Cuproptosis-Inducible Chemotherapeutic/Cascade Catalytic Reactor System for Combating with Breast Cancer.

Cascade hydroxyl radical generating hydrogel reactor structures including a chemotherapeutic agent are invented for multiple treatment of breast cancer. Glucose oxidase (GOx) and cupric sulfate (Cu) are introduced for transforming accumulated glucose (in cancer cells) to hydroxyl radicals for starvation/chemodynamic therapy. Cu may also suppress cancer cell growth via cuproptosis-mediated cell death. Berberine hydrochloride (BER) is engaged as a chemotherapeutic agent in the hydrogel reactor for combining with starvation/chemodynamic/cuproptosis therapeutic modalities. Moreover, Cu is participated as a gel crosslinker by coordinating with catechol groups in hyaluronic acid-dopamine (HD) polymer. Controlling viscoelasticity of hydrogel reactor can extend the retention time following local injection and provide sustained drug release patterns. Low biodegradation rate of designed HD/BER/GOx/Cu hydrogel can reduce dosing frequency in local cancer therapy and avoid invasiveness-related inconveniences. Especially, it is anticipated that HD/BER/GOx/Cu hydrogel system can be applied for reducing size of breast cancer prior to surgery as well as tumor growth suppression in clinical application.

Berberine and zinc oxide-based nanoparticles for the chemo-photothermal therapy of lung adenocarcinoma.

Organic/inorganic hydrid nanoparticles (NPs) composed of berberine (BER) and zinc oxide (ZnO) were developed for the therapy of lung cancers. Without the use of pharmaceutical excipients, NPs were fabricated with only dual anticancer agents (BER and ZnO) by facile blending method. The mean weight ratio between BER and ZnO in BER-ZnO NPs was 39:61 in this study. BER-ZnO NPs dispersed in water exhibited 200-300 nm hydrodynamic size under 5 mg/mL concentration. The exposure of both BER and ZnO in the outer layers of BER-ZnO NPs was identified by X-ray photoelectron spectroscopy analysis. The amorphization of BER and the maintenance of ZnO structure were observed in the results of X-ray powder diffractometer analysis. Improved antiproliferation efficacy, based on the chemo-photothermal therapeutic efficacy, of BER-ZnO NPs in A549 (human lung adenocarcinoma) cells was presented. According to the blood tests in rats after intravenous administration, BER-ZnO NPs did not induce severe hepatotoxicity, renal toxicity, and hemotoxicity. Developed BER-ZnO NPs can be used efficiently and safely for the chemo-photothermal therapy of lung cancers.

Eu(2+)-Activated Alkaline-Earth Halophosphates, M5(PO4)3X:Eu(2+) (M = Ca, Sr, Ba; X = F, Cl, Br) for NUV-LEDs: Site-Selective Crystal Field Effect.

Eu(2+)-activated M5(PO4)3X (M = Ca, Sr, Ba; X = F, Cl, Br) compounds providing different alkaline-earth metal and halide ions were successfully synthesized and characterized. The emission peak maxima of the M5(PO4)3Cl:Eu(2+) (M = Ca, Sr, Ba) compounds were blue-shifted from Ca to Ba (454 nm for Ca, 444 nm for Sr, and 434 nm for Ba), and those of the Sr5(PO4)3X:Eu(2+) (X = F, Cl, Br) compounds were red-shifted along the series of halides, F → Cl → Br (437 nm for F, 444 nm for Cl, and 448 nm for Br). The site selectivity and occupancy of the activator ions (Eu(2+)) in the M5(PO4)3X:Eu(2+) (M = Ca, Sr, Ba; X = F, Cl, Br) crystal lattices were estimated based on theoretical calculation of the 5d → 4f transition energies of Eu(2+) using LCAO. In combination with the photoluminescence measurements and theoretical calculation, it was elucidated that the Eu(2+) ions preferably enter the fully oxygen-coordinated sites in the M5(PO4)3X:Eu(2+) (M = Ca, Sr, Ba; X = F, Cl, Br) compounds. This trend can be well explained by "Pauling's rules". These compounds may provide a platform for modeling a new phosphor and application in the solid-state lighting field.

Luminescent properties of rare earth fully activated apatites, LiRE9(SiO4)6O2 (RE = Ce, Eu, and Tb): site selective crystal field effect.

Novel LiCe9(SiO4)6O2 and LiTb9(SiO4)6O2 compounds have been successfully synthesized, and the site selectivity and occupancy of activator ions have been estimated including LiEu9(SiO4)6O2 compound. The rare earth (RE) fully occupied compounds, as well as the RE partially occupied congeners are required for the assessment of site selectivity of RE (activator) ions in apatite-type compounds. The splitting energies of the 6H and 4F Wycoff positions of LiRE9(SiO4)6O2 (RE = Ce, Eu, and Tb) compounds are calculated based on crystal field theory: ΔECe(6H) = 3849.3 cm(-1), ΔECe(4F) = 4228.1 cm(-1), ΔEEu(6H) = 3870.0 cm(-1), ΔEEu(4F) = 4092.8 cm(-1), ΔETb(6H) = 3637.6 cm(-1), ΔETb(4F) = 4396.1 cm(-1), indicating that the splitting energy for the 4F site is larger than that for the 6H site in all compounds; thus the absorption energy is higher for the 6H site. In apatite-type LiRE9(SiO4)6O2 (RE = Ce, Eu, and Tb) compounds, the Ce(3+) ions predominantly occupy the 4F site associated with the absorption band around 300 nm at lower Ce(3+) concentration, and then enter the 6H site associated the absorption band around 245 nm. For the Eu(3+)-doped compounds, the 4F site and 6H site are mixed within the charge transfer band (CTB) between 220 and 350 nm. Eu(3+) ions initially preferentially occupy the 6H site (around 290 nm) at lower Eu(3+) concentration and subsequently enter the 4F site (around 320 nm) with increasing Eu(3+) concentration. For the Tb(3+)-doped compounds, the absorption due to the two different sites is mixed within f-d absorption band between 200 and 300 nm. At lower Tb(3+) concentration, the Tb(3+) ions enter favorably 6H site around 240 nm and then enter 4F site around 270 nm. These compounds may provide a platform for modeling a new phosphor and application in the solid-state lighting field.

Blue-emitting Eu2+-activated LaOX (X = Cl, Br, and I) materials: crystal field effect.

Novel blue-emitting LaOBr:Eu(2+) and LaOI:Eu(2+) phosphors have been successfully synthesized and compared to LaOCl:Eu(2+). The emission spectra of LaOX:Eu(2+) (X = Cl, Br, and I) show that the peak maxima change somewhat to the red-shift region; 425 nm for LaOCl:Eu(2+), 427 nm for LaOBr:Eu(2+), and 431 nm for LaOI:Eu(2+), which is quite opposite to one based on spectrochemical series (I(-) < Br(-) < Cl(-)). From diffuse reflectance spectra, the band gap energies for LaOCl, LaOBr, and LaOI host lattice are estimated as 5.53 eV (44,594 cm(-1)), 5.35 eV (43,142 cm(-1)), and 4.82 eV (38,868 cm(-1)), respectively, using the Kubelka-Munk function. For LaOX host lattices, the band gap energies are gradually decreased going from Cl to I as the order of energy levels of np orbitals is Cl 3p < Br 4p < I 5p. A quantum wave function calculation from crystal field theory (CFT) indicates the same tendency with experimental data in the LaOX:Eu(2+) (X = Cl, Br, and I) phosphor materials. With considerations of the radial wave function shape, crystral structure differences and electronegativities among phosphor materials, the splitting energies of 5d orbitals are calculaed; ΔECl = 14,597 cm(-1), ΔEBr = 14,864 cm(-1), ΔEI = 15,001 cm(-1) for LaOX:Eu(2+) (X = Cl, Br, and I). It is noteworthy that the crystal field strength decreases when the interatomic distance decreases, which is probably dependent on the ionic radius of halide ions in the series of LaOX:Eu(2+) phosphor materials.

Investigating the Immune-Stimulating Potential of ß-Glucan from Aureobasidium pullulans in Cancer Immunotherapy.

ß-glucan, a polysaccharide found in various sources, exhibits unique physicochemical properties, yet its high polymerization limits clinical applications because of its solubility. Addressing this limitation, we introduce PPTEE-glycan, a highly purified soluble ß-1,3/1,6-glucan derived from Aureobasidium pullulans. The refined PPTEE-glycan demonstrated robust immune stimulation in vitro, activated dendritic cells, and enhanced co-stimulatory markers, cytokines, and cross-presentation. Formulated as a PPTEE + microemulsion (ME), it elevated immune responses in vivo, promoting antigen-specific antibodies and CD8+ T cell proliferation. Intratumoral administration of PPTEE + ME in tumor-bearing mice induced notable tumor regression, which was linked to the activation of immunosuppressive cells. This study highlights the potential of high-purity Aureobasidium pullulans-derived ß-glucan, particularly PPTEE, as promising immune adjuvants, offering novel avenues for advancing cancer immunotherapy.

Hydrogel design to overcome thermal resistance and ROS detoxification in photothermal and photodynamic therapy of cancer.

Responsive heat resistance (by heat shock protein upregulation) and spontaneous reactive oxygen species (ROS) detoxification have been regarded as the major obstacles for photothermal/photodynamic therapy of cancer. To overcome the thermal resistance and improve ROS susceptibility in breast cancer therapy, Au ion-crosslinked hydrogels including indocyanine green (ICG) and polyphenol are devised. Au ion has been introduced for gel crosslinking (by catechol-Au3+ coordination), cellular glutathione depletion, and O2 production from cellular H2O2. ICG can generate singlet oxygen from O2 (for photodynamic therapy) and induce hyperthermia (for photothermal therapy) under the near-infrared laser exposure. (-)-Epigallocatechin gallate downregulates heat shock protein to overcome heat resistance during hyperthermia and exerts multiple anticancer functions in spite of its ironical antioxidant features. Those molecules are concinnously engaged in the hydrogel structure to offer fast gel transformation, syringe injection, self-restoration, and rheological tuning for augmented photo/chemotherapy of cancer. Intratumoral injection of multifunctional hydrogel efficiently suppressed the growth of primary breast cancer and completely eliminated the residual tumor mass. Proposed hydrogel system can be applied to tumor size reduction prior to surgery of breast cancer and the complete remission after its surgery.

Nanorod/nanodisk-integrated liquid crystalline systems for starvation, chemodynamic, and photothermal therapy of cancer.

Indocyanine green (ICG), glucose oxidase (GOx), and copper(II) sulfate (Cu)-installed hybrid gel based on organic nanorod (cellulose nanocrystal [CNC]) and inorganic nanodisk (Laponite [LAP]) was developed to perform a combination of starvation therapy (ST), chemodynamic therapy (CDT), and photothermal therapy (PTT) for localized cancers. A hybrid CNC/LAP network with a nematic phase was designed to enable instant gelation, controlled viscoelasticity, syringe injectability, and longer in vivo retention. Moreover, ICG was introduced into the CNC/LAP gel system to induce hyperthermia of tumor tissue, amplifying the CDT effect; GOx was used for glucose deprivation (related to the Warburg effect); and Cu was introduced for hydroxyl radical generation (based on Fenton-like chemistry) and cellular glutathione (GSH) degradation in cancer cells. The ICG/GOx/Cu-installed CNC/LAP gel in combination with near-infrared (NIR) laser realized improved antiproliferation, cellular reactive oxygen species (ROS) generation, cellular GSH degradation, and apoptosis induction in colorectal cancer (CT-26) cells. In addition, local injection of the CNC/ICG/GOx/Cu/LAP gel into the implanted CT-26 tumor while irradiating it with NIR laser provided strong tumor growth suppression effects. In conclusion, the designed hybrid nanorod/nanodisk gel network can be efficiently applied to the local PTT/ST/CDT of cancer cells.

Alum-tuned hyaluronic acid-based hydrogel with immune checkpoint inhibition for immunophoto therapy of cancer.

Alum-crosslinked hyaluronic acid-dopamine (HD) hydrogel containing indocyanine green (ICG) with anti-programmed cell death-1 (PD-1) antibody (Ab) administration was developed for immunophoto therapy of cancer. Alum modulates the rheological characteristics of hydrogel for enabling syringe injection, shear-thinning feature, and slower biodegradation. In addition, alum in HD-based hydrogel provided CD8+ T cell-mediated immune responses for cancer therapy. ICG in the hydrogel under near-infrared (NIR) light exposure may induce hyperthermia and generate singlet oxygen for selective cancer cell killing. HD/alum/ICG hydrogel injection with NIR laser irradiation elevated PD-1 level in CD8+ T cells. Administration of PD-1 Ab aiming at highly expressed PD-1 in T cells may amplify the anticancer efficacies of HD/alum/ICG hydrogel along with NIR laser. HD/alum/ICG hydrogel with NIR light may have both CD8+ T cell-linked immune responses and ICG-related photodynamic/photothermal effects. Additional injection of immune checkpoint inhibitor can ultimately suppress primary and distant tumor growth by combination with those therapeutic actions.

Manganese Sulfate Nanocomposites Fabricated by Hot-Melt Extrusion for Chemodynamic Therapy of Colorectal Cancer.

The development of metal salts-based nanocomposites is highly desired for the Fenton or Fenton-like reaction-based chemodynamic therapy of cancer. Manganese sulfate (MnSO4)-dispersed nanoparticles (NPs) were fabricated with a hot-melt extrusion (HME) system for the chemodynamic therapy of colorectal cancer in this study. MnSO4 was homogeneously distributed in polyethylene glycol (PEG) 6000 (as a hydrophilic polymer) with the aid of surfactants (Span 80 and Tween 80) by HME processing. Nano-size distribution was achieved after dispersing the pulverized extrudate of MnSO4-based composite in the aqueous media. The distribution of MnSO4 in HME extrudate and the interactions between MnSO4 and pharmaceutical additives were elucidated by Fourier-transform infrared, X-ray diffractometry, X-ray photoelectron spectroscopy, and scanning electron microscopy analyses. Hydroxyl radical generation efficiency by the Fenton-like chemistry capability of Mn2+ ion was also confirmed by catalytic assays. By using the intrinsic H2O2 in cancer cells, MnSO4 NPs provided an elevated cellular reactive oxygen species level, apoptosis induction capability, and antiproliferation efficiency. The designed HME-processed MnSO4 formulation can be efficiently used for the chemodynamic therapy of colorectal cancer.

Donepezil hydrochloride-reinforced cellulose nanocrystal-aggregated gel structure for long-acting drug delivery.

A donepezil hydrochloride (DPZ)-reinforced cellulose nanocrystal (CNC) hydrogel structure with pH control was developed for sustained drug delivery through subcutaneous injection. In the present study, an aggregated CNC gel was fabricated by reducing the electrostatic repulsion between CNC particles by incorporating DPZ and adjusting the pH value to 7.7. The crosslinked CNC/DPZ (cCNC/DPZ) gel exhibited immediate gelation, injection capability through a single syringe, improved viscoelasticity, and shear-thinning properties. Interactions between the CNCs and DPZ and pH regulation were assessed using several solid-state studies, and a sustained release profile of the DPZ from the cCNC/DPZ gel was also observed. In the pharmacokinetic study, a higher half-life and mean residence time and lower maximum drug concentration values were obtained in the cCNC/DPZ group than in the DPZ solution and CNC/DPZ groups after subcutaneous injection. Drug salt form-incorporated and pH-controlled CNC hydrogel systems can be safely applied to the subcutaneous delivery of DPZ.

Dreaming in sedation during spinal anesthesia: a comparison of propofol and midazolam infusion.

BACKGROUND: Although sedation is often performed during spinal anesthesia, the details of intraoperative dreaming have not been reported. We designed this prospective study to compare 2 different IV sedation protocols (propofol and midazolam infusion) with respect to dreaming during sedation. METHODS: Two hundred twenty adult patients were randomly assigned to 2 groups and received IV infusion of propofol or midazolam for deep sedation during spinal anesthesia. Patients were interviewed on emergence and 30 minutes later to determine the incidence, content, and nature of their dreams. Postoperatively, patient satisfaction with the sedation was also evaluated. RESULTS: Two hundred fifteen patients (108 and 107 in the propofol and midazolam groups, respectively) were included in the final analysis. The proportion of dreamers was 39.8% (43/108) in the propofol group and 12.1% (13/107) in the midazolam group (odds ratio=4.78; 95% confidence interval: 2.38 to 9.60). Dreams of the patients receiving propofol were more memorable and visually vivid than were those of the patients receiving midazolam infusion. The majority of dreams (36 of 56 dreamers, 64.3%) were simple, pleasant ruminations about everyday life. A similarly high level of satisfaction with the sedation was observed in both groups. CONCLUSIONS: In cases of spinal anesthesia with deep sedation, dreaming was almost 5 times more common in patients receiving propofol infusion than in those receiving midazolam, although this did not influence satisfaction with the sedation. Thus, one does not need to consider intraoperative dreaming when choosing propofol or midazolam as a sedative drug in patients undergoing spinal anesthesia.

Fenton-like reaction, glutathione reduction, and photothermal ablation-built-in hydrogels crosslinked by cupric sulfate for loco-regional cancer therapy.

Fenton-like reaction-associated chemodynamic therapy (CDT) and hyperthermia-inducing photothermal therapy (PTT)-combined crosslinked hydrogel systems were developed for loco-regional cancer therapy. Cupric sulfate (Cu) has been employed to crosslink the catechol-functionalized hyaluronic acid (HC) polymer-based gel via metal-catechol coordination and covalent bonding of the catechol group (by pH adjustment). Cu can also be used as a hydroxyl radical-generating agent with endogenous H2O2 in cancer cells mediated by Fenton-like reaction and it can reduce intracellular glutathione (GSH) levels leading to the inhibition of reactive oxygen species (ROS) scavenging. These two strategies can amplify the ROS-initiated CDT efficiency for combating cancer. The Cu-incorporated crosslinked hydrogel structure with pH modulation was appropriate for injectable gel formation via a single syringe. The incorporation of indocyanine green (ICG) into the hydrogel network and near-infrared (NIR) laser irradiation provided a temperature elevation sufficient for induction of hyperthermia in cancer therapy. It is expected that the designed HC/Cu/ICG hydrogel can be used safely and efficiently for local CDT and PTT of breast cancer.

Hyaluronidase Inhibitor-Incorporated Cross-Linked Hyaluronic Acid Hydrogels for Subcutaneous Injection.

Hyaluronidase (HAase) inhibitor-incorporated hyaluronic acid (HA) hydrogel cross-linked with 1,4-butanediol diglycidyl ether (BDDE) was designed to reduce the toxicity risk induced by BDDE and its biodegradation rate in subcutaneous tissue. The formulation composition of hydrogel and its preparation method were optimized to have a high swelling ratio and drug content. Quercetin (QCT) and quetiapine (QTP), as an HAase inhibitor and model drug, respectively, were incorporated into the cross-linked hydrogel using the antisolvent precipitation method for extending their release after subcutaneous injection. The cross-linked HA (cHA)-based hydrogels displayed appropriate viscoelasticity and injectability for subcutaneous injection. The incorporation of QCT (as an HAase inhibitor) in the cHA hydrogel formulation resulted in slower in vitro and in vivo degradation profiles compared to the hydrogel without QCT. Single dosing of optimized hydrogel injected via a subcutaneous route in rats did not induce any acute toxicities in the blood chemistry and histological staining studies. In the pharmacokinetic study of rats following subcutaneous injection, the cHA hydrogel with QCT exhibited a lower maximum QTP concentration and longer half-life and mean residence time values compared to the hydrogel without QCT. All of these results support the designed HAase inhibitor-incorporated cHA hydrogel being a biocompatible subcutaneous injection formulation for sustained drug delivery.

Fast dissolving nanofiber mat for the local antimicrobial application of roxithromycin in oral cavity.

Fast disintegrating and dissolving nanofiber (NF) mat was devised to deliver roxithromycin for the treatment of the respiratory tract infection. NF membrane was made by an electrospinning process with poly(vinyl alcohol) (PVA), hydroxypropyl-ß-cyclodextrin (HP-ß-CD), and d-α-tocopheryl polyethylene glycol succinate (TPGS) for local application of roxithromycin. Roxithromycin has a poor water solubility thus HP-ß-CD is introduced for enhancing drug solubility by forming an inclusion complex in this study. The addition of TPGS provided multiple roles such as accelerating wetting, disintegration, and dissolution speed and overcoming bacterial resistance. Roxithromycin was successfully entrapped in NF structure and drug amorphization occurred during the electrospinning process. PVA/HP-ß-CD/TPGS/roxithromycin (PHTR) NF exhibited faster wetting, disintegration, and dissolution speed rather than the other NF mats. PHTR NF displayed higher antibacterial potentials in Gram-negative bacteria (E. coli) and Gram-positive bacteria (S. aureus) compared to other NF mat formulations. The administration of PHTR NF to oral cavity in pneumococcal disease mouse model provided the most efficient therapeutic potentials in lung tissue. Designed multiple phase-based NF mat may be one of powerful local drug delivery systems for the therapy of respiratory tract infection.

Tanc2-mediated mTOR inhibition balances mTORC1/2 signaling in the developing mouse brain and human neurons.

mTOR signaling, involving mTORC1 and mTORC2 complexes, critically regulates neural development and is implicated in various brain disorders. However, we do not fully understand all of the upstream signaling components that can regulate mTOR signaling, especially in neurons. Here, we show a direct, regulated inhibition of mTOR by Tanc2, an adaptor/scaffolding protein with strong neurodevelopmental and psychiatric implications. While Tanc2-null mice show embryonic lethality, Tanc2-haploinsufficient mice survive but display mTORC1/2 hyperactivity accompanying synaptic and behavioral deficits reversed by mTOR-inhibiting rapamycin. Tanc2 interacts with and inhibits mTOR, which is suppressed by mTOR-activating serum or ketamine, a fast-acting antidepressant. Tanc2 and Deptor, also known to inhibit mTORC1/2 minimally affecting neurodevelopment, distinctly inhibit mTOR in early- and late-stage neurons. Lastly, Tanc2 inhibits mTORC1/2 in human neural progenitor cells and neurons. In summary, our findings show that Tanc2 is a mTORC1/2 inhibitor affecting neurodevelopment.

Attenuation of cell cycle progression by 2,3,7,8-tetrachlorodibenzo-p-dioxin eliciting ovulatory blockade in gonadotropin-primed immature rats.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) reduces ovulation rate in rats. The present study was to investigate whether TCDD alters the progression of cell cycle, and thus resulting in the blockade of ovulation in gonadotropin-primed, immature rats. The ovulation rate and ovarian weight were reduced in intact rats given TCDD (32 µg/kg BW in corn oil) by gavage one day before pregnant mare's serum gonadotropin (PMSG; 5 IU/rat) injection. Flow cytometry demonstrated that the percentage of granulosa cells in S-phase was increased at 24 h following PMSG treatment, but declined at 8 h following hCG treatment in corn oil-treated rats. Interestingly, the number of S-phase cells in TCDD-treated rats was reduced 24 and 48 h following PMSG treatment. TCDD, however, increased the percentage of cells in G2/M-phase at 24 h following PMSG treatment. TCDD inhibited the mRNA levels of Cdk2 at 0 h and 24 h, and cyclin D2 at 24 h and 48 h following PMSG treatment. Protein levels of aryl hydrocarbon receptor in granulosa cells were elevated in TCDD-treated rats at 12 h and 24 h following PMSG treatment. The present study indicates that TCDD reduces S-phase cells and inhibits levels of Cdk2 and cyclin D2 at 24 h following PMSG treatment, implying the ovulation-inhibiting action of TCDD may be exerted through the attenuation of cell cycle progression via AhR-mediated cascade.

A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum.

BACKGROUND: DLG2, also known as postsynaptic density protein-93 (PSD-93) or chapsyn-110, is an excitatory postsynaptic scaffolding protein that interacts with synaptic surface receptors and signaling molecules. A recent study has demonstrated that mutations in the DLG2 promoter region are significantly associated with autism spectrum disorder (ASD). Although DLG2 is well known as a schizophrenia-susceptibility gene, the mechanisms that link DLG2 gene disruption with ASD-like behaviors remain unclear. METHODS: Mice lacking exon 14 of the Dlg2 gene (Dlg2-/- mice) were used to investigate whether Dlg2 deletion leads to ASD-like behavioral abnormalities. To this end, we performed a battery of behavioral tests assessing locomotion, anxiety, sociability, and repetitive behaviors. In situ hybridization was performed to determine expression levels of Dlg2 mRNA in different mouse brain regions during embryonic and postnatal brain development. We also measured excitatory and inhibitory synaptic currents to determine the impacts of Dlg2 deletion on synaptic transmission in the dorsolateral striatum. RESULTS: Dlg2-/- mice showed hypoactivity in a novel environment. They also exhibited decreased social approach, but normal social novelty recognition, compared with wild-type animals. In addition, Dlg2-/- mice displayed strong self-grooming, both in home cages and novel environments. Dlg2 mRNA levels in the striatum were heightened until postnatal day 7 in mice, implying potential roles of DLG2 in the development of striatal connectivity. In addition, the frequency of excitatory, but not inhibitory, spontaneous postsynaptic currents in the Dlg2-/- dorsolateral striatum was significantly reduced. CONCLUSION: These results suggest that homozygous Dlg2 deletion in mice leads to ASD-like behavioral phenotypes, including social deficits and increased repetitive behaviors, as well as reductions in excitatory synaptic input onto dorsolateral spiny projection neurons, implying that the dorsal striatum is one of the brain regions vulnerable to the developmental dysregulation of DLG2.

Selenium and dopamine-crosslinked hyaluronic acid hydrogel for chemophotothermal cancer therapy.

Sodium selenite (Se)-directed crosslinked hydrogels based on hyaluronic acid (HA)-dopamine (HD), including indocyanine green (ICG), were developed for local therapy of breast cancer. Se can induce polymerization of dopamine (in HD conjugate) by making alkaline pH value, coordinate with the functional groups of HD, and kill cancer cells by pro-oxidant effects. ICG can be entrapped in the crosslinked HD/Se hydrogel network and long lasting photothermal efficacies can be maintained for cancer therapy. HD conjugate was synthesized via an amide linkage between carboxylic acid group of HA and amine group of dopamine. HD/Se gel was fabricated by covalent bonding of dopamine group (in HD conjugate) and the coordination between selenium and functional groups of HD. Controlled rheological properties of HD/Se/ICG gel may provide easy injectability and slow biodegradability. Sufficient photothermal efficiencies were acquired after near-infrared (NIR) laser irradiation. HD/Se/ICG gel structure was remained in the mouse for 2 weeks and severe systemic toxicities were not observed in blood and histological assays. Intratumoral injection of HD/Se/ICG gel with NIR laser irradiation provided the most efficient tumor growth inhibition capability without severe systemic toxicities. HD/Se/ICG hydrogel structure can be introduced as a promising multifunctional platform for local therapy of breast cancers.

Possible contribution of sialic acid to the enhanced tumor targeting efficiency of nanoparticles engineered with doxorubicin.

Doxorubicin (DOX)-engineered poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) including phloretin (PHL) were designed and the feasible contribution of sialic acid (SA) to the improved tumor targeting and penetration capabilities was elucidated in lung adenocarcinoma models. DOX has been clinically used as liposomal formulations after its introduction to the inner side of vehicles, however DOX is anchored in the outer surface of PLGA NPs for improved tumor penetration by interactions with SA in this study. DOX (positively charged at physiological pH) was adsorbed onto the negatively charged PLGA NPs via electrostatic interactions and consequent binding of SA (negatively charged at physiological pH) to DOX located in NPs was also elucidated. DOX layer in DOX@PLGA NPs rendered improved endocytosis and partial contribution of SA (expressed in cancer cells) to that endocytosis was demonstrated. DOX@PLGA/PHL NPs provided enhanced antiproliferation potentials in A549 cells rather than single agent (DOX or PHL)-installed NPs. In addition, DOX-SA interactions seemed to play critical roles in tumor infiltration and accumulation of DOX@PLGA NPs in A549 tumor-xenografted mouse model. All these findings support the novel use of DOX which is used for the surface engineering of NPs for improved tumor targeting and penetration.