Enhancement of ultralow-intensity NIR light-triggered photodynamic therapy based on exo- and endogenous synergistic effects through combined glutathione-depletion chemotherapy.

Although photodynamic therapy (PDT), which uses a photosensitizer (PS) to generate toxic reactive oxygen species (ROS) upon laser irradiation to kill cancer cells, has been widely applied, the relatively high laser intensity required causes photodamage to healthy neighboring cells and limits its success. Furthermore, glutathione (GSH, an antioxidant) is overexpressed in cancer cells, which can scavenge the generated ROS, thus lowering PDT efficacy. Herein, ultralow-intensity near-infrared (NIR) light-triggered PDT was developed and enhanced through combined GSH-depletion chemotherapy (Chemo) based on exo- and endogenous synergistic effects. Highly emissive upconversion nanoparticles (UCNPs) were prepared and coated with a solid silica shell, which was used to encapsulate the PS rose bengal and bond the drug camptothecin with a disulfide-bond linker. The combination of highly emissive UCNPs and a matchable PS with an optimized loading dosage enabled ROS to be generated for PDT even upon 808 nm laser irradiation with ultralow intensity (0.30 W cm-2). According to the American National Standard, this laser intensity is below the maximum permissible exposure of skin (MPE, 0.33 W cm-2). Once the prepared nanoparticles endocytosed and encountered intracellular GSH, the disulfide-bond linker was cleaved by GSH, leading to drug release and GSH depletion. PDT was therefore simultaneously enhanced through the exogenous synergic effect of Chemo (namely, the "1 + 1 > 2" therapeutic effect) and the endogenous synergic effect as a result of GSH depletion. It was proven both in vitro and in vivo that this novel dual-synergistic Chemo/PDT system exhibits remarkable therapeutic efficacy with minimal photodamage to healthy neighboring cells.

Near-Infrared Light-Triggered Hydrophobic-to-Hydrophilic Switch Nanovalve for On-Demand Cancer Therapy.

An on-demand drug delivery nanoplatform based on mesoporous silica (mSiO2) coated upconversion nanoparticles (UCNP@mSiO2) with a novel near-infrared (NIR) light-triggered hydrophobic-to-hydrophilic switch nanovalve was fabricated. The surface of UCNP@mSiO2 was first immobilized with hydrophobic 2-diazo-1,2-naphthoquinones (DNQ) guest molecules. After doxorubicin hydrochloride (DOX, a universal anticancer drug) was loaded into channels of mSiO2 shell, ß-cyclodextrin (ß-CD) host molecules with a hydrophobic cavity were added as gatekeepers to cap DNQ stalk molecules via hydrophobic affinity, which may play a role in the OFF state of the nanovalve to prevent the drug from being released. Upon 980 nm light irradiation, a NIR light-triggered hydrophobic-to-hydrophilic switch, that transformed the hydrophobic guest DNQ into hydrophilic guest 3-indenecarboxylic acid (ICA), took place so that the capped ß-CD gatekeepers dissociated due to repulsion between ß-CD host (hydrophobic) and ICA guest (hydrophilic), activating the ON state of the nanovalves to release drug. The in vitro studies prove that the nanoplatform enables on-demand drug release to efficiently kill HeLa cell upon NIR light regulation. The in vivo experiment results further confirm that the nanoplatform with such fabricated nanovalves is able to inhibit tumor growth in mice. The designed nanovalves based on the novel NIR light-triggered hydrophobic-to-hydrophilic switch strategy therefore may shed new light on future development of on-demand cancer therapy.

Design and Synthesis of Core-Shell-Shell Upconversion Nanoparticles for NIR-Induced Drug Release, Photodynamic Therapy, and Cell Imaging.

Novel core-shell-shell structured nanoparticles 75 nm in diameter with all-in-one "smart" functional capabilities for simultaneous photoresponsive drug release, photodynamic therapy, and cell imaging are designed and prepared. These nanoparticles consist of an upconversion (UC) emission core, a photosensitizer-embodied silica sandwich shell, and a ß-cyclodextrin (ß-CD) gated mesoporous silica outmost shell with drugs (Rhodamine B as a model) loaded inside. We show in this proof-of-concept demonstration that, under 980 nm near-infrared irradiation, UC 540 nm green light emissions were emitted for cell imaging, and 660 nm red light emissions were excited for activating photosensitizers to generate singlet oxygen, which could be exploited directly to kill cancer cells and simultaneously dissociate ß-CD gatekeeper to release drugs. The preliminary results reported here will shed new light on the future design and applications of multifunctional platforms for cancer therapy and diagnostic.

[Nasal submicron emulsion of Scutellariae Radix extract preparation technology research based on phase transfer of solute technology].

Based on the demand of nasal drug delivery high drug loadings, using the unique phase transfer of solute, integrating the phospholipid complex preparation and submicron emulsion molding process of Scutellariae Radix extract, the study obtained the preparation of the high drug loadings submicron emulsion of Scutellariae Radix extract. In the study of drug solution dispersion method, the uniformity of drug dispersed as the evaluation index, the traditional mixing method, grinding, homogenate and solute phase transfer technology were investigated, and the solute phase transfer technology was adopted in the last. With the adoption of new technology, the drug loading capacity reached 1.33% (phospholipid complex was 4%). The drug loading capacity was improved significantly. The transfer of solute method and timing were studied as follows,join the oil phase when the volume of phospholipid complex anhydrous ethanol solution remaining 30%, the solute phase transfer was completed with the continued recycling of anhydrous ethanol. After drug dissolved away to oil phase, the preparation technology of colostrum was determined with the evaluation index of emulsion droplet form. The particle size of submicron emulsion, PDI and stability parameters were used as evaluation index, orthogonal methodology were adopted to optimize the submicron emulsion ingredient and main influential factors of high pressure homogenization technology. The optimized preparation technology of Scutellariae Radix extract nasal submicron emulsion is practical and stable.

[Nasal Mucosa Absorption of Scutellariae Radix Extract in Rats and Its Two Preparations Phospholipid Complex and Submicron Emulsion].

OBJECTIVE: To study the nasal mucosa absorption of Scutellariae Radix extract in rats and its two preparations phospholipid complex and submicron emulsion, and to evaluate the rationality of Scutellariae Radix extract modification technology and preparation form. METHODS: According to the nasal absorption method, the absorption amount of Scutellariae Radix extract, phospholipid complex and submicron emulsion were determined. RESULTS: The absorption amount of Scutellariae Radix extract, phospholipid complex and submicron emulsion under the experimental conditions was improved in turn in 2 h and the absorption amount of submicron emulsion increased significantly. The absorption characteristics were passive diffusion. CONCLUSION: The modification methods and preparation form of Scutellariae Radix extract were scientific and reasonable.

[Study on formulation of Scutellaria baicalensis extract phospholipid complex nasal preparation].

OBJECTIVE: To screen suitable nasal dosage forms of Scutellaria baicalensis extract phospholipid complex. METHODS: Used the permeable performance of hyorrinis mucosa, nasal irritation and other evaluation indexes to screen five different formulations. RESULTS: The submicroemulsion's apparent permeability coefficient was the largest, irritant was the smallest, and drug loading was higher than those of other formulations, which could meet the requirements of intranasal administration. CONCLUSION: The optimum formulation of Scutellria baicalensis extract phospholipid complex nasal preparation is submicroemulsion.