Changyou Zhan

Efficient Triplet−Triplet Annihilation-Based Upconversion for Nanoparticle Phototargeting

High-efficiency upconverted light would be a desirable stimulus for triggered drug delivery. Here we present a general strategy to achieve photoreactions based on triplet-triplet annihilation upconversion (TTA-UC) and Förster resonance energy transfer (FRET). We designed PLA-PEG micellar nanoparticles containing in their cores hydrophobic photosensitizer and annihilator molecules which, when stimulated with green light, would undergo TTA-UC. The upconverted energy was then transferred by FRET to a hydrophobic photocleavable group (DEACM), also in the core. The DEACM was bonded to (and thus inactivated) the cell-binding peptide cyclo-(RGDfK), which was bound to the PLA-PEG chain. Cleavage of DEACM by FRET reactivated the PLA-PEG-bound peptide and allowed it to move from the particle core to the surface. TTA-UC followed by FRET allowed photocontrolled binding of cell adhesion with green light LED irradiation at low irradiance for short periods. These are attractive properties in phototriggered systems.

Phototriggered Local Anesthesia.

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.

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.

Enhanced Precision of Nanoparticle Phototargeting in Vivo at a Safe Irradiance

A large proportion of the payload delivered by nanoparticulate therapies is deposited not in the desired target destination but in off-target locations such as the liver and spleen. Here, we demonstrate that phototargeting can improve the specific targeting of nanoparticles to tumors. The combination of efficient triplet-triplet annihilation upconversion (TTA-UC) and Förster resonance energy transfer (FRET) processes allowed in vivo phototargeting at a safe irradiance (200 mW/cm(2)) over a short period (5 min) using green light.

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

Significance We demonstrate an injectable drug-delivery system that would allow patients to adjust the timing, duration, and intensity of local anesthesia in painful parts of the body. Such on-demand analgesia could greatly enhance the management of a variety of pain states. Light-sensitive liposomes containing the potent local anesthetic tetrodotoxin induced sensory and motor nerve block in vivo upon irradiation with a 730-nm laser. The timing, duration, and intensity of the nerve blockade were adjustable by the timing, irradiance, and duration of irradiation. Tissue reaction to the formulation and associated irradiation was benign. 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.

Phototriggered Drug Delivery Using Inorganic Nanomaterials

Light has many desirable properties as the stimulus for triggerable drug delivery systems. Inorganic nanomaterials are often key components in transducing light into drug delivery events. The nature of the light and the inorganic materials can affect the efficacy and safety of the drug delivery system.

A Supramolecular Shear-Thinning Anti-Inflammatory Steroid Hydrogel

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.

Extended Release of Native Drug Conjugated in Polyketal Microparticles

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.

Corneal Anesthesia With Site 1 Sodium Channel Blockers and Dexmedetomidine

PURPOSE Amino-amide or amino-ester local anesthetics, which are currently used for topical ocular anesthesia, are short acting and may delay corneal healing with long-term use. In contrast, site 1 sodium channel blockers (S1SCBs) are potent local anesthetics with minimal adverse tissue reaction. In this study, we examined topical local anesthesia with two S1SCBs, tetrodotoxin (TTX) or saxitoxin (STX) individually or in combination with α2-adrenergic receptor agonists (dexmedetomidine or clonidine), and compared them with the amino-ester ocular anesthetic proparacaine. The effect of test solutions on corneal healing was also studied. METHODS Solutions of TTX ± dexmedetomidine, TTX ± clonidine, STX ± dexmedetomidine, dexmedetomidine, or proparacaine were applied to the rat cornea. Tactile sensitivity was measured by recording the blink response to probing of the cornea with a Cochet-Bonnet esthesiometer. The duration of corneal anesthesia was calculated. Cytotoxicity from anesthetic solutions was measured in vitro. The effect on corneal healing was measured in vivo after corneal debridement followed by repeated drug administration. RESULTS Addition of dexmedetomidine to TTX or STX significantly prolonged corneal anesthesia beyond that of either drug alone, whereas clonidine did not. Tetrodotoxin or STX coadministered with dexmedetomidine resulted in two to three times longer corneal anesthesia than did proparacaine. S1SCB-dexmedetomidine formulations were not cytotoxic. Corneal healing was not delayed significantly by any of the test solutions. CONCLUSIONS Coadministration of S1SCBs with dexmedetomidine provided prolonged corneal anesthesia without delaying corneal wound healing. Such formulations may be useful for the management of acute surgical and nonsurgical corneal pain.

Core-Shell Nanostars for Multimodal Therapy and Imaging

The coupling of diagnostic capability and effective therapy in a single multifunctional nanomedicine is desirable but remains challenging. Here, we developed multifunctional nanoparticles consisting of a gold nanostar (AuNS) core with a shell of metal-drug coordination polymer (CP). The AuNS core enabled plasmonic photothermal effect and two-photon photoluminescence (TPL), while the CP shell of gadolinium and gemcitabine monophosphate allowed chemotherapy and MRI imaging. The AuNS@CP nanoparticles exhibited a strong T1 contrast signal and could monitor the localization of nanoparticles in vivo through noninvasive MR imaging, while intravital TPL imaging could be used to study nanoparticle behavior in tumors at the microscopic level. The combination of photothermal therapy and chemotherapy inhibited tumor growth in vivo.