NO-1. The ability to detect nitric oxide quant. at the single-mol. level may find applications in new cellular assays for the study of nitric oxide carcinogenesis and chem. signaling, as well as medical diagnostics for inflammation. [on SciFinder(R)