Multifunctional dendrimer/combretastatin A4 inclusion complexes enable in vitro targeted cancer therapy

Mengen Zhang1,2, Rui Guo2, Yin Wang2, Xueyan Cao2, Mingwu Shen2, Xiangyang Shi1-31State Key Laboratory for Modification of Chemical Fibers and Polymer Materials; 2College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, People’s Republic of China; 3Centro de Química da Madeira, Universidade da Madeira, Campus da Penteada, Funchal, PortugalBackground: We report here a unique approach to using multifunctional dendrimer/combretastatin A4 (CA4) inclusion complexes for targeted cancer therapeutics.Methods: Amine-terminated generation 5 polyamidoamine dendrimers were first partially acetylated to neutralize a significant portion of the terminal amines, and then the remaining dendrimer terminal amines were sequentially modified with fluorescein isothiocyanate as an imaging agent and folic acid as a targeting ligand. The multifunctional dendrimers formed (G5.NHAc-FI-FA) were utilized to encapsulate the anticancer drug, CA4, for targeted delivery into cancer cells overexpressing folic acid receptors.Results: The inclusion complexes of G5.NHAc-FI-FA/CA4 formed were stable and are able to significantly improve the water solubility of CA4 from 11.8 to 240 µg/mL. In vitro release studies showed that the multifunctional dendrimers complexed with CA4 could be released in a sustained manner. Both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay and morphological cell observation showed that the inhibitory effect of the G5.NHAc-FI-FA/CA4 complexes was similar to that of free CA4 at the same selected drug concentration. More importantly, the complexes were able to target selectively and display specific therapeutic efficacy to cancer cells overexpressing high-affinity folic acid receptors.Conclusion: Multifunctional dendrimers may serve as a valuable carrier to form stable inclusion complexes with various hydrophobic anticancer drugs with improved water solubility, for targeting chemotherapy to different types of cancer.Keywords: PAMAM dendrimers, combretastatin A4, inclusion complexes, targeted cancer therap

Intermittent hypoxia-induced enhancement of sociability and working memory associates with CNTNAP2 upregulation

IntroductionHypoxia is an environmental risk factor for many disorders throughout life. Perinatal hypoxia contributes to autism spectrum disorder (ASD), while hypoxic conditions in the elderly facilitate memory deficits. However, the effects of hypoxia on adolescence remains elusive. CNTNAP2 is a critical molecule in ASD pathogenesis with undefined mechanisms. We investigate hypoxia’s impact on adolescence and the underlying mechanism related to CNTNAP2.MethodsThree-chamber social approach test, Y maze, Morris Water Maze and Open Field Test were applied to evaluate behavioral alterations. Immunoblotting, 5′- RACE and dual-luciferase reporter assay were performed to examine CNTNAP2 protein expression, transcription start site (TSS) of human CNTNAP2 gene and CNTNAP2 promoter activity, respectively.ResultsIntermittent hypoxia treatment improved social behaviors and working memory in adolescent mice. CNTNAP2 was increased in the brains of hypoxia-treated mice. The sequencing results identified the TSS at 518 bp upstream of the translation start site ATG. Hypoxia upregulated CNTNAP2 by interacting with functional hypoxia response elements in CNTNAP2 promoter.ConclusionIntermittent hypoxia enhanced sociability and working memory associated with CNTNAP2 upregulation. Our study provides novel insights into intermittent hypoxia’s impact on development and the interaction between genetic and environmental risk factors in ASD pathogenesis

The Development of Oxygen-generating Materials and Cell Separation Techniques for Tissue Engineering

University of Minnesota Ph.D. dissertation. 2018. Major: Biomedical Engineering. Advisor: Wei Shen. 1 computer file (PDF); 167 pages.Abstract Oxygen and cells play a key role in tissue engineering. In this work, we have developed methods to address two key factors: (1) fabrication of oxygen-generating biomaterials for a sustained release of oxygen, (2) isolation of target cells with collective merits of high specificity, high yield, and minimal biochemical and biophysical perturbation. Inability to supply sufficient oxygen is one of the major reasons for cell death and tissue necrosis in the initial phase after transplantation of engineered constructs. In this work oxygen-generating microparticles and films were developed by incorporating polycaprolactone (PCL) with calcium peroxide (CaO2) to achieve a sustained oxygen delivery. Electrospraying and heat-press techniques were used for the preparation of PCL/CaO2 microparticles and films and compared with traditional techniques of homogenization and solvent-cast. Pancreatic β cells was utilized to evaluate the ability of oxygen-generating materials to support cell survival. The results show that cell viability and metabolic activity were significantly improved both in two-dimensional and three-dimensional hypoxic culture with the presence of oxygen-generating biomaterials. Heat-press technique enables fabricated PCL/CaO2 films to release oxygen for more than 3 weeks in a hypoxia incubator with 2% oxygen, and the oxygen release rate can be adjusted to a manner without compromising in vitro angiogenesis process. To compare with most of reported studies with peroxide/biodegradable polymer-based oxygen-generating biomaterials, a prolonged oxygen release with an elevated metabolic activity of cells was achieved in this work. Affinity‐based cell separation is label‐free and highly specific, but it is difficult to efficiently and gently release affinity‐captured cells due to the multivalent nature of cell‐material interactions. A label-free cell separation platform composed of a capture substrate and a cell‐releasing molecular trigger was developed in this work to address this challenge. The capture substrate is functionalized with an antibody, which captures target cells specifically, and a coiled-coil A. The cell-releasing molecular trigger B-PEG, a conjugate of a coiled-coil B and polyethylene glycol, can drive efficient and gentle release of the captured cells, because A/B heterodimerization brings B-PEG molecules to the substrate and PEG chains adopt extended conformations and break nearby multivalent cell-substrate interactions. Unlike most of current cell isolation strategies, no enzymes or excessive shear stress are involved, and the released cells have neither external molecules attached nor endogenous cell-surface molecules cleaved, which might be critical for the viability, phenotype, and function of sensitive cells

A Study on the Structural Relationships between COVID-19 Coping Strategies, Positive Expectations, and the Behavioral Intentions of Various Tourism-Related Behaviors

The purpose of this study was to investigate the impact of coping strategies, attitudes, and positive anticipated emotions on the positive expectations and behavioral intentions of Korean tourists during the COVID-19 pandemic. An integrated model was proposed and tested, and the results indicate that effective coping strategies, attitudes, and positive anticipated emotions have a positive effect on the positive expectations of tourism during the pandemic, which in turn positively influences behavioral intentions. Practical suggestions were also provided based on the findings. This research has implications for understanding the ways in which individuals cope with and adapt to travel during times of crisis, and for identifying strategies that may facilitate positive expectations and behavioral intentions in the tourism industry

Copper-Doped Bioactive Glass/Poly (Ether-Ether-Ketone) Composite as an Orbital Enucleation Implant in a Rabbit Model: An In Vivo Study

An orbital enucleation implant is used to compensate for the orbital volume deficits in the absence of the globe. In this work, copper-doped bioactive glass in poly(ether-ether-ketone) (CuBG/PEEK) composite scaffolds as an orbital enucleation implant were designed and fabricated by cool-pressed sintering and particle-leaching techniques, the incorporation of copper-doped bioactive glass in poly(ether-ether-ketone) (CuBG/PEEK) was expected to significantly improve the biocompatibility of the PEEK implant. The consequences after implantation of the CuBG/PEEK composite scaffolds in experimental, eviscerated rabbits was observed and assayed in term of histopathological examination. In detail, 24 rabbits were randomly divided into three groups: Group A, PEEK scaffolds; Group B, 20% CuBG/PEEK composite scaffolds; Group C, 40% CuBG/PEEK composite scaffolds; the rabbits were sacrificed at week 4 and week 12, followed by histochemical staining and observation. As a result, the PEEK group exhibited poor material exposure and tissue healing, while the CuBG/PEEK scaffolds showed good biocompatibility, and the 40% CuBG/PEEK composite scaffold exhibited the best performance in angiogenesis and tissue repair. Therefore, this study demonstrates the potential of CuBG/PEEK composite scaffolds as an orbital enucleation implant

Enhancing bone regeneration with a novel bioactive glass-functionalized polyetheretherketone scaffold by regulating the immune microenvironment

Polyetheretherketone (PEEK) has become a promising material for bone engineering due to its excellent mechanical properties, radiolucency and chemical resistance. However, its inherent bioinertness and lack of osteogenic activity induce a foreign body reaction and fibrous encapsulation, which limits its effectiveness in promoting bone regeneration. Herein, we develop a novel bioactive glass–functionalized PEEK scaffold (ADSP) to accelerate bone regeneration by immunoregulation. Strontium-doped bioactive glass nanoparticles loaded with alendronate (A-SrBG) were coated on the sulfonated PEEK scaffold by the strong adhesion ability of polydopamine. The released bioactive ions from the scaffold can improve the biocompatibilities and osteogenic activity of PEEK. In vitro results showed the ADSP scaffold promoted polarization of the M2 macrophages via the NF-κB pathway to enhance the osteogenic differentiation of rat bone mesenchymal stem cells (rBMSCs). Further, in vivo rat skull drilling model assessment revealed efficient polarization of M2 macrophage and desirable new bone formation. Thus, ADSP scaffold exerted osteoimmunomodulation effect to promote bone regeneration

Analysis of Flexural Vibrations of a Piezoelectric Semiconductor Nanoplate Driven by a Time-Harmonic Force

The performance of devices fabricated from piezoelectric semiconductors, such as sensors and actuators in microelectromechanical systems, is superior; furthermore, plate structures are the core components of these smart devices. It is thus important to analyze the electromechanical coupling properties of piezoelectric semiconductor nanoplates. We established a nanoplate model for the piezoelectric semiconductor plate structure by extending the first-order shear deformation theory. The flexural vibrations of nanoplates subjected to a transversely time-harmonic force were investigated. The vibrational modes and natural frequencies were obtained by using the matrix eigenvalue solver in COMSOL Multiphysics 5.3a, and the convergence analysis was carried out to guarantee accurate results. In numerical cases, the tuning effect of the initial electron concentration on mechanics and electric properties is deeply discussed. The numerical results show that the initial electron concentration greatly affects the natural frequency and electromechanical fields of piezoelectric semiconductors, and a high initial electron concentration can reduce the electromechanical fields and the stiffness of piezoelectric semiconductors due to the electron screening effect. We analyzed the flexural vibration of typical piezoelectric semiconductor plate structures, which provide theoretical guidance for the development of new piezotronic devices

Context‐aware Siamese network for object tracking

Abstract At present, temporal and spatial contexts are widely used to improve the adaptability of a tracker. However, most existing methods usually focus on one aspect of the temporal or spatial context and rarely exploit them simultaneously. In this paper, a context‐aware Siamese Network (CSNet) is proposed, which skilfully integrates the modelling of temporal and spatial context into the Siamese tracking framework. Specifically, CSNet consists of a context‐based channel attention module and a context‐based cross‐attention module. The former aggregates spatial context information from different channels and dynamically emphasizes target features, which makes it easier for the tracker to distinguish the target from the background. The latter propagates the temporal context from the previous frames to the current frame to establish the part‐level relationship between the search region and the historical target state, which enables the tracker better adapt to the target deformation. In addition, to further mine context information, the CSNet is equipped with a state‐aware strategy to control the contribution of different context information in tracking. Extensive experiments on OTB2015, UAV123, GOT‐10k, LaSOT, and TrackingNet show that the proposed tracking method achieves comparable performance to the advanced trackers