Cleavable PEGylation and Hydrophobic Histidylation of Polylysine for siRNA Delivery and Tumor Gene Therapy

Polylysine with cleavable PEGylation and hydrophobic histidylation (mPEG-SS-Lys_<i>n</i>-r-His_<i>m</i>) was designed and developed for efficient siRNA delivery and tumor therapy. mPEG-SS-Lys_<i>n</i>-r-His_<i>m</i> was used to carry and deliver small interfering RNA (siRNA) for silencing endogenous vascular endothelial growth factor (VEGF) expression and inhibiting tumor growth in HepG2 tumor-bearing mice. In this gene vector, histidine­(Bzl) was selected for hydrophobic histidylation for the proton sponge ability of the imidazole ring and hydrophobic benzyl group. Cleavable PEGylation was introduced for in vivo circulation as well as selective PEG detachment in response to intracellular reduction condition in order to release the genetic payload. PEG detachment induced gene release was supported by agarose gel electrophoresis retardation assay, undertaken in the intracellular relevant reduction condition. In vitro transfection evaluation of histidylated copolymers, using pEGFP as genetic model, indicated significantly higher GFP expression than unmodified counterparts, comparable to the gold standard PEI. The efficacy of hydrophobic histidylation was found to be pronounced in mesenchymal stem cells (MSCs). In vivo application of the VEGF-siRNA package by tailored mPEG-SS-Lys_<i>n</i>-r-His_<i>m</i> showed distinct tumor suppression in terms of macroscopic tumor volume and molecular analysis

Nebulized pH-Responsive Nanospray Combined with Pentoxifylline and Edaravone to Lungs for Efficient Treatments of Acute Respiratory Distress Syndrome

The COVID-19 pandemic has become an unprecedented global medical emergency, resulting in more than 5 million deaths. Acute respiratory distress syndrome (ARDS) caused by COVID-19, characterized by the release of a large number of pro-inflammatory cytokines and the production of excessive toxic ROS, is the most common serious complication leading to death. To develop new strategies for treating ARDS caused by COVID-19, a mouse model of ARDS was established by using lipopolysaccharide (LPS). Subsequently, we have constructed a novel nanospray with anti-inflammatory and antioxidant capacity by loading pentoxifylline (PTX) and edaravone (Eda) on zeolite imidazolate frameworks-8 (ZIF-8). This nanospray was endowed with synergetic therapy, which could kill two birds with one stone: (1) the loaded PTX played a powerful anti-inflammatory role by inhibiting the activation of inflammatory cells and the synthesis of pro-inflammatory cytokines; (2) Eda served as a free radical scavenger in ARDS. Furthermore, compared with the traditional intravenous administration, nanosprays can be administered directly and inhaled efficiently and reduce the risk of systemic adverse reactions greatly. This nanospray could not only coload two drugs efficiently but also realize acid-responsive release on local lung tissue. Importantly, ZIF8-EP nanospray showed an excellent therapeutic effect on ARDS in vitro and in vivo, which provided a new direction for the treatment of ARDS

The Precambrian Khondalite Belt in the Daqingshan area, North China Craton: evidence for multiple metamorphic events in the Palaeoproterozoic era

<p>High-grade pelitic metasedimentary rocks (khondalites) are widely distributed in the northwestern part of the North China Craton and were named the ‘Khondalite Belt’. Prior to the application of zircon geochronology, a stratigraphic division of the supracrustal rocks into several groups was established using interpretative field geology. We report here SHRIMP U–Pb zircon ages and Hf-isotope data on metamorphosed sedimentary and magmatic rocks at Daqingshan, a typical area of the Khondalite Belt. The main conclusions are as follows: (1) The early Precambrian supracrustal rocks belong to three sequences: a 2.56–2.51 Ga supracrustal unit (the previous Sanggan ‘group’), a 2.51–2.45 Ga supracrustal unit (a portion of the previous upper Wulashan ‘group’) and a 2.0–1.95 Ga supracrustal unit (including the previous lower Wulashan ‘group’, a portion of original upper Wulashan ‘group’ and the original Meidaizhao ‘group’) the units thus do not represent a true stratigraphy; (2) Strong tectono-thermal events occurred during the late Neoarchaean to late Palaeoproterozoic, with four episodes recognized: 2.6–2.5, 2.45–2.37, 2.3–2.0 and 1.95–1.85 Ga, with the latest event being consistent with the assembly of the Palaeoproterozoic supercontinent Columbia; (3) During the late Neoarchaean to late Palaeoproterozoic (2.55–2.5, 2.37 and 2.06 Ga) juvenile, mantle-derived material was added to the crust. </p