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We demonstrate that several visible-light mediated carbon–heteroatom cross-couplings can be carried out using a photoactive NiII precatalyst that forms in situ from a nickel salt and a bipyridine ligand decorated with two carbazole groups (Ni(Czbpy)Cl2). The activation of this precatalyst towards cross-couplings follows a hitherto undisclosed mechanism that is different from previously reported light-responsive nickel complexes that were reported to undergo metal-to-ligand charge transfer. Theoretic and spectroscopic investigations revealed that irradiation of Ni(Czbpy)Cl2 with visible-light causes an initial intraligand charge transfer event that triggers productive catalysis. Ligand polymerization affords a porous, recyclable organic polymer for heterogeneous nickel catalysis of cross-couplings. The heterogeneous catalyst shows stable performance in a packed-bed flow reactor during a week of continuous operation.

Zwitterionic hydrogels have promising potential as a result of their anti-fouling and biocompatible properties, but they have recently also gained further attention due to their controllable stimuli responses. We successfully synthesized two zwitterionic polymers, poly(2-methacryloyloxyethyl phosphorylcholine) (poly-MPC) and poly(2-(methacryloyloxy)ethyl dimethyl-(3-sulfopropyl)ammonium hydroxide) (poly-DMAPS), which have complementary ionic sequences in their respective zwitterionic side groups and likely form an interpenetrating double network to improve their mechanical strength. The synthesized poly-MPC was blended in a poly-DMAPS matrix (MD gel) and showed high viscosity, while poly-DMAPS was blended in a poly-MPC hydrogel (DM gel) and revealed UCST behavior as the temperature increased. In addition, cross-section images of the MD hydrogel exhibited its compact and uniform structure, while the DM gel was found to exhibit a porous micro-structure with clear boundaries. The results explained the low viscosity of the DM gel, which was also confirmed via 3D Raman mapping. To sum up, the preliminary data demonstrated that binary zwitterionic hydrogels have thermosensitive mechanical properties, promoting further bio-applications in the future, such as in wound healing.

Biotin receptors are overexpressed by various types of solid cancer cells and play a significant role in tumor metabolism, growth, and metastasis. Thus, targeting the biotin receptors on tumor cells may enhance the efficiency and reduce the side-effects of chemotherapy. The aim of this study was to develop a biotin-coupled poly(amido)amine (PAMAM) (PG4.5) dendrimer nanoparticle to enhance the tumor-specific delivery and intracellular uptake of anticancer drugs via receptor-mediated endocytosis. We modified PG4.5 with diethylenetriamine (DETA) followed by biotin via an amide bond and characterized the resulting PG4.5-DETA-biotin nanoparticles by 1H NMR, FTIR, and Raman spectroscopy. Loading and releasing of gemcitabine (GEM) from PG4.5-DETA-biotin were evaluated by UV&ndash, Visible spectrophotometry. Cell viability and cellular uptake were examined by MTT assay and flow cytometry to assess the biocompatibility, cellular internalization efficiency and antiproliferative activity of PG4.5-DETA-biotin/GEM. Gemcitabine-loaded PG4.5-DETA-biotin nanoparticles were spherical with a particle size of 81.6 &plusmn, 6.08 nm and zeta potential of 0.47 &plusmn, 1.25 mV. Maximum drug-loading content and encapsulation efficiency were 10.84 &plusmn, 0.16% and 47.01 &plusmn, 0.71%, respectively. Nearly 60.54 &plusmn, 1.99% and 73.96 &plusmn, 1.14% of gemcitabine was released from PG4.5-DETA-biotin/GEM nanoparticles after 48 h at the acidic pH values of 6.5 and 5, respectively. Flow cytometry and fluorescence microscopy of cellular uptake results revealed PG4.5-DETA-biotin/GEM nanoparticles selectively targeted cancer cells in vitro. Cytotoxicity assays demonstrated gemcitabine-loaded PG4.5-DETA-biotin significantly reduced cell viability and induced apoptosis in HeLa cells. Thus, biotin-coupled PG4.5-DETA nanocarrier could provide an effective, targeted drug delivery system and selectively convey gemcitabine into tumor cells.

This is the peer reviewed version of the following article: Hsu, W‐H., Csaba, N., Alexander, C., Garcia‐Fuentes, M. (2020), Polyphosphazenes for the delivery of biopharmaceuticals. J Appl Polym Sci, 137, 48688. doi: https://doi.org/10.1002/app.48688, which has been published in final form at https://doi.org/10.1002/app.48688. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions Polyphosphazenes (PPZs) are a relatively new family of polymers based on a nitrogen- phosphorous backbone where organic side-groups can be grafted. The synthetic route to PPZs is highly versatile such that it is possible to add many different functionalities that change completely the physicochemical and biological properties of the polymers. For instance, PPZs can be designed with a variety of organic side groups that render these materials biodegradable and highly biocompatible. Based on these positive features, PPZs have been explored for many biomedical applications including the design of numerous advanced drug delivery systems. In this area, PPZs have been particularly investigated as materials for the formulation of biopharmaceuticals of high added value. These include protein- and polynucleotide-based medicines, applications where PPZ carriers have obtained very positive results in pre-clinical models. A further area of major interest for PPZs has been vaccination, where these materials have obtained excellent results in vivo as polymer adjuvants and have advanced to clinical evaluation. This work has been funded by Ministerio de Economía y Competitividad (MINECO-RETOS, Grant MAT2017-84361-R, Feder Funds) and Xunta de Galicia (Grupos de Referencia Competitiva, Feder Funds) to MGF and Engineering and Physical Sciences Research Council Grants EP/N006615/1, EP/ N03371X/1 to CA. WHH was a recipient of a contract from EU Erasmus Mundus NanoFar joint doctorate program SI

This is the peer reviewed version of the following article: Hsu, W.‐H., Sánchez‐Gómez, P., Gomez‐Ibarlucea, E., Ivanov, D.P., Rahman, R., Grabowska, A.M., Csaba, N., Alexander, C. and Garcia‐Fuentes, M. (2019), Structure‐Optimized Interpolymer Polyphosphazene Complexes for Effective Gene Delivery against Glioblastoma. Adv. Therap., 2: 1800126. doi:10.1002/adtp.201800126, which has been published in final form at https://doi.org/10.1002/adtp.201800126. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions Safe and efficient gene delivery vectors would enhance the prospects for polynucleotide-based therapies. Herein we describe a new approach towards structurally-optimized gene vector design based on the preparation of clickable poly(allylamino-phosphazene)s that can be converted to several cationic and anionic derivatives via thiol-ene addition. Simultaneous co-incubation of alkylamine- and alkylcarboxylate-poly(phosphazenes) with polynucleotides generated binary-polyelectrolyte nanoparticles. Screening of a series of these complexes for transfection in glioblastoma cells showed that the inclusion of 6-mercaptohexanoic acid substituted poly(phosphazene)s in the complexes resulted in 6-fold and 19-fold higher luciferase expression in U87MG cells and primary GBM1 cell- line, respectively. This effect was attributed to the specific ionization properties of this materials that improved polyplex intracellular trafficking. Transfection in 3D-spheroid models and subcutaneous xenograft U87MG tumors confirmed higher transgene expression for the binary cationic/anionic poly(phosphazene) complexes compared to the related polycation-pDNA complexes and to PEI- pDNA complexes. The data also indicated a notable capacity of the mixed complexes to deliver genes to the inner cores of tumor spheroids. Extension of this approach to siRNA delivery showed that the mixed poly(phosphazene) complexes were able to silence DYRK1A, a gene implicated in tumor initiation and progression, reducing U87MG cell renewal in vitro and delaying tumor growth in vivo. This work has been funded by Ministerio de Economía y Competitividad (MINECO-RETOS, Grant MAT2017-84361-R, Feder Funds) and Xunta de Galicia (Grupos de Referencia Competitiva, Feder Funds) to MGF and Engineering and Physical Sciences Research Council Grants EP/N006615/1, EP/ N03371X/1 to CA. WHH was a recipient of a contract from EU Erasmus Mundus NanoFar joint doctorate program SI

Rhenium-188 (188Re) displays abundant intermediate energy β emission and possesses a physical half-life of 16.9 h. Sorafenib is an orally available multikinase inhibitor that targets Raf kinases and vascular endothelial growth factor receptors (VEGFRs). Sorafenib has demonstrated preclinical and clinical activity against several types of tumors, such as renal cell and colorectal carcinoma. In this study, we investigated the efficacy of radiotherapeutics of 188Re-liposomes combined with sorafenib in a C26-luc metastatic colorectal liver tumour mouse model. Liver metastases were established by intrasplenic injection of C26-luc murine colon cancer cells. Based on the results of the toxicity assessment, an administration dose of 80% the maximum tolerated dose was selected. 188Re-liposomes were administered on day 1, when metastases of several hundred micrometers in diameter were observed. In the combination therapy group, 10 mg/kg sorafenib (co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar) was administered every other day for 1 week and the survival of mice was assessed. The tumor growth was more significantly inhibited in the 188Re-liposome plus sorafenib group compared with the 188Re-liposome alone, sorafenib alone and untreated normal saline groups (P=0.0000). Furthermore, 188Re-liposomes combined with sorafenib achieved higher survival rates compared with the 188Re-liposome alone, sorafenib alone and untreated normal saline groups (P=0.0000). These results support the use of combined radio-chemotherapy with 188Re-liposomes plus sorafenib as a viable treatment option in the adjuvant setting for liver metastases of colorectal cancer.

Rhenium-188 (188Re) displays abundant intermediate energy β emission and possesses a physical half-life of 16.9 h. Sorafenib is an orally available multikinase inhibitor that targets Raf kinases and vascular endothelial growth factor receptors (VEGFRs). Sorafenib has demonstrated preclinical and clinical activity against several types of tumors, such as renal cell and colorectal carcinoma. In this study, we investigated the efficacy of radiotherapeutics of 188Re-liposomes combined with sorafenib in a C26-luc metastatic colorectal liver tumour mouse model. Liver metastases were established by intrasplenic injection of C26-luc murine colon cancer cells. Based on the results of the toxicity assessment, an administration dose of 80% the maximum tolerated dose was selected. 188Re-liposomes were administered on day 1, when metastases of several hundred micrometers in diameter were observed. In the combination therapy group, 10 mg/kg sorafenib (co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar) was administered every other day for 1 week and the survival of mice was assessed. The tumor growth was more significantly inhibited in the 188Re-liposome plus sorafenib group compared with the 188Re-liposome alone, sorafenib alone and untreated normal saline groups (P=0.0000). Furthermore, 188Re-liposomes combined with sorafenib achieved higher survival rates compared with the 188Re-liposome alone, sorafenib alone and untreated normal saline groups (P=0.0000). These results support the use of combined radio-chemotherapy with 188Re-liposomes plus sorafenib as a viable treatment option in the adjuvant setting for liver metastases of colorectal cancer.

The aim of this study was to investigate the correlation between Facebook involvement and internet addiction. We sampled 577 university students in Taiwan and administered a survey of Facebook usage, Facebook involvement scale (FIS), and internet addiction scale. The FIS comprises three factors (salience, emotional support, and amusement). Results showed that the Facebook involvement scale had good reliability and validity. The correlation between Facebook involvement and internet addiction was measured at .395. This means that a higher degree of Facebook involvement indicates a greater degree of psychological dependency on the internet, and a greater propensity towards social withdrawal and other negative psychological consequences associated with internet addiction. Besides, the correlations between three factors of FIS (salience, emotional support, and amusement) and internet addiction ranged from .313-372, indicating that these neither of these factors (salience, emotional support, and amusement) is more effective than the others in predicting internet dependency., {"references":["N. B. Ellison, C. Steinfield, and Lampe, C. \"The benefits of Facebook\n\"friends:\" Social capital and college students' use of online social network\nsites.\" Journal of Computer-Mediated Communication, vol 12\n,pp.1143-1168, 2007.","F. K. Hew,\" Students- and teachers- use of Facebook\". Computers in\nHuman Behavior, vol 27(2),pp 662-676, 2011.","C. Steinfield, N. Ellison, and C. Lampe, \"Social capital, self-esteem, and\nuse of online social network sites: A longitudinal analysis\". Journal of\nApplied Developmental Psychology, vol 29, pp.434-445, 2008.","T. A., Pempek, Y. A. Yermolayeva, , and S. L. Calvert, \"College students'\nsocial networking experiences on Facebook\". Journal of Applied\nDevelopmental Psychology,vol 30(3), pp.227-238, 2009.","K. S. Young, Pathological Internet Use:\" A case that breaks the\nstereotype.\" Psychological Reports, vol 79, pp.899-902, 1996","M. Griffiths, (1998), \"Internet addiction: Does it really exist?\" In\nPsychology and the internet: Intrapersonal, interpersonal and\ntranspersonal, J. Gackenbach (Ed.), New\nYork: Academic Press, 1998, pp. 61-75.","P. Sheldon, \"The relationship between unwillingness-to-communicate\nand students- facebook use.\" Journal of Media Psychology, vol 20(2), pp.\n67-75, 2008.","R. B. Kline, , \"Principles and Practice of Structural Equation Modeling\".\nNew York: The Guilford Press, 2005.","S. C. Yu, and M, M. Yu,\" Comparison of Internet-Based and Paper-Based\nQuestionnaires in Taiwan Using Multi-Sample Invariance Approach.\"\nCyberPsychology and Behavior, vol10, pp.501-507, 2007."]}

Feng-Yun J Huang,1 Te-Wei Lee,2 Chih-Hsien Chang,2 Liang-Cheng Chen,2 Wei-Hsin Hsu,2 Chien-Wen Chang,1 Jem-Mau Lo1 1Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan; 2Institute of Nuclear Energy Research, Longtan, Taiwan Purpose: In this study, the 188Re-labeled PEGylated nanoliposome (188Re-liposome) was prepared and evaluated as a therapeutic agent for glioma.Materials and methods: The reporter cell line, F98luc was prepared via Lentivector expression kit system and used to set up the orthotopic glioma-bearing rat model for non-invasive bioluminescent imaging. The maximum tolerated dose applicable in Fischer344 rats was explored via body weight monitoring of the rats after single intravenous injection of 188Re-liposome with varying dosages before the treatment study. The OLINDA/EXM 1.1 software was utilized for estimating the radiation dosimetry. To assess the therapeutic efficacy, tumor-bearing rats were intravenously administered 188Re-liposome or normal saline followed by monitoring of the tumor growth and animal survival time. In addition, the histopathological examinations of tumors were conducted on the 188Re-liposome-treated rats.Results: By using bioluminescent imaging, the well-established reporter cell line (F98luc) showed a high relationship between cell number and its bioluminescent intensity (R2=0.99) in vitro; furthermore, it could also provide clear tumor imaging for monitoring tumor growth in vivo. The maximum tolerated dose of 188Re-liposome in Fischer344 rats was estimated to be 333 MBq. According to the dosimetry results, higher equivalent doses were observed in spleen and kidneys while very less were in normal brain, red marrow, and thyroid. For therapeutic efficacy study, the progression of tumor growth in terms of tumor volume and/or tumor weight was significantly slower for the 188Re-liposome-treated group than the control group (P

Parathyroid carcinoma accounts for 0.5 to 4.0% of cases of primary hyperparathyroidism. The prognosis depends largely on the extent of successful resection at the time of initial operation. Therefore, early diagnosis before surgery is important. We report 3 cases of primary hyperparathyroidism. The first patient, a 20-year-old uremic female, had refractory hypercalcemia after 5 years of hemodialysis treatment. Hypercalcemia persisted despite repeated parathyroidectomy. Pathology revealed diffuse hyperplasia of the parathyroid glands with focal adenomatous changes. Multiple pulmonary metastases were found later. The second patient, a 45-year-old female with history of nephrolithiasis, presented with severe osteoporosis. She underwent repeated parathyroidectomy for local recurrence. Pathology disclosed typical features of parathyroid carcinoma with adjacent lymph node metastasis. The third patient, a 34-year-old male, had recurrent episodes of extremity fracture and hypercalcemia with palpable neck mass. He underwent resection of the parathyroid tumor. Vascular and capsular invasions were noted microscopically. All three patients were relatively young and had extremely high intact parathyroid hormone (iPTH) level (15 to 31 times the upper limit of normal). The first patient died of hypercalcemia and respiratory failure and the other 2 were treated successfully with surgical excision and, in case 2, combined chemotherapy and radiotherapy. The latter 2 patients had no recurrence during 18 months and 14 months of follow-up, respectively. Our experience with these cases suggests that the combination of the following characteristics are highly suggestive of parathyroid carcinoma: young age, palpable neck mass, concomitant renal and skeletal disease, and extremely high iPTH level in patients with PTH-dependent hypercalcemia.