[Safety and Effectiveness of NEPTIS Plug-01 and Florbetapir (18F) in Daily Clinical Setting: Based on the Post-Marketing Surveillance Study].

OBJECTIVE: Obtaining the information on safety and effectiveness of radiopharmaceutical synthesizer NEPTIS plug - 01 and florbetapir (18F) injection solution synthesized by NEPTIS plug - 01 from the post marketing surveillance study. METHODS: Regarding the safety evaluation, failure of device and adverse events were recorded. Regarding the effectiveness evaluation, we assessed the quality of PET images and the impact on the clinical diagnosis. RESULT: During the study period, 12 patients were enrolled. No adverse event was reported from those 12 patients. Two events in 2 patients were reported as a failure of device (In a subsequent investigation, those failures were thought to be caused by inadequacy of procedure manual, which has been revised now). For the quality of PET images, all 12 cases were "good" or "excellent", regardless of the positive or negative of amyloid plaque. The attending physician's diagnosis was changed in 9 patients following the PET imaging. CONCLUSION: NEPTIS plug-01 and florbetapir (18F) were safe and has a favorable effectiveness profile in 12 patients under daily clinical setting.

Tailor-Engineered POSS-Based Hybrid Gels for Bone Regeneration.

Organic-inorganic oligo(ethylene glycol)-polyhedral oligomeric silsesquioxanes (OEGn-POSS) hybrid materials are woven into macroscopically shaped entities by thiol-ene chemistry. The mechanical behavior and interfacial nature of the OEGn-POSS materials are easily tailored by changing the length of OEGn. The nanostructured OEGn-POSS materials exhibited excellent bioactivity to form hydroxyapatite, whose morphology was also dependent on the molecular weight of OEGn. Among them, OEG2-POSS materials enhanced the in vitro differentiation of adipose-derived stem cells to osteoblasts and promoted the in vivo bone formation within a femoral condyle defect site, but they could be limited by the mismatch rates between the degradation and new bone formation. Thus, OEG2-POSS could be practically applied for bone regeneration by optimizing the degradation rate based on its key structural features, which would be of great benefit to bone tissue engineering in the future.

Dual-responsive nanoparticles based on chitosan for enhanced breast cancer therapy.

In this study, we report a novel pH and temperature responsive paclitaxel-loaded drug delivery system based on chitosan and di(ethylene glycol) methyl ether methacrylate. This was functionalized with hyaluronic acid to permit active targeting of CD44-overexpressing human breast cancer cells. The resultant HA-CS-g-PDEGMA-PTX nanoparticles (NPs) have small and uniform sizes (˜170 nm), a high drug loading (13.6 ±â€¯1.3%) and high encapsulation efficiency (76.2 ±â€¯8.5%). Cell viability and confocal microscopy experiments demonstrated that the NPs could effectively target and kill MDA-MB-231 human breast cancer cells, but were much less toxic to healthy human umbilical vein endothelial cells. In vivo biodistribution studies in mice showed that the NPs accumulated in the tumor site, while free drug was distributed more widely and rapidly cleared from the body. Histopathological studies revealed that the NPs led to enhanced apoptosis in the tumor site, which resulted in reduced tumor growth. The NPs prepared in this work have great potential for the treatment of breast cancers, and further offer a platform with which to target other cancers.

Synthesis of ( R)- and ( S)-Fmoc-Protected Diethylene Glycol Gamma PNA Monomers with High Optical Purity.

A robust synthetic route has been developed for preparing optically pure, Fmoc-protected diethylene glycol-containing ( R)- and ( S)-γPNA monomers. The strategy involves the application of 9-(4-bromophenyl)-9-fluorenyl as a temporary, safety-catch protecting group for the suppression of epimerization in the O-alkylation and reductive amination steps. The optical purities of the final monomers were determined to be greater than 99.5% ee, as assessed by 19F-NMR and HPLC. The new synthetic methodology is well-suited for large-scale monomer production, with most synthetic steps providing excellent chemical yields without the need for chromatographic purification other than a simple workup and precipitation.

Development of a daphnetin transdermal patch using chemical enhancer strategy: insights of the enhancement effect of Transcutol P and the assessment of pharmacodynamics.

OBJECTIVE: The aim of this study was to develop a drug-in-adhesive patch for transdermal delivery of daphnetin (DA), which is a coumarin derivative in Girald Daphne, and to investigate the role of Transcutol P (TP) in the release and percutaneous permeation processes of DA. METHODS: Backing films, permeation enhancers and enhancer content in the transdermal patch were investigated through in vitro experiments using rat skin. Anti-inflammatory and analgesic effects of the optimized formulation were evaluated using the adjuvant arthritis model and the pain model induced by acetic acid, respectively. In addition, the enhancement effect of TP was investigated using differential scanning calorimetry (DSC), FTIR, and molecular dynamic simulation. RESULTS: The optimal formulation, composed of DURO-TAK® 87-2852, CoTranTM 9680, 1% DA, and 10% TP showed anti-inflammatory and analgesic effects. It was found that TP only promoted the release process of DA from its transdermal patch. Furthermore, the decrease of interaction between drug and pressure sensitive adhesive (PSA) as well as the improvement of PSA mobility due to TP addition were the main factors that enhanced the release of DA from patch. CONCLUSIONS: This study successfully used TP to develop a DA patch with good anti-inflammatory and analgesic effects, proving that TP promotes the release of DA by reducing the interaction between DA and PSA and increasing the mobility of PSA.

Detailed Analysis of Pancreatic Tumor Cell Attachment on Gradient PDEGMA Brushes.

Poly(di(ethylene glycol) methyl ether methacrylate) (PDEGMA) brushes show interesting thermoresponsive behavior that can be applied for cell release surfaces. Here it is shown that PDEGMA thickness gradients, which are synthesized by surface-initiated atom transfer radical polymerization, allow the systematic and precise analysis of the attachment of PaTu 8988 cells. By pumping the polymerization solution into the reactor with vertically fixed initiator samples, PDEGMA gradients with linearly increasing dry ellipsometric thickness with typical slopes of 2.5 nm cm-1 are obtained. A very narrow transition of PaTu 8988t cell attachment is observed that starts for a thickness larger than 7.1 ± 0.2 nm. For PDEGMA layers thicker than 8.7 ± 0.2 nm no attached cells are found. This very narrow transition in brush properties within a thickness difference of <2 nm from cell-adherent to cell-nonadherent can be determined in much greater detail than before owing to the thickness gradients with shallow slope.

Targeted glioma chemotherapy by cyclic RGD peptide-functionalized reversibly core-crosslinked multifunctional poly(ethylene glycol)-b-poly(ε-caprolactone) micelles.

Cyclic RGD peptide-functionalized reversibly core-crosslinked biodegradable poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-PCL) micelles (cRGD-RCCMs) were designed and developed for highly potent and targeted glioma chemotherapy. To achieve crosslinkable core, dithiolane-functionalized trimethylene carbonate (DTC) was incorporated into PCL block. Interestingly, cRGD-RCCMs displayed a high doxorubicin (DOX) loading content of ∼18wt%, small hydrodynamic size of ∼50nm, and excellent colloidal stability with minimum drug leakage under physiological conditions while fast DOX release under cytoplasmic-mimicking reductive environments. MTT, confocal microscopy and flow cytometry measurement results pointed out that cRGD-RCCMs with 30% cRGD surface density (cRGD30-RCCMs) showed an evident selectivity, efficient cytoplasmic drug release, and superior antitumor activity to clinically used pegylated liposomal doxorubicin (DOX-LPs) in αvß3 integrin overexpressing U87MG glioblastoma cells. Strikingly, DOX-loaded cRGD30-RCCMs demonstrated a prolonged circulation time showing an elimination half-life of ∼4.7h, three times exceeding that of the non-crosslinked counterparts, and a remarkably enhanced tumor accumulation of 7.7%ID/g. Furthermore, in vivo therapeutic studies revealed that DOX-loaded cRGD30-RCCMs effectively suppressed tumor growth, significantly prolonged survival time, and lessened side effects in subcutaneous U87MG glioblastoma-bearing nude mice. These reversibly core-crosslinked multifunctional biodegradable micelles might be developed into advanced and clinically viable targeted anticancer nanomedicines. STATEMENT OF SIGNIFICANCE: Nanomedicines based on biodegradable micelles and nanoparticles offer a most promising treatment for malignant tumors. The therapeutic outcomes of current nanomedicines are, however, trimmed by their instability, low tumor retention, inefficient tumor cell uptake, and inferior drug release control. We report herein that cRGD-functionalized, rapidly glutathione-responsive, and reversibly core-crosslinked biodegradable micellar doxorubicin based on PEG-PCL block copolymer mediates potent and targeted glioma chemotherapy, affording significantly better treatment efficacy and lower systemic toxicity than the non-crosslinked micellar doxorubicin and clinically used pegylated liposomal doxorubicin controls. These reversibly core-crosslinked multifunctional biodegradable micelles have emerged as a robust, simple, versatile, and safe nanoplatform that might elegantly bridge the gap between the scientific and translational anticancer nanomedicine research.

Design, synthesis and pharmacological evaluation of 4-hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives as GPR88 agonists.

The orphan receptor GPR88 is an attractive therapeutic target because of its implications in a number of basal ganglia-associated disorders. To date, pharmacological characterization of GPR88 has been limited due to the lack of potent and selective agonists and antagonists appropriate for CNS investigations. We have previously reported that GPR88 couples to Gαi proteins and modulates cAMP levels upon treatment with a small molecule agonist 2-PCCA. Recently, another chemotype of GPR88 agonist, represented by 2-AMPP [(2S)-N-((1R)-2-amino-1-(4-(2-methylpentyloxy)-phenyl)ethyl)-2-phenylpropanamide], has also been discovered. In this report, a new series of 2-AMPP structurally related 4-hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives have been designed and evaluated for agonist activity at GPR88. The structure-activity relationship (SAR) studies suggest that the amine group in 2-AMPP can be replaced by hydroxyl, ester and amide groups, resulting in analogues with good to moderate potency, whereas the phenyl group on the amide cap is essential for activity and has limited size, shape and electronic tolerance.

Supramolecular Hydrogel from Nanoparticles and Cyclodextrins for Local and Sustained Nanoparticle Delivery.

Injectable and biodegradable supramolecular hydrogel mPECT NP/α-CD(gel) composed of high-concentration nanoparticle dispersion (≤20% W/V) and α-cyclodextrins (α-CD) are prepared by a two-level physical cross-linking using amphiphilic block polymer methoxy poly(ethylene glycol)-b-poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (mPECT) and α-CD. The gelation behavior depends on the concentration of nanoparticles and α-CD. The viscoelasticity and shear thinning of mPECT NP/α-CD(gel) are confirmed. In vitro hydrogel erosion is demonstrated to be mainly a concentration-dependent dissociation process with general release of discrete mPECT nanoparticles about 50 nm that can be easily taken up by cells. The in vitro release behavior can be modulated by changing the concentration of nanoparticles or α-CD. In vitro and in vivo cytotoxicity study demonstrates its biocompatibility and biosafety. Gel formation after subcutaneous injection is also confirmed and mPECT NP/α-CD(gel) shows about 2 weeks retention time. This work validates the potential application for this supramolecular hydrogel in local and sustained delivery of nanoparticles.

Reversible Interactions of Proteins with Mixed Shell Polymeric Micelles: Tuning the Surface Hydrophobic/Hydrophilic Balance toward Efficient Artificial Chaperones.

Molecular chaperones can elegantly fine-tune its hydrophobic/hydrophilic balance to assist a broad spectrum of nascent polypeptide chains to fold properly. Such precious property is difficult to be achieved by chaperone mimicking materials due to limited control of their surface characteristics that dictate interactions with unfolded protein intermediates. Mixed shell polymeric micelles (MSPMs), which consist of two kinds of dissimilar polymeric chains in the micellar shell, offer a convenient way to fine-tune surface properties of polymeric nanoparticles. In the current work, we have fabricated ca. 30 kinds of MSPMs with finely tunable hydrophilic/hydrophobic surface properties. We investigated the respective roles of thermosensitive and hydrophilic polymeric chains in the thermodenaturation protection of proteins down to the molecular structure. Although the three kinds of thermosensitive polymers investigated herein can form collapsed hydrophobic domains on the micellar surface, we found distinct capability to capture and release unfolded protein intermediates, due to their respective affinity for proteins. Meanwhile, in terms of the hydrophilic polymeric chains in the micellar shell, poly(ethylene glycol) (PEG) excels in assisting unfolded protein intermediates to refold properly via interacting with the refolding intermediates, resulting in enhanced chaperone efficiency. However, another hydrophilic polymer-poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) severely deteriorates the chaperone efficiency of MSPMs, due to its protein-resistant properties. Judicious combination of thermosensitive and hydrophilic chains in the micellar shell lead to MSPM-based artificial chaperones with optimal efficacy.

Nucleophilic Hydroxylation in Water Media Promoted by a Hexa-Ethylene Glycol-Bridged Dicationic Ionic Liquid.

Hexaethylene glycol bis(3-hexaethylene glycol imidazolium) dimesylate ionic liquid (hexaEG-DHIM) was designed and prepared as a highly efficient promoter for the nucleophilic hydroxylation of alkyl halides to the corresponding alcohol products in neat water media. It was observed that hexaEG-DHIM promoter enhanced the nucleophilicity of water significantly in the reaction. In addition, the hexaEG-DHIM could be reused several times without loss of activity. Moreover, the hydroxylation reactions of base-sensitive and/or polar alkyl halide substrates proceeded highly chemoselectively in excellent yields.

Construction of a portable sample preparation device with a magnetic poly(methacrylic acid-co-ethylene dimethacrylate) monolith as the extraction medium and its application in the enrichment of UV filters in water samples.

A portable sample preparation device with a magnetic polymer monolith as the extraction medium was constructed. The monolith was synthesized by polymerizing methacrylic acid and ethylene dimethacrylate around a cylindrical magnet. In this way, the monolith with a magnetic core could be readily attached to the extraction device by magnetism. The constructed device was evaluated for the enrichment of UV filters in water samples, followed by high-performance liquid chromatographic analysis. The extraction efficiency for the targets was satisfactory with no matrix interference. Good linearities were obtained for the UV filters with the correlation coefficients >0.9986. The limits of detection and quantification for the UV filters were 0.3-0.8 and 1.0-2.4 ng/mL, respectively. The recoveries of the UV filters from the spiked water samples at the concentration of 100 ng/mL were 95.3-101.7%, with relative standard deviations <10%. Accordingly, the proposed portable device was demonstrated to be suitable for on-site simultaneous sampling, purification, and preconcentration within a single step.

Polymeric micelle assembly for preparation of large-sized mesoporous metal oxides with various compositions.

Here we report the synthesis of mesoporous metal oxide materials with various compositions by assembly of spherical polymeric micelles consisting of triblock copolymer poly(styrene-b-2-vinyl pyridine-b-ethylene oxide) (PS-b-PVP-b-PEO) with three chemically distinct units. The PVP block interacts strongly with the inorganic precursors for the target compositions. The hydrophobic PS block is kinetically frozen in the precursor solutions, enabling the spherical micelles to remain in a stable form. The frozen PS cores serve as templates for preparing robust mesoporous materials. The PEO corona helps the micelles to stay well dispersed in the precursor solutions, which plays a key role in the orderly arrangement of the micelles during solvent evaporation. This approach is based on assembly of the stable micelles using a simple, highly reproducible method and is widely applicable toward numerous compositions that are difficult for the formation of mesoporous structures.

Tackling lipophilicity of peptide drugs: replacement of the backbone N-methyl group of cilengitide by N-oligoethylene glycol (N-OEG) chains.

Cilengitide is an RGD-peptide of sequence cyclo[RGDfNMeV] that was was developed as a highly active and selective ligand for the αvß3 and αvß5 integrin receptors. We describe the synthesis of three analogues of this peptide in which the N-Me group has been replaced by N-oligoethylene glycol (N-OEG) chains of increasing size: namely N-OEG2, N-OEG11, and N-OEG23, which are respectively composed of 2, 11, and 23 ethylene oxide monomer units. The different N-OEG cyclopeptides and the original peptide were compared with respect to lipophilicity and biological activity. The N-OEG2 analogue was straightforward to synthesize in solid phase using an Fmoc-N-OEG2 building block. The syntheses of the N-OEG11 and N-OEG23 cyclopeptides are hampered by the increased steric hindrance of the N-substituent, and could only be achieved by segment coupling, which takes place with epimerization and thus requires extensive product purification. All the N-OEG analogues were found to be more hydrophobic than the parent peptide, and their hydrophobicity was systematically enhanced upon increasing the length of the OEG chain. The N-OEG2 cyclopeptide displayed the same capacity as Cilengitide to inhibit the integrin-mediated adhesion of HUVEC endothelial, DAOY gliobastoma, and HT-29 colon cancer cells to their ligands vitronectin and fibrinogen. The N-OEG11 and N-OEG23 analogues also inhibited cell adhesion to these immobilized ligands, but their IC50 values dropped by 1 order of magnitude with respect to the parent peptide. These results indicate that replacement of the backbone N-Me group of Cilengitide by a short N-OEG chain provides a more lipophilic analogue with a similar biological activity. Upon increasing the size of the N-OEG chain, liophilicity is enhanced, but synthetic yields drop and the longer polymer chains may impede targeted binding.

Positron emission tomography radioligands for in vivo imaging of Aß plaques.

The development of positron emission tomography (PET) radioligands for the non-invasive imaging of amyloid-ß plaque burden has been the focus of intense research efforts over the last decade. A variety of structural backbones have been investigated and several radiolabeled molecules have been evaluated in phase I (and later) clinical studies. These efforts have been driven by the desire not only to develop a suitable diagnostic imaging agent but also to develop a means to evaluate potential therapies for Alzheimer's disease. This review focuses on the development of these ligands, as well as the radiochemistry and current regulatory status of these PET radioligands. Particular attention is given to those ligands that have progressed to the later stages of drug development (phase II/III clinical trial studies) or approved New Drug Application status.

Preparation and stability of ethanol-free solution of [18F]florbetapir ([18F]AV-45) for positron emission tomography amyloid imaging.

We have developed an ethanol-free formulation method of [(18) F]florbetapir ([(1) (8) F]AV-45) using a commercially available automated JFE multi-purpose synthesizer. We have also evaluated the radiochemical stability in an ethanol-free solution of [(18) F]AV-45 under visible light irradiation and dark conditions by comparison with a conventional 10% ethanol solution of [(18) F]AV-45. [(18) F]AV-45 was obtained with a radiochemical yield of 55.1 ± 2.2% (decay-corrected to end of bombardment), specific activity of 591.6 ± 90.3 GBq/µmol and radiochemical purity of >99% within a total synthesis time of about 73 min. The radiochemical purity of [(18) F]AV-45 formulated by dissolving the ethanol-free solution was found to decrease as a function of the period of exposure to visible light. In contrast, the visible light photolysis could be suppressed by adding 10% ethanol to the formulation or by avoiding exposure to visible light. In the radiosynthesis of [(18) F]AV-45 formulated by dissolving the ethanol-free solution, [(18) F]AV-45 could be obtained with high radiochemical purity and high stability by avoiding exposure to visible light.

Enantioconvergent biohydrolysis of racemic styrene oxide to R-phenyl-1, 2-ethanediol by a newly isolated filamentous fungus Aspergillus tubingensis TF1.

An effort was made to isolate biocatalysts hydrolyzing epoxides from various ecological niches of northeast India, a biodiversity hot spot zone of the world and screened for epoxide hydrolase activity to convert different racemic epoxides to the corresponding 1, 2-vicinal diols. Screening of a total of 450 microorganisms isolated was carried out using NBP colorimetric assay. One of the strains TF1, after internal transcribed spacer sequence analysis, identified as Aspergillus tubingensis, showed promising enantioconvergent epoxide hydrolase activity. The hydrolysis of unsubstituted styrene oxide (1) occurred to give 97 % ee of R-(-)-1-phenylethane-1, 2-diol (6) with more than 99 % conversion within 45 min incubation. It is shown to be a cheap and practical biocatalyst for one step asymmetric synthesis of chiral R-diol. The other representative substrates (2-5), although underwent hydrolysis with more than 99 % conversion beyond 15 h, exhibited poor enantioselectivity.

Photo-crosslinked poly(ethylene glycol)-b-poly(ϵ-caprolactone) nanoparticles for controllable paclitaxel release.

Novel biodegradable core-crosslinked nanoparticles (CNPs) consisting of methoxy poly(ethylene glycol)-block-poly(ϵ-caprolactone-co-γ-cinnamoyloxy-ϵ-caprolactone) (mPEG-b-P(CL-co-CCL)) were prepared and evaluated for paclitaxel (PTX) delivery. mPEG113-b-P(CL65.2-co-CCL10.1) had a higher drug loading efficiency (95%) compared to mPEG113-b-PCL93.1 (43%). The stability of NPs has been largely improved and PTX release was significantly inhibited by crosslinking via UV irradiation at λ = 254 nm. MTT assays demonstrated that both blank non-crosslinked and crosslinked NPs showed low cytotoxicity to NCL-H460 cells while PTX-loaded non-crosslinked and crosslinked NPs exhibited obvious cytotoxicity against NCL-H460 cells, and the cytotoxicity was both dose-dependent and time-dependent. Furthermore, after 48 h incubation the cell viability of PTX-loaded crosslinked NPs was lower compared to that of PTX-loaded non-crosslinked NPs or free PTX. These properties indicated that CNPs prepared from mPEG-b-P(CL-co-CCL) have great potentials as carriers for drug delivery.

Synthesis and in vitro photodynamic activity of oligomeric ethylene glycol-quinoline substituted zinc(II) phthalocyanine derivatives.

A new series of zinc(II) phthalocyanine derivatives have been synthesized and characterized. These macrocycles exhibited a sharp absorption band in the red visible region in DMF, which indicated that they were dissolved well and almost did not aggregate in this solvent. Compared with the unsubstituted zinc(II) phthalocyanine, all these phthalocyanines have a red-shifted Q-band (at 678-699 vs 670 nm) and exhibit a relatively weaker fluorescence emission and a higher efficiency at generating singlet oxygen. The monosubstituted photosensitizers also exhibit high photocytotoxicity toward HepG2 human hepatocarcinoma cells with IC50 values as low as 0.02-0.05 µM (λ = 670 nm, 80 mW·cm(-2), 1.5 J·cm(-2)). The high photodynamic activities of these compounds are in accordance with their low aggregation tendency and high cellular uptake. Their structure-activity relationship was assessed by determining the photophysical properties, cellular uptake, and in vitro photodynamic activities of this series of compounds. As shown by confocal microscopy, monosubstituted phthalocyanines can target the mitochondria and lysosomes of the cells, and tetrasubstituted phthalocyanines tend to target the lysosomes of the cells.

Nucleophilic trifluoromethylation of carbonyl compounds: trifluoroacetaldehyde hydrate as a trifluoromethyl source.

A feasible nucleophilic trifluoromethylating protocol has been developed using trifluoroacetaldehyde hydrate as an atom-economical trifluoromethyl source. The reaction was found to be applicable to the nucleophilic trifluoromethylation of a broad spectrum of carbonyl compounds with satisfactory yields in general. DFT calculations have been performed to provide mechanistic insight into the present and related reactions employing 2,2,2-trifluoro-1-methoxyethanol and hexafluoroacetone hydrate.