Fucoidan-based, tumor-activated nanoplatform for overcoming hypoxia and enhancing photodynamic therapy and antitumor immunity.

Multifunctional nanoplatforms combined with photodynamic therapy (PDT) and anticancer drugs have shown great promising in cancer therapy. However, their efficacy is limited by the low specificity, low oxygen levels, and a tolerant tumor immune microenvironment. Herein, we developed a biocompatible theranostic nanoplatform (FM@VP) based on co-assembly of a nanocomplex formed by a functional polysaccharide fucoidan and a bioreducible polyamidoamine (PAMAM) dendrimer, a photosensitizer verteporfin (VP), and MnO2 nanoparticles (a tumor microenvironment responsive oxygen evolving nanomaterial) into a multifunctional nanoparticle cluster. The dendrimer-fucoidan polyionic nanocomplex (DFPN) specifically targeted P-selectin-overexpressed triple-negative breast cancer (TNBC) and the tumor-associated vasculature, and was sensitive to glutathione (GSH) in tumor. More importantly, this FM@VP nanocomplex simultaneously overcame tumor hypoxia, suppressed oncogenic signaling, and attenuated tumor-mediated immunosuppression, resulting in improving therapeutic efficacy of PDT while enhancing antitumor immunity and anti-metastasis. This discovery provides a powerful strategy for synergetic cancer targeting/photodynamic/immunotherapy and could serve as a safe clinical translational approach.

Correction: Evaluation of a novel biodegradable thermosensitive keto-hydrogel for improving postoperative pain in a rat model.

[This corrects the article DOI: 10.1371/journal.pone.0186784.].

Evaluation of a novel biodegradable thermosensitive keto-hydrogel for improving postoperative pain in a rat model.

This study evaluates the sustained analgesic effect of ketorolac-eluting thermosensitive biodegradable hydrogel in the plantar incisional pain model of the rat hind-paw. A ketorolac-embedded 2, 2'-Bis (2-oxazolin) (BOX) linking methoxy-poly(ethylene glycol) and poly(lactide-co-glycolide) (mPEG-PLGA) diblock copolymer (BOX copolymer) was synthesized as keto-hydrogel based on optimal sol-gel phase transition and in vitro drug release profile. The effect of keto-hydrogel on postoperative pain (POP) was assessed using the established plantar incisional pain model in hind-paw of rats and compared to that of ketorolac solution. Pain and sensory threshold, as well as pain scoring, were evaluated with behavioral tests by means of anesthesiometer and incapacitance apparatus, respectively. Pro-inflammatory cytokine levels (TNF-α, IL-6, VEGF, and IL-1ß) around incisional wounds were measured by ELISA. Tissue histology was assessed using hematoxylin and eosin and Masson's trichrome staining. Ten mg/mL (25 wt%) keto-hydrogel showed a sol-gel transition at 26.4°C with a 10-day sustained drug release profile in vitro. Compared to ketorolac solution group, the concentration of ketorolac in tissue fluid was higher in the keto-hydrogel group during the first 18 h of application. Keto-hydrogel elevated pain and sensory threshold, increased weight-bearing capacity, and significantly reduced the levels of TNF-α, IL-6, and IL-1ß while enhanced VEGF in tissue fluid. Histologic analysis reveals greater epithelialization and collagen deposition around wound treated with keto-hydrogel. In conclusion, our study suggests that keto-hydrogel is an ideal compound to treat POP with a secondary gain of improved incisional wound healing.

Intravitreal triamcinolone injection for macular edema secondary to increased retinal vascular permeability.

BACKGROUND AND PURPOSE: Macular edema is an important cause of visual loss in various retinal diseases, and may be refractory to conventional treatment. We investigated the efficacy of intravitreal injection of triamcinolone acetonide for the treatment of intractable macular edema. METHODS: A prospective study was conducted in 17 patients (18 eyes) with a diagnosis of macular edema unresponsive to conventional treatment, resulting from inflammatory or retinal vascular diseases. The underlying diseases associated with the development of macular edema were: diabetic retinopathy (6 eyes), branch retinal vein occlusion (5 eyes), Irvine-Gass syndrome (3 eyes), and central retinal vein occlusion (4 eyes). Triamcinolone acetonide 4 mg was injected intravitreally. Ophthalmological examinations, fundus photography, fluorescein angiography, and optical coherence tomography were performed before treatment, 3 months and 6 months after treatment. During the follow-up period, recurrent macular edema was retreated with the same dosage and followed for another 6 months. RESULTS: Sixteen eyes received a single injection and 2 others (11%) underwent reinjection after the 3-month follow-up examination. Among the eyes that received a single injection, 10 (63%) showed visual acuity gain of 2 or more Snellen lines at the 6-month follow-up. The pretreatment central macular thickness averaged 581 microm [corrected] and reduced to 215 microm [corrected] at the 6-month follow-up. In the 2 eyes that received reinjection, macular edema also showed significant reduction 6 months after retreatment. Sterile endophthalmitis was noted in 3 eyes (17%). Two eyes (11%) developed significant cataract. Three eyes (17%) developed high intraocular pressure; 1 of them (5.5%) ultimately required filtering surgery. CONCLUSIONS: Intravitreal injection of triamcinolone temporarily reduced refractory macular edema. Potential complications should be monitored after treatment.

Effects of surface modification of PLGA-PEG-PLGA nanoparticles on loperamide delivery efficiency across the blood-brain barrier.

In this study, we developed a nanoparticle system for drug delivery across the blood-brain barrier (BBB). The nanoparticle consisting of loperamide and poly(lactide-co-glycolide)-poly(ethylene glycol)-poly(lactide-co-glycolide) (PLGA-PEG-PLGA) triblock copolymer were prepared by the nanoprecipitation method; then the nanoparticles were coated with poloxamer 188 or polysorbate 80. The effects of poloxamer 188 or polysorbate 80 on the physicochemical and pharmaceutical properties of the coated nanoparticles were investigated. Loperamide, which does not cross the blood-brain barrier (BBB) but exerts antinociceptive effects after direct injection into the brain, was encapsulated by different polymeric materials and used as a model drug. The in vitro BBB penetration study shows that the surfactant-coated PLGA-PEG-PLGA nanoparticles could have penetration of 14.4-21.2%, which was better than the PLGA-PEG-PLGA nanoparticles (PEP) (8.2%) and the PLGA nanoparticles (PN) (4.3%). The biopsy studies also confirm that the PEP coated by surfactant could increase the penetration. The results of nanoparticles accumulation in brain tissue show that the PEP coated by surfactant had a much higher concentration than both the PEP and the PN. Moreover, the maximal possible antinociception effect (MPE) for the surfactant-coated PEP was 21-35% at 150 min after administering the drug intravenously, which was significantly better than just the PEP (MPE: 11.6%). The results of the formalin test show that the surfactant-coated PEP administered intravenously 150 min prior to the formalin injection could greatly reduce the pain response in the first phase. The results demonstrate that the surfactant-coated PEP could help to deliver loperamide across the BBB.

Paclitaxel and iron oxide loaded multifunctional nanoparticles for chemotherapy, fluorescence properties, and magnetic resonance imaging.

The multifunctional nanoparticles constructed from triphenylamine-poly(lactide-co-glycolide)-poly(ethyleneglycol)-poly(lactide-co-glycolide) (TPA-PEP) and folate-poly(2-ethyl-2oxazoline)-poly(D,L-lactide) (folate-PEOz-PLA) were developed in this study. Iron oxide nanoparticles (IOP) and paclitaxel (PTX) were coencapsulated in the nanoparticles with diameter less than 200 nm. The drug-loaded nanoparticles emit fluorescence peak at 460 nm when excited with wavelength of 350 nm. The in vitro antitumor activity of the drug-loaded nanoparticles was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays against HeLa cells. When the cells were exposed to the nanoparticles with different levels of folate but the same drug loading, cell viability decreases as the level of folate increases. Confocal laser scanning microscopy (CLSM) analysis shows that cellular uptake is lower for the non-folate-nanoparticles than that for the folate-nanoparticles. The in vitro and in vivo magnetic resonance imaging (MRI) studies indicate the better T2-Weighted images can be obtained for the folate-nanoparticles. In the anticancer effect evaluation, tumor-bearing mice administered with the 30%-folate-nanoparticles showed ~50% reduction in tumor volume after 23 days. The multifunctional nanoparticles as drug carrier with capabilities of both tumor-targeting and MRI present a new direction in drug delivery system development.

Learning-based prediction of visual attention for video signals.

Visual attention, which is an important characteristic of human visual system, is a useful clue for image processing and compression applications in the real world. This paper proposes a computational scheme that adopts both low-level and high-level features to predict visual attention from video signal by machine learning. The adoption of low-level features (color, orientation, and motion) is based on the study of visual cells, and the adoption of the human face as a high-level feature is based on the study of media communications. We show that such a scheme is more robust than those using purely single low- or high-level features. Unlike conventional techniques, our scheme is able to learn the relationship between features and visual attention to avoid perceptual mismatch between the estimated salience and the actual human fixation. We also show that selecting the representative training samples according to the fixation distribution improves the efficacy of regressive training. Experimental results are shown to demonstrate the advantages of the proposed scheme.

Synthesis and drug-release behavior of porous biodegradable amphiphilic co-polymeric hydrogels.

A series of amphiphilic random block co-polymers were synthesized by the condensation of hydrophobic polycaprolactone diol (PCL diol) with hydrophilic dicarboxy poly(ethylene glycol) (PEG-diacid), obtained by reacting poly(ethylene glycol) (PEG) with succinic anhydride. The PEG/PCL random block co-polymers were then acrylated with acryloyl chloride to form PEG/PCL diacrylates (PCEdA), and then characterized by FT-IR, (1)H-NMR and GPC. The porous biodegradable gels were prepared through photo-polymerization of the PCEdA dissolved in DMSO at low temperature. Thermal behavior, swelling ratio and morphological characteristics as well as biodegradability of the presented gels were investigated. Results showed that the swelling ratio of the gel in deionized water increased with an increase of the PEG chain length in the copolymeric gel. DSC thermograms indicated that the melting point of the PCEdA was lower than that of PCL and PEG blocks, but a new crystalline peak of the co-polymeric gel appeared with increasing of the segmental length of the PEG. Thermal stability of PCE gel was higher than that of PCE diol. The pore size of the gel was influenced by the concentration of PCEdA. The drug-release behavior of PCE gels was also investigated.

Effect of gelatin on the drug release behaviors for the organic hybrid gels based on N-isopropylacrylamide and gelatin.

A series of organic hybrid gels were prepared based on poly(N-isopropylacrylamide), poly(NIPAAm), and gelatin. The hybrid gels were crosslinked through a two-step process with genipin or glutaraldehyde. The swelling behavior and physical properties of the gels were investigated in the previous report. In this study, we loaded sulfanilamide, caffeine, vitamin B12, phenol red, and neutral red in the hybrid gels. The effects of gelatin on the drug release profile were demonstrated. The ionicity of hybrid gels strongly influenced the release of phenol red (anionic) and neutral red (cationic). However, the releases of sulfanilamide, caffeine and vitamin B12 were not influenced by the ionicity of hybrid gel. The drug released from the gels crosslinked with genipin was significantly smaller than that released from the gels crosslinked with glutaraldehyde.