A Novel Topical Fluorescent Probe for Detection of Glioblastoma.

PURPOSE: Five-aminolevulinic acid (5-ALA) is widely used as an intraoperative fluorescent probe for radical resection of high-grade glioma, and thus aids in extending progression-free survival of patients. However, there exist some cases where 5-ALA fails to fluoresce. In some other cases, it may undergo fluorescence quenching but cannot be orally readministered during surgery. This study aimed to develop a novel hydroxymethyl rhodamine green (HMRG)-based fluorescence labeling system that can be repeatedly administered as a topical spray during surgery for the detection of glioblastoma. EXPERIMENTAL DESIGN: We performed a three-stage probe screening using tumor lysates and fresh tumor tissues with our probe library consisting of a variety of HMRG probes with different dipeptides. We then performed proteome and transcript expression analyses to detect candidate enzymes responsible for cleaving the probe. Moreover, in vitro and ex vivo studies using U87 glioblastoma cell line were conducted to validate the findings. RESULTS: The probe screening identified proline-arginine-HMRG (PR-HMRG) as the optimal probe that distinguished tumors from peritumoral tissues. Proteome analysis identified calpain-1 (CAPN1) to be responsible for cleaving the probe. CAPN1 was highly expressed in tumor tissues which reacted to the PR-HMRG probe. Knockdown of this enzyme suppressed fluorescence intensity in U87 glioblastoma cells. In situ assay using a mouse U87 xenograft model demonstrated marked contrast of fluorescence with the probe between the tumor and peritumoral tissues. CONCLUSIONS: The novel fluorescent probe PR-HMRG is effective in detecting glioblastoma when applied topically. Further investigations are warranted to assess the efficacy and safety of its clinical use.

Enhancement of the Mechanical and Drug-Releasing Properties of Poloxamer 407 Hydrogels with Casein.

PURPOSE: Topical therapy of local disease (e.g. skin) is advantageous over oral therapy since there is less systemic drug distribution (so fewer side-effects), no first-pass effect, etc. However, patient compliance with topical therapy can be poor as it may require many applications a day and can last months. Here we propose a topical controlled release formulation with thermoresponsive gelation at body temperature and improved adhesiveness, making it easier to remain in contact with the body. METHODS: The formulation contains two excipients, poloxamer 407 (P407) and casein. Casein can modify the properties of the hydrogel through molecular entanglement. In addition, tissue reaction and drug release profile were evaluated. RESULTS: Changes in casein concentration affected adhesive strength, viscosity, mechanical properties and drug release, presumably by hydrophobic interactions between casein and P407. Two different concentrations of P407 were tested with two different concentrations of casein. Formulations containing 5% and 10% casein released 80% of model drug in 48 h, while formulations without casein released the same fraction in around 24 h hours. Formulations with 10% casein had almost twice the adhesive strength of those without casein. CONCLUSIONS: Addition of casein modified the mechanical properties and drug release rate of the hydrogel. There was no inflammation or injury after brief exposure in vivo.

Study on the fabrication and characterization of tip-loaded dissolving microneedles for transdermal drug delivery.

In order to increase the utilization rate of drug carried by microneedles and reduce waste, a two-step casting method was proposed to fabricate tip-loaded dissolving microneedles in this paper. The tip-loaded dissolving microneedles, also named layered microneedles, was consisted of two layers. The tip layer of the microneedles carried model drug, while the backing layer was fabricated with pure dissolving material. Polyvinyl alcohol, polyvinylpyrrolidone and hyaluronic acid were used as the base materials to fabricate the dissolving layers of the microneedle patches. Rhodamine B was chosen as the model drug to show the layered structure of tip-loaded microneedles. The material formulation and fabricating conditions of the tip-loaded dissolving microneedles and their transdermal insulin delivery efficiency were systematically studied. Nanoindentation testing showed that the tips of all three kinds of dissolving microneedles can bear the maximum loading of 50 mN with no damages, indicated sufficient mechanical strength for smooth skin puncturing as the minimum pressure required was 10 mN only. Moreover, our fabricated tip-loaded dissolving microneedles can greatly reduce the drug waste cause by unused backing layer in normal microneedles and realize a 30% enhancement of drug delivery efficiency after puncture treatment.

Versatile composite hydrogels for drug delivery and beyond.

Hydrogels have extended applications across multiple fields. A novel hydrogel material is often evaluated for its properties and applications in either a wet or dry state, but not both. In this study, we investigated a protein-based, composite hydrogel system in both its wet and dry states. Bovine serum albumin (BSA) was used as the hydrogel base. With the assistance of organosilanes, BSA solutions became hydrogels under facile reaction conditions. In the first part, the wet gel was prepared in situ in a syringe; upon injecting through a needle, the gel retained its structure. The use of the nascent gel system as an injectable drug-delivery vehicle is of particular interest. We therefore developed a microplate platform that allows a "one-plate" study-i.e. gel preparation, payload loading and release-all being performed in a single plate. This one-plate method further enables a systematic study of various controlling parameters for drug release. For example, we can tune the release rate by simply adjusting the phosphate content in the hydrogel formulation. Besides, for low-releasing compounds, the release profile was also tunable while using the one-plate method. In the second part, we further demonstrate the versatility of our composite hydrogels. By simply varying the feed ratio of two organosilanes, (3-mercaptopropyl)methyldimethoxysilane and (3-mercaptopropyl)trimethoxysilane, and phosphate concentrations, dry gels exhibiting various absorption capacities towards water, organic solvents, and oil can be prepared. Further characterizations using SEM and 29Si NMR spectroscopy revealed porous structures and hybrid siloxane bridges within the composite material.

Biodegradable Nanoparticles Based on Pseudo-Proteins Show Promise as Carriers for Ophthalmic Drug Delivery.

Purpose: Drug delivery to treat ocular diseases still is a challenge in ophthalmology. One way to achieve drug delivery that is investigated currently is topical administration of drug-loaded polymeric nanoparticles (NPs) that are able to penetrate ocular barriers. The purpose of this study was optimal preparation of NPs made from pseudo-proteins and evaluation of their ability to penetrate ocular tissues. Methods: Biodegradable NPs of various types were prepared by nanoprecipitation of pseudo-protein composed of l-leucine (L), 1,6-hexanediol (6), and sebacic acid (8) (8L6). Arginine-based cationic polyester amides 8R6 and comb-like polyester amide containing lateral PEG-2000 chains along with 8L6 anchoring fragments in the backbones were used to construct positively charged and PEGylated NPs. They were loaded with fluorescein diacetate (FDA) or rhodamine 6G (Rh6G) as fluorescent probes. Suspensions of the NPs were given to cultivated microglial cells and retinal pigment epithelial (RPE) cells as well as topically on eyes of C57BL/6 mice. Penetration of NPs into the eyes was checked by fluorescence analysis. Results: NPs were prepared, and their properties were characterized. Cultured microglial cells and RPE cells took up the NPs. After topical administration, penetration of NPs into the cornea of the eyes was clearly seen. Small amounts of fluorescent dyes were also found in the lens, the retina, and the sclera depending on the type of NPs. Conclusions: The results showed that the new NPs penetrate ocular tissues after topical administration and are internalized by the cells. This raises confidence that the NPs may be useful carriers of therapeutic agents for ocular delivery.

Effect of Common Excipients on Intestinal Drug Absorption in Wistar Rats.

The aim of the present paper is to study the effect of common excipients on the permeability of atenolol (as drug absorbed mainly by passive diffusion) and rhodamine (as P-glycoprotein substrate). The apparent permeability was measured by an in situ perfusion method in Wistar rats using the closed loop Doluisio's method. Permeability values were characterized in the absence and presence of 18 commonly used excipients. Excipient concentrations were selected based on the amounts in oral immediate release dosage forms, which failed the test during the human bioequivalence studies. Atenolol was studied with and without excipients in the whole small intestine, whereas rhodamine was tested in three different intestinal segments to account for the differential expression of P-glycoprotein, and it was further on tested in the ileum, in the presence of excipients. Atenolol presented higher permeability values when it was administered with colloidal silica, croscarmellose, hydroxypropyl methylcellulose (HPMC), magnesium stearate, MgCO3, poly(ethylene glycol) 400, poly(vinylpyrrolidone), sorbitol, starch, and TiO2 rhodamine showed higher permeability values when it was administered with croscarmellose and HPMC. On the one hand, the mechanisms of action were not discernible with the proposed experiments. On the other hand, commercial formulations do not present a single excipient but several, which can counteract their effects. The in situ perfusion technique can be useful for a preliminary screening and risk analysis, while the in vivo pharmacokinetic results would be needed to define conclusive effects.

Squalene-based nanoparticles for the targeting of atherosclerotic lesions.

Native low-density lipoproteins (LDL) naturally accumulate at atherosclerotic lesions and are thought to be among the main drivers of atherosclerosis progression. Numerous nanoparticular systems making use of recombinant lipoproteins have been developed for targeting atherosclerotic plaque. These innovative formulations often require complicated purification and synthesis procedures which limit their eventual translation to the clinics. Recently, squalenoylation has appeared as a simple and efficient technique for targeting agents to endogenous lipoproteins through a bioconjugation approach. In this study, we have developed a fluorescent squalene bioconjugate to evaluate the biodistribution of squalene-based nanoparticles in an ApoE-/- model of atherosclerosis. By accumulating in LDL endogenous nanoparticles, the squalene bioconjugation could serve as an efficient targeting platform for atherosclerosis. Indeed, in this proof of concept, we show that our squalene-rhodamine (SQRho) nanoparticles, could accumulate in the aortas of atherosclerotic animals. Histological evaluation confirmed the presence of atherosclerotic lesions and the co-localization of SQRho bioconjugates at the lesion sites.

Ultrasonically and Iontophoretically Enhanced Drug-Delivery System Based on Dissolving Microneedle Patches.

A multifunctional system comprised of hyaluronic acid microneedles was developed as an effective transdermal delivery platform for rapid local delivery. The microneedles can regulate the filling amount on the tip, by controlling the concentration of hyaluronic acid solution. Ultrasonication induces dissolution of the HA microneedles via vibration of acoustic pressure, and AC iontophoresis improves the electrostatic force-driven diffusion of HA ions and rhodamine B. The effect of ultrasound on rhodamine release was analyzed in vitro using a gelatin hydrogel. The frequency and voltage dependence of the AC on the ion induction transfer was also evaluated experimentally. The results showed that the permeability of the material acts as a key material property. The delivery system based on ultrasonication and iontophoresis in microneedles increases permeation, thus resulting in shorter initial delivery time than that required by delivery systems based on passive or ultrasonication alone. This study highlights the significance of the combination between ultrasonic waves and iontophoresis for improving the efficiency of the microneedles, by shortening the reaction duration. We anticipate that this system can be extended to macromolecular and dependence delivery, based on drug response time.

Delivery Strategies for Skin: Comparison of Nanoliter Jets, Needles and Topical Solutions.

Drug diffusion within the skin with a needle-free micro-jet injection (NFI) device was compared with two well-established delivery methods: topical application and solid needle injection. A permanent make-up (PMU) machine, normally used for dermal pigmentation, was utilized as a solid needle injection method. For NFIs a continuous wave (CW) laser diode was used to create a bubble inside a microfluidic device containing a light absorbing solution. Each method delivered two different solutions into ex vivo porcine skin. The first solution consisted of a red dye (direct red 81) and rhodamine B in water. The second solution was direct red 81 and rhodamine B in water and glycerol. We measured the diffusion depth, width and surface area of the solutions in all the injected skin samples. The NFI has a higher vertical dispersion velocity of 3 × 105µm/s compared to topical (0.1 µm/s) and needle injection (53 µm/s). The limitations and advantages of each method are discussed, and we conclude that the micro-jet injector represents a fast and minimally invasive injection method, while the solid needle injector causes notable tissue damage. In contrast, the topical method had the slowest diffusion rate but causes no visible damage to the skin.

Conception of nanosized hybrid liposome/poloxamer particles to thicken the interior core of liposomes and delay hydrophilic drug delivery.

Liposomes are nanocarriers composed of phospholipids, especially designed to potentially carry drugs. However, liposomes suffer in terms of leakage of small hydrophilic drugs. To control the release, a system with lipid shell and polymeric viscous core, namely Hybrid liposome/polymer inside (HLPin), has been designed. For this purpose, we setup a syringe pump apparatus equipped with homemade tubing system. HLPin formulation consisting of poloxamer (5% w/v) was found to be optimal when produced at injection rates of 5 mL.min-1. Then, we tend to characterize the HLPin with DLS, TEM, TRPS, thermal analysis and densitometry in comparison with a polymer added after formation of the liposomes. The optimal formulation was evaluated for its stability and cytotoxicity. The selected conditions and composition resulted in nanocarriers which are highly reproducible with mono-disperse size distribution with an average size of 206 ±â€¯4.8 nm and a polydispersity index of 0.15 ±â€¯0.015. Densitometry and thermal analysis results confirmed the formation of HLPin. Interestingly, HLPin were stable over 2 months, produced no cytotoxicity and exhibited slow release of rhodamine and Doxorubicin in comparison to liposome formulation. Our homemade tubing system coupled with syringe pump apparatus achieved reproducible, precisely controlled production for the HLPin formulation which can be scale up.

Injection of Fluoro-Gold into the tibial nerve leads to prolonged but reversible functional deficits in rats.

Tract tracing with neuronal tracers not only represents a straightforward approach to identify axonal projection connection between regions of the nervous system at distance but also provides compelling evidence for axonal regeneration. An ideal neuronal tracer meets certain criteria including high labeling efficacy, minimal neurotoxicity, rapid labeling, suitable stability in vivo, and compatibility to tissue processing for histological/immunohistochemical staining. Although labeling efficacy of commonly used fluorescent tracers has been studied extensively, neurotoxicity and their effect on neural functions remains poorly understood. In the present study, we comprehensively evaluated motor and sensory nerve function 2-24 weeks after injection of retrograde tracer Fluoro-Gold (FG), True Blue (TB) or Fluoro-Ruby (FR) in the tibial nerve in adult Spague-Dawley rats. We found that motor and sensory nerve functions were completely recovered by 24 weeks after tracer exposure, and that FG lead to a more prolonged delay in functional recovery than TB. These findings shed light on the long-term effect of tracers on nerve function and peripheral axonal regeneration, and therefore have implications in selection of appropriate tracers in relevant studies.

Sustained release of a model water-soluble compound via dry powder aerosolizable acetalated dextran microparticles.

Objective: To design and characterize aerosol microparticles (MP) to provide sustained release of the water-soluble compound sulforhodamine B (SRB) and achieve effective aerosol dispersion. Significance: Modulating the release of water-soluble compounds remains a challenge in pulmonary drug delivery. Methods: SRB and water made up an aqueous solution, while acetalated dextran (Ac-Dex) and isopropyl alcohol made up an organic solution. The two solutions were mixed together, and the solution was spray dried to produce MP. MP were characterized for morphology, size, release kinetics, aerosol dispersion, and cellular interactions. Results: Ac-Dex MP exhibited corrugated morphology and aerodynamic diameters from 2.06 to 2.86 µm. MP deposited in all stages of a Next Generation Impactor, with >90% fine particle fraction. MP exhibited encapsulation efficiencies >129% with SRB loading values up to 16.7 µg SRB/mg MP. MP exhibited sustained release of SRB at pH 7 and fast release at pH 5. In vitro experiments showed minimal cytotoxicity, successful uptake of MP in epithelial cells, and no disruption to the integrity of epithelial monolayers. Conclusions: Ac-Dex MP systems demonstrated the ability to provide sustained the release of a water-soluble therapeutic in addition to effective aerosol dispersion for pulmonary applications.

Organic anion-transporting polypeptide 1a4-mediated heterogeneous distribution of sulforhodamine-101 in rat hepatic lobules.

It has been known that organic anion-transporting polypeptides (Oatps) involve hepatic transports several organic anionic compounds and drugs. This study aimed to investigate sulforhodamine-101 (SR-101) distribution in the rat liver, determine the molecules responsible for the distribution, and delineate the manner of distribution. After intravenous SR-101 administration, its distribution in frozen rat hepatic sections was examined. SR-101-derived signals were detected in regions around the hepatic central vein (CV), where immunohistochemistry (IHC) indicated high Oatp1a4 expression. The signals decreased with treatment by digoxin, a specific substrate for Oatp1a4. In vitro studies using isolated rat hepatocytes and rat Oatp1a4-expressing Xenopus laevis oocytes have suggested that SR-101 is an Oatp1a4 substrate and is taken up into rat hepatocytes mainly via Oatp1a4. Therefore, results suggested SR-101 zonation because of Oatp1a4 involvement and that Oatp1a4 function is dominant in the region around the hepatic CV in rat hepatic lobules.

MOFBOTS: Metal-Organic-Framework-Based Biomedical Microrobots.

Motile metal-organic frameworks (MOFs) are potential candidates to serve as small-scale robotic platforms for applications in environmental remediation, targeted drug delivery, or nanosurgery. Here, magnetic helical microstructures coated with a kind of zinc-based MOF, zeolitic imidazole framework-8 (ZIF-8), with biocompatibility characteristics and pH-responsive features, are successfully fabricated. Moreover, it is shown that this highly integrated multifunctional device can swim along predesigned tracks under the control of weak rotational magnetic fields. The proposed systems can achieve single-cell targeting in a cell culture media and a controlled delivery of cargo payloads inside a complex microfluidic channel network. This new approach toward the fabrication of integrated multifunctional systems will open new avenues in soft microrobotics beyond current applications.

Layer-by-layer coated porous 3D printed hydroxyapatite composite scaffolds for controlled drug delivery.

Interconnected porous scaffolds are widely used in the applications of tissue repair and regeneration. Sustained local delivery of drugs and growth factors around the implanted scaffolds could accelerate the growth of cells and contribute to the regeneration of damaged tissues. In this study, porous hydroxyapatite composite scaffolds were prepared through 3D bio-printing for bone tissue engineering and were subsequently coated with chitosan and sodium hyaluronate by layer-by-layer (LBL) deposition. It was found that the LBL coating on the porous scaffolds could reduce the swelling ratio of scaffolds in size and increase the compressive strength by about 70%. The degradation rate of the scaffolds slowed down due to the LBL coating. Rhodamine B (RHB) and bovine serum albumin (BSA) were chosen as model drugs in order to understand the loading and release behaviors of the scaffolds. Small RHB molecules could penetrate deep into the LBL coated scaffolds and released a little slower than that without coating. Meanwhile, large BSA molecules showed faster release rate compared to that without coating. In addition, there was no significant cytotoxicity effect of these composite scaffolds towards MC-3T3E1 cells and the scaffolds provided proper conditions for cell adhesion and proliferation, indicating that the printed hydroxyapatite composite scaffolds exhibit a great potential in hard tissue engineering as a sustained delivery system.

Post-irradiation recovery time strongly influences fractional laser-facilitated skin absorption.

Fractional CO2 laser treatment has been used in some clinical trials to promote topical drug delivery. Currently, there is no standard for laser settings to achieve a feasible therapy. The cutaneous recovery following laser treatment and its influence on drug absorption have not been well explored. This study evaluated the kinetics of laser-treated skin-barrier restoration and drug permeation in nude mice. The skin recovery and observation of the process were characterized by transdermal water loss (TEWL), erythema measurement, gross appearance, optical microscopy, and scanning electron microscopy (SEM). The skin absorption of a lipophilic small permeant (tretinoin), a hydrophilic small permeant (acyclovir), and a large molecule (fluorescein isothiocyanate dextran 4 kDa, FD4) was examined in vitro using Franz cell. TEWL suggested that the laser-treated skin restored its barrier function at 16 h after irradiation. The fractional laser produced microchannels of about 150 µm in diameter and 25 µm in depth that were surrounded with thermal coagulation. The bright-field imaging indicated that the micropores were progressively closed during the recovery period but had not completely closed even after a 16-h recovery. The laser treatment led to a rapid tretinoin penetration across the skin immediately after irradiation, with a 5-fold enhancement compared to intact skin. This enhancement was gradually reduced following the increase of recovery time. Conversely, the acyclovir and FD4 permeation peaked at 1-2 h post-irradiation. The FD4 flux was even elevated as the recovery time increased. The reasons for this could have been the subsequent inflammation after laser exposure and the deficient tight junction (TJ) barrier. The confocal imaging demonstrated the perpendicular diffusion of rhodamine B and FD4 through microchannels immediately after laser exposure. The lateral diffusion from the microchannels was observed at 2 h post-irradiation. Our results revealed a time-dependent recovery of skin permeation. The time frame for applying the drugs after laser irradiation was dependent upon the permeants and their various physicochemical properties.

Organic Anion-Transporting Polypeptide 1a4 (Oatp1a4/Slco1a4) at the Blood-Arachnoid Barrier is the Major Pathway of Sulforhodamine-101 Clearance from Cerebrospinal Fluid of Rats.

The blood-arachnoid barrier (BAB), which is formed by arachnoid epithelial cells linked by tight junctions, has generally been considered impermeable to water-soluble substances. However, we recently demonstrated that organic anion transporters 1 and 3 (Oat1 and Oat3) play roles in drug clearance at the BAB. Here, we examined whether an organic anion-transporting polypeptide (Oatp) also plays a role, using the fluorescent organic anion sulforhodamine-101 (SR-101) as a model substrate. SR-101 was injected into the cisterna magna of rats in order to minimize the contribution of choroid plexus transport. The in vivo cerebrospinal fluid (CSF) elimination clearance of SR-101 after intracisternal administration was ninefold greater than that of fluorescein-labeled inulin, a bulk flow marker. In the case of pre-administration of taurocholate, a broad-spectrum inhibitor of Oatps, or digoxin, a strong substrate/inhibitor for Oatp1a4 but not for Oatp1a1, Oat1, and Oat3, the CSF elimination of SR-101 was significantly reduced, becoming similar to that of inulin, and thus indicating complete inhibition of SR-101 clearance from the CSF. The distribution of SR-101 fluorescence was restricted to the arachnoid mater in the absence of inhibitor, whereas the fluorescence was increased in the parenchyma of the spinal cord after co-injection of taurocholate or digoxin. Immunostaining confirmed the localization of Oatp1a4 in the arachnoid mater. These results indicate that Oatp1a4 at the BAB acts as an avid clearance pathway of SR-101 in the CSF to the blood. Thus, Oatp1a4 appears to play a major role in CSF detoxification by limiting the distribution of organic anions to the brain and spinal cord.

Evaluation of various tissue-clearing techniques for the three-dimensional visualization of liposome distribution in mouse lungs at the alveolar scale.

PURPOSE: To develop a three-dimensional visualization method for evaluating the distribution of pulmonary drug delivery systems and compare four tissue-clearing techniques (ClearT2, CUBIC, ScaleS, and SeeDB2) using intrapulmonary liposomes as drug carriers. METHODS: Rhodamine B-labeled liposomes were administered intrapulmonarily to mice using a MicroSprayer, and then fluorescent-labeled tomato lectin was administered intravenously to visualize the general lung structure. Tissue-clearing treatment of the mouse lungs was performed using the standard protocols of the ClearT2, CUBIC, ScaleS, and SeeDB2 techniques. Lung clearing was clarified using laser-scanning confocal microscopy, and three-dimensional images were reconstructed. RESULTS: Fluorescent-labeled tomato lectin was preserved using ClearT2 and SeeDB2 but not using CUBIC and ScaleS. In addition, the liposomes were stable in ClearT2 reagent, but they were mostly degraded in other reagents by surface-active agents. ClearT2 treatment enabled the three-dimensional visualization of intrapulmonary rhodamine B-labeled liposomes at the alveolar scale. CONCLUSIONS: These results suggest that the ClearT2 tissue-clearing technique was appropriate for the three-dimensional visualization of intrapulmonary liposomes at the alveolar scale. This study provides important information for selecting and optimizing suitable optical tissue-clearing techniques in lungs for evaluating the distribution of pulmonary drug delivery systems.

Silica-coated magnetic nanoparticles induce glucose metabolic dysfunction in vitro via the generation of reactive oxygen species.

Nanoparticles are a useful material in biomedicine given their unique properties and biocompatibility; however, there is increasing concern regarding the potential toxicity of nanoparticles with respect to cell metabolism. Some evidence suggests that nanoparticles can disrupt glucose and energy homeostasis. In this study, we investigated the metabolomic, transcriptomic, and integrated effects of silica-coated magnetic nanoparticles containing rhodamine B isothiocyanate dye [MNPs@SiO2(RITC)] on glucose metabolism in human embryonic kidney 293 (HEK293) cells. Using gas chromatography-tandem mass spectrometry, we analysed the metabolite profiles of 14 organic acids (OAs), 20 amino acids (AAs), and 13 fatty acids (FAs) after treatment with 0.1 or 1.0 µg/µl MNPs@SiO2(RITC) for 12 h. The metabolic changes were highly related to reactive oxygen species (ROS) generation and glucose metabolism. Additionally, effects on the combined metabolome and transcriptome or "metabotranscriptomic network" indicated a relationship between ROS generation and glucose metabolic dysfunction. In the experimental validation, MNPs@SiO2(RITC) treatment significantly decreased the amount of glucose in cells and was associated with a reduction in glucose uptake efficiency. Decreased glucose uptake efficiency was also related to ROS generation and impaired glucose metabolism in the metabotranscriptomic network. Our results suggest that exposure to high concentrations of MNPs@SiO2(RITC) produces maladaptive alterations in glucose metabolism and specifically glucose uptake as well as related metabolomic and transcriptomic disturbances via increased ROS generation. These findings further indicate that an integrated metabotranscriptomics approach provides useful and sensitive toxicological assessment for nanoparticles.

Highly Porous Silk Fibroin Scaffold Packed in PEGDA/Sucrose Microneedles for Controllable Transdermal Drug Delivery.

Polymeric microneedles have attracted increasing attention as a minimally invasive platform for delivering drugs or vaccines in a more patient-friendly manner. However, traditional microfabrication techniques using negative molds with needle-shaped cavities usually require cumbersome centrifugation and vacuum degassing processes, which have restricted the scaled-up mass production of polymeric microneedles. Herein, a novel polydimethylsiloxane (PDMS)-based negative mold with cavities packed with silk fibroin scaffold is developed for rapid fabrication of polymeric microneedles, which comprise primarily the composition of poly(ethylene glycol) diacrylate (PEGDA) and sucrose as the needle matrix. Fibroin scaffolds can instantly adsorb prepolymer solution due to capillary force, and subsequently initiate the formation of microneedles via photoinduced polymerization. Based on three types of model drugs, including Rhodamine B (RhB), indocyanine green (ICG), and doxorubicin (DOX), the fabricated PEGDA/sucrose microneedles can realize effective transdermal delivery and controllable release of therapeutic molecules by regulating the sucrose content. The presented method provides a simple strategy for quick fabrication of polymeric microneedles toward transdermal drug delivery applications.