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Bcl-2 inhibitor uploaded upconversion nanophotosensitizers to overcome the photodynamic therapy resistance of cancer through adjuvant intervention strategy

Biomaterials - Fri, 2017-08-18 17:04
Publication date: November 2017
Source:Biomaterials, Volume 144

Author(s): Xiaomin Liu, Zhongqi Fan, Li Zhang, Zheng Jin, Dongmei Yan, Youlin Zhang, Xiaodan Li, Langping Tu, Bin Xue, Yulei Chang, Hong Zhang, Xianggui Kong

Similar to many other anticancer therapies, photodynamic therapy (PDT) also suffers from the intrinsic cancer resistance mediated by cell survival pathways. These survival pathways are regulated by various proteins, among which anti-apoptotic protein Bcl-2 plays an important role in regulation of programmed cell death and has been proved to involve in protecting against oxidative stimuli. Confronted by this challenge, we propose and validate here a novel upconversion photosensitizing nanoplatform which enables significant reduction of cancer resistance and improve PDT efficacy. The upconversion nanophotosensitizer contains the photosensitizing molecules - Zinc phthalocyanine (ZnPc) and Bcl-2 inhibitor - ABT737 small molecules, denoted as ABT737@ZnPc-UCNPs. ABT737 molecules were encapsulated, in a pH sensitive way, into the nanoplatform through Poly (ethylene glycol)-Poly (l-histidine) diblock copolymers (PEG-b-PHis). This nanosystem exhibits the superiority of sensitizing tumor cells for PDT through adjuvant intervention strategy. Upon reaching to lysosomes, the acidic environment changes the solubility of PEG-b-PHis, resulting in the burst-release of ABT737 molecules which deplete the Bcl-2 level in tumor cells and leave the tumor cells out from the protection of anti-apoptotic survival pathway in advance. Owing to the sensitization effect of ABT737@ZnPc-UCNPs, the PDT therapeutic efficiency of cancer cells can be significantly potentiated in vitro and in vivo.





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Covalent coupling of high-affinity ligands to the surface of viral vector particles by protein trans-splicing mediates cell type-specific gene transfer

Biomaterials - Fri, 2017-08-18 17:04
Publication date: November 2017
Source:Biomaterials, Volume 144

Author(s): Alexander Muik, Johanna Reul, Thorsten Friedel, Anke Muth, Karen Patricia Hartmann, Irene C. Schneider, Robert C. Münch, Christian J. Buchholz

We have established a novel approach for the covalent coupling of large polypeptides to the surface of fully assembled adeno-associated viral gene transfer vector (AAV) particles via split-intein mediated protein-trans-splicing (PTS). This way, we achieved selective gene transfer to distinct cell types. Single-chain variable fragments (scFvs) or designed ankyrin repeat proteins (DARPins), exhibiting high-affinity binding to cell surface receptors selectively expressed on the surface of target cells, were coupled to AAV particles harboring mutations in the capsid proteins which ablate natural receptor usage. Both, the AAV capsid protein VP2 and multiple separately produced targeting ligands recognizing Her2/neu, EpCAM, CD133 or CD30 were genetically fused with complementary split-intein domains. Optimized coupling conditions led to an effective conjugation of each targeting ligand to the universal AAV capsid and translated into specific gene transfer into target receptor-positive cell types in vitro and in vivo. Interestingly, PTS-based AAVs exhibited significantly less gene transfer into target receptor-negative cells than AAVs displaying the same targeting ligand but coupled genetically. Another important consequence of the PTS technology is the possibility to now display scFvs or other antibody-derived domain formats harboring disulfide-bonds in a functionally active form on the surface of AAV particles. Hence, the custom combination of a universal AAV vector particle and targeting ligands of various formats allows for an unprecedented flexibility in the generation of gene transfer vectors targeted to distinct cell types.





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Hinge-Deficient IgG1 Fc Fusion: Application to Human Lactoferrin

Molecular Pharmaceutics - Fri, 2017-08-18 13:41

Molecular PharmaceuticsDOI: 10.1021/acs.molpharmaceut.7b00221
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Donut-Shaped Nanoparticles Templated by Cyclic Bottlebrush Polymers

Macromolecules - Fri, 2017-08-18 11:33

MacromoleculesDOI: 10.1021/acs.macromol.7b01512
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Component Dynamics in Polymer/Polymer Blends: Role of Spatial Compositional Heterogeneity

Macromolecules - Fri, 2017-08-18 10:14

MacromoleculesDOI: 10.1021/acs.macromol.7b00092
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Collective Molecular Mechanisms in the CH3NH3PbI3 Dissolution by Liquid Water

ACS Nano - Fri, 2017-08-18 08:36

ACS NanoDOI: 10.1021/acsnano.7b04116
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High-Spin Iron Imido Complexes Competent for C–H Bond Amination

Journal of the American Chemical SocietyDOI: 10.1021/jacs.7b06682
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Dual Quantification of MicroRNAs and Telomerase in Living Cells

Journal of the American Chemical SocietyDOI: 10.1021/jacs.7b03617
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Tracking Hole Transport in DNA Hairpins Using a Phenylethynylguanine Nucleobase

Journal of the American Chemical SocietyDOI: 10.1021/jacs.7b06998
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