I. Introduction 4443 II. Challenges of Glycoside Synthesis 4444 III. Brief Survey of Post-1980 Methods of Anomeric Activation 4444 1. Non-Bromide, -Chloride, -Iodide Methods for Anomeric Activation 4444 2. New Generations of Anomeric Leaving Groups and Activation Methods 4445 IV. Glycosylation with Unprotected Glycosyl Donors 4446 1. O-Glycosides 4446 A. Fischer-type Glycosylation of Alcohols 4446 B. Miscellaneous Methods 4447 2. Glycosylamines and Glycosyl Azides 4447 3. C-Glycosides 4448 V. Remote Activation Concept 4448 VI. Stereocontrolled Glycosylation Using 3-Methoxypyridyl (MOP) O-Unprotected Glycosyl Donors 4449 1. Design, Concept, and Activation Mechanism 4449 2. Preparation of MOP Glycosyl Donors 4451 3. Glycosylation with O-Unprotected MOP Glycosyl Donors 4452 A. Synthesis of O-Glycosides and Oligosaccharides 4452 B. Selective Activation 4453 C. Stereocontrolled Synthesis of Glycosyl 1-Carboxylates and Glycosyl Azides 4456 D. Stereocontrolled Synthesis of Glycosyl 1-Phosphates and Glycosyl Nucleotides 4457 4. Solid-Phase Synthesis Using MOP Donors and Acceptors 4458 A. Linking Strategy 4458 B. Synthesis of O-Glycosides and Oligosaccharides on Solid Support 4459 VII. Conclusion 4460 VIII. Acknowledgments 4461 IX. References 4461
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Vaccines based on mRNA have emerged as potent systems to elicit CD8 T cell responses against various cancers and viral infectious diseases. The efficient intracellular delivery of mRNA molecules encoding antigens into the cytosol of antigen-presenting cells (APCs) is still challenging, requiring cell attachment, active uptake, and subsequent endosomal escape. Here, we report a facile approach for the formulation of peptide-functionalized mRNA polyplexes using copper-free click chemistry to promote presentation of mRNA antigen by dendritic cells (DCs). After screening different membrane active peptides, GALA modified mRNA polyplexes (PPx-GALA) with a size around 350 nm and with a slightly negative surface charge (-7 mV), exhibited the highest EGFP-mRNA transfection in RAW 246.7 macrophages (∼36%) and D1 dendritic cells (∼50%) as compared to polyplexes decorated with melittin or LEDE peptides. Interestingly, we found that PPx-GALA enters DCs through sialic acid mediated endo/phagocytosis, which was not influenced by DC maturation. The PPx-GALA formulation exhibited 18-fold higher cellular uptake compared to a lipofectamine mRNA formulation without inducing cytotoxicity. Live cell imaging showed that PPx-GALA that were taken up by endocytosis induced calcein release from endosomes into the cytosol. DCs treated with PPx-GALA containing mRNA encoding for OVA displayed enhanced T cell responses and DC maturation. Collectively, these data provide a strong rationale for further study of this PPx-GALA formulation in vivo as a promising mRNA vaccine platform.
Multidrug resistance (MDR) contributes to failure of chemotherapy. We here show that biodegradable polymeric nanogels are able to overcome MDR via folic acid targeting. The nanogels are based on hydroxyethyl methacrylamide-oligoglycolates-derivatized poly(hydroxyethyl methacrylamide-co-N-(2-azidoethyl)methacrylamide) (p(HEMAm-co-AzEMAm)-Gly-HEMAm), covalently loaded with the chemotherapeutic drug doxorubicin (DOX) and subsequently decorated with a folic acid-PEG conjugate via copper-free click chemistry. pH-Responsive drug release is achieved via the acid-labile hydrazone bond between DOX and the methacrylamide polymeric network. Cellular uptake and cytotoxicity analyses in folate receptor-positive B16F10 melanoma versus folate receptor-negative A549 lung carcinoma cells confirmed specific uptake of the targeted nanogels. Confocal microscopy demonstrated efficient internalization, lysosomal trafficking, drug release and nuclear localization of DOX. We also show that DOX resistance in 4T1 breast cancer cells results in upregulation of the folate receptor, and that folic acid targeted nanogels can be employed to bypass drug efflux pumps, resulting in highly efficient killing of resistant cancer cells. In conclusion, folic acid functionalized nanogels with pH-controlled drug release seem to hold significant potential for treating multidrug resistant malignancies.
Summary Energy plays an important role in a fast‐paced modern society. With the depletion of fossil energy, effective utilization of solar energy is getting increasingly urgent. Thermal energy storage is an inevitable choice for effective utilization of renewable energy sources. As one of the most promising renewable energy sources, solar energy is inexhaustible. But it has some shortcomings such as instability and intermittency, affected by time, climate, and geographical location. Thermal energy storage technology, which can effectively reduce the cost of concentrated solar power generation, plays a crucial role in bridging the gap between energy supply and demand. In addition, thermal energy storage subsystem can improve performance and reliability of the whole energy system. According to different principles, thermal storage technology is generally classified as sensible heat storage, latent heat storage, and thermochemical energy storage. Most solar thermal power generation systems, currently demonstrated and operated in the world, adopt the method of sensible thermal energy storage. In contrast, thermochemical energy storage is a relatively new concept, which is still in the stage of basic test and verification. Thermochemical energy storage technology stores and releases energy through endothermic and exothermic reversible reactions. A closed system with separated reactants and products, in theory, can store energy indefinitely. The main thermochemical energy storage systems include redox system, metal hydride system, carbonate decomposition system, ammonia decomposition system, methane reforming system, and inorganic hydroxide system.
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