A novel graphene oxide-doxorubicin hydrochloride nanohybrid (GO-DXR) was prepared via a simple noncovalent method, and the loading and release behaviors of DXR on GO were investigated. An efficient loading of DXR on GO as high as 2.35 mg/mg was obtained at the initial DXR concentration of 0.47 mg/mL. The loading and release of DXR on GO showed strong pH dependence, which may be due to the hydrogenbonding interaction between GO and DXR. The fluorescent spectrum and electrochemical results indicate that strong π-π stacking interaction exists between them.
A superparamagnetic graphene oxide -Fe 3 O 4 nanoparticles hybrid (GO-Fe 3 O 4 ) was prepared via a simple and effective chemical precipitation method. The amount of loading of Fe 3 O 4 on GO was estimated as 18.6 wt% by atomic absorption spectrometry. The hybrid was then loaded with doxorubicin hydrochloride (DXR) and the loading capacity was as high as 1.08 mg mg À1 . Both of the GO-Fe 3 O 4 hybrids before and after loading with DXR can be dispersed well in aqueous solution. They can congregate under acidic conditions and move regularly under the force of an external magnet. Furthermore, the aggregated hybrid can be redispersed to form a stable suspension under basic conditions. These properties make it a potential candidate for controlled targeted drug delivery and release.
A dual-targeting drug delivery and pH-sensitive controlled release system based on multifunctionalized graphene oxide (GO) was established in order to enhance the effect of targeted drug delivery and realize intelligently controlled release. A superparamagnetic GO-Fe 3 O 4 nanohybrid was firstly prepared via a simple and effective chemical precipitation method. Then folic acid, a targeting agent toward some tumor cells, was conjugated onto Fe 3 O 4 nanoparticles via the chemical linkage with amino groups of the 3-aminopropyl triethoxysilane (APS) modified superparamagnetic GO-Fe 3 O 4 nanohybrid, to give the multi-functionalized GO. Doxorubicin hydrochloride (Dox) as an anti-tumor drug model was loaded onto the surface of this multi-functionalized GO via p-p stacking. The drug loading capacity of this multi-functionalized GO is as high as 0.387 mg mg À1 and the drug release depends strongly on pH values. Cell uptake studies were carried out using fluorescein isothiocyanate labeled or Dox loaded multi-functionalized GO to evaluate their targeted delivery property and toxicity to tumor cells. The results show that this multi-functionalized GO has potential applications for targeted delivery and the controlled release of anticancer drugs.
Purpose: To determine whether -CONH-(CH 2 ) 6 -NH 3 + Cl À functionalized single-walled carbon nanotubes (SWNT) carrying complexed small interfering RNA (siRNA) can enter into tumor cells, wherein they release the siRNA to silence the targeted gene. Experimental Design: -CONH-(CH 2 ) 6 -NH 3 + Cl À was used to mediate the conjugation of telomerase reverse transcriptase (TERT) siRNA to SWNTs. The ability of TERT siRNA delivered via SWNTcomplexes to silence the expression of TERT was assessed by their effects on the proliferation and growth of tumor cells both in vitro and in mouse models. Results: The functionalized SWNTs -CONH-(CH 2 ) 6 -NH 3 + Cl À could facilitate the coupling of siRNAs that specifically target murine TERT expression to form the mTERT siRNA:SWNT+ complex. These functionalized SWNTs rapidly entered three cultured murine tumor cell lines, suppressed mTERT expression, and produced growth arrest. Injection of mTERT siRNA:SWNT+ complexes into s.c. Lewis lung tumors reduced tumor growth. Furthermore, human TERT siRNA:SWNT+ complexes also suppressed the growth of human HeLa cells both in vitro and when injected into tumors in nude mice. Conclusions: -CONH-(CH 2 ) 6 -NH 3 + Cl À functionalized SWNTs carry complexed siRNA into tumor cells, wherein they release the siRNA from the nanotube sidewalls to silence the targeted gene.The -CONH-(CH 2 ) 6 -NH 3 + Cl À functionalized SWNTs may represent a new class of molecular transporters applicable for siRNA therapeutics.
are employees of Genentech, Inc, a member of the Roche group, and own Roche stock. C. E. Brightling is a consultant with fees paid to his institution from Genentech, Inc, and Regeneron; received research grants and was a consultant with fees paid to his institution from AstraZeneca, GlaxoSmithKline, Sanofi, Boehringer Ingelheim, Roche/Genentech, Chiesi, 4D Pharma, Mologics, and Novartis.Background: The IL-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived ''alarmin.'' Astegolimab, a human IgG 2 mAb, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (type 2-high), but limited options are available for patients with low blood eosinophils (type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics. Objectives: This study evaluated astegolimab efficacy and safety in patients with severe asthma. Methods: This double-blind, placebo-controlled, dose-ranging study (ZENYATTA [A Study to Assess the Efficacy and Safety of MSTT1041A in Participants With Uncontrolled Severe Asthma]) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg doses of astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at week 54. Enrollment caps ensured 30 patients who were eosinophil-high (> _300 cells/mL) and 95 patients who were eosinophil-low (<300 cells/mL) per arm. Results: Overall, adjusted AER reductions relative to placebo were 43% (P 5 .005), 22% (P 5 .18), and 37% (P 5 .01) for 490mg, 210-mg, and 70-mg doses of astegolimab, respectively. Adjusted AER reductions for patients who were eosinophil-low were comparable to reductions in the overall population: 54% (P 5 .002), 14% (P 5 .48), and 35% (P 5 .05) for 490-mg, 210mg, and 70-mg doses of astegolimab. Adverse events were similar in astegolimab-and placebo-treated groups. Conclusions: Astegolimab reduced AER in a broad population of patients, including those who were eosinophil-low, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated. (J Allergy Clin Immunol 2021;nnn:nnnnnn.)
Metastasis is one of the main causes of failure in the treatment of triple-negative breast cancer (TNBC). Immunotherapy brings hope and opportunity to solve this challenge, while its clinical applications are greatly inhibited by the tumor immunosuppressive environment. Here, an intelligent biomimetic nanoplatform was designed based on dendritic large-pore mesoporous silica nanoparticles (DLMSNs) for suppressing metastatic TNBC by combining photothermal ablation and immune remodeling. Taking advantage of the ordered large-pore structure and easily chemically modified property of DLMSNs, the copper sulfide (CuS) nanoparticles with high photothermal conversion efficiency were in situ deposited inside the large pores of DLMSNs, and the immune adjuvant resiquimod (R848) was loaded controllably. A homogenous cancer cell membrane was coated on the surfaces of these DLMSNs, followed by conjugation with the anti-PD-1 peptide AUNP-12 through a polyethylene glycol linker with an acid-labile benzoic-imine bond. The thus-obtained AM@DLMSN@CuS/R848 was applied to holistically treat metastatic TNBC in vitro and in vivo. The data showed that AM@DLMSN@CuS/R848 had a high TNBC-targeting ability and induced efficient photothermal ablation on primary TNBC tumors under 980 nm laser irradiation. Tumor antigens thus generated and increasingly released R848 by response to the photothermal effect, combined with AUNP-12 detached from AM@DLMSN@CuS/R848 in the weakly acidic tumor microenvironment, synergistically exerted tumor vaccination, and T lymphocyte activation functions on immune remodeling to prevent TNBC recurrence and metastasis. Taken together, this study provides an intelligent biomimetic nanoplatform to enhance therapeutic outcomes in metastatic TNBC.
Background “Western” style dietary patterns are characterized by a high proportion of highly processed foods rich in fat and low in fiber. This diet pattern is associated with a myriad of metabolic dysfunctions, including neuroinflammation and cognitive impairment. β-glucan, the major soluble fiber in oat and barley grains, is fermented in the lower gastrointestinal tract, potentially impacting the microbial ecosystem and thus may improve elements of cognition and brain function via the gut-brain axis. The present study aimed to evaluate the effect of β-glucan on the microbiota gut-brain axis and cognitive function in an obese mouse model induced by a high-fat and fiber-deficient diet (HFFD). Results After long-term supplementation for 15 weeks, β-glucan prevented HFFD-induced cognitive impairment assessed behaviorally by object location, novel object recognition, and nesting building tests. In the hippocampus, β-glucan countered the HFFD-induced microglia activation and its engulfment of synaptic puncta, and upregulation of proinflammatory cytokine (TNF-α, IL-1β, and IL-6) mRNA expression. Also, in the hippocampus, β-glucan significantly promoted PTP1B-IRS-pAKT-pGSK3β-pTau signaling for synaptogenesis, improved the synaptic ultrastructure examined by transmission electron microscopy, and increased both pre- and postsynaptic protein levels compared to the HFFD-treated group. In the colon, β-glucan reversed HFFD-induced gut barrier dysfunction increased the thickness of colonic mucus (Alcian blue and mucin-2 glycoprotein immunofluorescence staining), increased the levels of tight junction proteins occludin and zonula occludens-1, and attenuated bacterial endotoxin translocation. The HFFD resulted in microbiota alteration, effects abrogated by long-term β-glucan supplementation, with the β-glucan effects on Bacteroidetes and its lower taxa particularly striking. Importantly, the study of short-term β-glucan supplementation for 7 days demonstrated pronounced, rapid differentiating microbiota changes before the cognitive improvement, suggesting the possible causality of gut microbiota profile on cognition. In support, broad-spectrum antibiotic intervention abrogated β-glucan’s effects on improving cognition, highlighting the role of gut microbiota to mediate cognitive behavior. Conclusion This study provides the first evidence that β-glucan improves indices of cognition and brain function with major beneficial effects all along the gut microbiota-brain axis. Our data suggest that elevating consumption of β-glucan-rich foods is an easily implementable nutritional strategy to alleviate detrimental features of gut-brain dysregulation and prevent neurodegenerative diseases associated with Westernized dietary patterns.
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