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3.
J Inorg Biochem ; 202: 110857, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31669695

RESUMO

Thirteen novel palladium(II) complexes of the general formula [Pd(bipy)(O,O'-dkt)](PF6), (where bipy is 2,2'-bipyridine and O,O'-dkt is ß-diketonate ligand hispolon or its derivative) have been prepared through a metal-ligand coordination method that involves spontaneous formation of the corresponding diketonate scaffold. The obtained palladium(II) complexes have been characterized by NMR spectroscopy, ESI-mass spectrometry as well as elemental analysis. The cytotoxicity analysis indicates that most of the obtained palladium(II) complexes show promising growth inhibition in three human cancer cell lines. Flow cytometry analysis shows complex 3e could promote intracellular reactive oxygen species (ROS) accumulation and lead cancer cell death. And the suppression of ROS accumulation and the rescue of cell viability in HeLa cells by N-acetyl-L-cysteine (NAC) suggest the possible link between the increase in ROS generation and cytotoxicity of complex 3e. Flow cytometry analysis also reveal that complex 3e cause cell cycle arrest in the G2/M phase and collapse of the mitochondrial membrane potential, promote the generation of ROS and lead to tumor cell apoptosis. The interactions of complex 3e with calf thymus DNA (CT-DNA) have been evaluated by UV-Vis spectroscopy, fluorescence quenching experiments and viscosity measurements, which reveal that the complex interact with CT-DNA through minor groove binding and/or electrostatic interactions. Further, the results of fluorescence titration and site marker competitive experiment on bovine serum albumin (BSA) suggest that complex 3e can quench the fluorescence of BSA via a static quenching process and bind to BSA in Sudlow's site II.

4.
Trials ; 20(1): 674, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801593

RESUMO

BACKGROUND: Psoriasis is a chronic, immune-mediated disorder with chronic plaque psoriasis being the primary manifestation during the remission stage. Patients often have a slow course and long history of the disease. The refractory type of psoriasis is a stubborn rash that does not subside easily. We designed this randomized controlled trial to compare the effectiveness and relapse rates of plaque psoriasis in patients treated with either acupuncture, moxibustion or calcipotriol ointment. The ultimate aim of the study is to select an effective traditional Chinese medicine therapy for patients with plaque psoriasis. METHODS: The study will be a multicenter, prospective, randomized controlled trial that compares the effectiveness of fire needle therapy, moxibustion and calcipotriol ointment. In total, 160 patients with plaque psoriasis who meet the inclusion criteria will be recruited from three hospitals in Beijing and then randomly assigned to receive either fire needle therapy (group A1), moxibustion (group A2) or calcipotriol ointment (group B). All participants will receive an 8-week treatment and will then be followed up for another 24 weeks, with time points at weeks 12 and 24 after treatment completion. The primary outcomes to be measured are relapse rates and psoriasis area and severity index score of the target lesions. In addition, the target lesion onset time, dermatology life quality index, traditional Chinese medicine syndrome score, and the relapse interval of the target lesion will be measured. Adverse events will be recorded for safety assessment. DISCUSSION: The aim of this study is to determine whether fire needle therapy or moxibustion could improve the clinical effectiveness for psoriasis lesions and reduce the relapse rate. Once completed, it will provide information regarding therapeutic evaluation on fire needle therapy or moxibustion for plaque psoriasis, which will assist clinicians in selecting the most effective treatment options for patients. TRIAL REGISTRATION: International Clinical Trials Registry Platform (ICTRP), ChiCTR1800019588. Registered on 19 November 2018.

5.
Commun Biol ; 2: 392, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31667366

RESUMO

Programmed cell death 1 (PD-1) is inhibitory receptor and immune checkpoint protein. Blocking the interaction of PD-1 and its ligands PD-L1/ L2 is able to active T-cell-mediated antitumor response. Monoclonal antibody-based drugs targeting PD-1 pathway have exhibited great promise in cancer therapy. Here we show that MW11-h317, an anti-PD-1 monoclonal antibody, displays high affinity for PD-1 and blocks PD-1 interactions with PD-L1/L2. MW11-h317 can effectively induce T-cell-mediated immune response and inhibit tumor growth in mouse model. Crystal structure of PD-1/MW11-h317 Fab complex reveals that both the loops and glycosylation of PD-1 are involved in recognition and binding, in which Asn58 glycosylation plays a critical role. The unique glycan epitope in PD-1 to MW11-h317 is different from the first two approved clinical PD-1 antibodies, nivolumab and pembrolizumab. These results suggest MW11-h317 as a therapeutic monoclonal antibody of PD-1 glycosylation-targeting which may become efficient alternative for cancer therapy.

6.
Nano Lett ; 19(12): 8476-8487, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31711283

RESUMO

In contrast to the booming production and application of nanomaterials, research on the toxicological impacts and possible hazards of nanoparticles to tissues and organs is still in its infancy. Golgi apparatus is one of the most important organelles in cells and plays a key role in intracellular protein processing. The structural integrity of Golgi is vital for its normal function, and Golgi disturbance could result in a wide range of diseases and disorders. In this study, for the first time we found gold nanoparticles (Au NPs) induced size-dependent cytoplasmic calcium increase and Golgi fragmentation, which hampers normal Golgi functions, leads to abnormal protein processing, and causes cellular adhesion decrease, while cell viability was not significantly compromised. Additionally, early renal pathological changes were induced in vivo. This work is significant to nanoparticle research because it illustrates the important role of size on Au NP-induced changes in Golgi morphology and their consequences in vitro and in vivo, which has important implications for the biological applications of nanomaterials.

7.
Bioconjug Chem ; 30(11): 2828-2843, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31592652

RESUMO

A smart theranostic prodrug IMC-FDU-TZBC-NO2, releasing active drug on-demand based on hypoxia-activated and indomethacin-mediated, for solid tumor imaging and efficient therapy was designed. This prodrug was constructed by conjugating chemotherapy drug 5-fluoro-2-deoxyuridine (FDU), targeting moiety indomethacin (IMC), and the hypoxic trigger 4-nitrobenzyl group to a fluorescent dye precursor, which was mediated by IMC and activated by NTR under hypoxic conditions. The fluorescent dye IMC-TZBCM was generated and FDU was released at the same time in tumor cells. The rates and amounts of FDU release and IMC-TZBCM generation were regulated by hypoxia status, and increased with increasing degree of hypoxia. Nevertheless, it is "locked" in normal cells. It combined the advantages of tumor targeting, diagnosis, and chemotherapy functions, showed excellent targeting ability to cancer cells, excellent stability in physiological conditions, high cellular uptake efficiency, and on-demand drug release behavior. The in vitro and in vivo assays demonstrated that IMC-FDU-TZBC-NO2 exhibits enhanced anticancer potency and low side effects. The novel targeted theranostic prodrug activated by hypoxia shows a great potential in cancer therapy.

8.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(8): 1039-1042, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31537236

RESUMO

OBJECTIVE: To apply the concept of evidence-based nursing in the practice of inhalation therapy for patients with chronic obstructive pulmonary disease (COPD) complicated respiratory failure, introduce the application method of self-made anti-carbon dioxide retention atomizer, and to observe the application effect. METHODS: Patients with COPD combine respiratory failure admitted to the respiratory department of Harrison International Peace Hospital Affiliated to Hebei Medical University from May 2018 to April 2019 were enrolled. All patients received atomization inhalation therapy in addition to anti-infection and spasmolysis. By using self-made carbon dioxide retention atomizer time node, 40 patients in the prospective study using home-made carbon dioxide retention atomizer inhalation therapy from November 2018 to April 2019 were enrolled as observation group. Through evidence-based nursing strategy, the related literature at home and abroad was retrieved, to find the clinical evidence, formulation and implementation of care plan. Forty patients who received inhalation therapy with normal mask atomizer from May to October in 2018 were enrolled as the control group in the retrospective analysis. The peripheral arterial blood gas analysis indexes [pH value, arterial oxygen partial pressure (PaO2), arterial carbon dioxide partial pressure (PaCO2)], the disappearance of pulmonary asthma at 5 minutes before atomization inhalation and 20 minutes after atomization inhalation, and the patient's cooperation in treatment were compared between the two groups. RESULTS: All patients were included in the final analysis. There was no significant difference in blood gas analysis indexes between the two groups. After 20 minutes of atomization inhalation, the pH value, PaO2 and PaCO2 of the two groups were improved, and the improvement was more obvious in the observation group [pH value: 7.32±0.35 vs. 7.25±1.25, PaO2 (mmHg, 1 mmHg = 0.133 kPa) : 61.50±1.55 vs. 59.50±1.05, PaCO2 (mmHg) : 43.25±1.65 vs. 49.05±1.75, all P < 0.05]. The lung asthma in the two groups was significantly improved with 20 minutes of atomization inhalation as compared with that before atomization, and the improvement of lung asthma in the observation group was significantly better than that in the control group (asthma score: 0.91±0.29 vs. 1.65±0.35, P < 0.05). The good coordination rate of the observation group was significantly higher than that of the control group [90% (36/40) vs. 70% (28/40), χ2 = 3.828, P = 0.048]. CONCLUSIONS: Compared with the inhalation treatment with ordinary mask nebulizer, inhalation treatment with self-made anti-carbon dioxide retention atomizer for COPD patients with respiratory failure can reduce carbon dioxide retention, significantly improve respiratory failure symptoms and improve compliance.


Assuntos
Nebulizadores e Vaporizadores , Doença Pulmonar Obstrutiva Crônica , Insuficiência Respiratória , Dióxido de Carbono , Humanos , Estudos Prospectivos , Estudos Retrospectivos
9.
ACS Nano ; 13(7): 7556-7567, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31259530

RESUMO

Bone metastasis, a clinical complication of patients with advanced breast cancer, seriously reduces the quality of life. To avoid destruction of the bone matrix, current treatments focus on inhibiting the cancer cell growth and the osteoclast activity through combination therapy. Therefore, it could be beneficial to develop a bone-targeted drug delivery system to treat bone metastasis. Here, a bone-targeted nanoplatform was developed using gold nanorods enclosed inside mesoporous silica nanoparticles (Au@MSNs) which were then conjugated with zoledronic acid (ZOL). The nanoparticles (Au@MSNs-ZOL) not only showed bone-targeting ability in vivo but also inhibited the formation of osteoclast-like cells and promoted osteoblast differentiation in vitro. The combination of Au@MSNs-ZOL and photothermal therapy (PTT), triggered by near-infrared irradiation, inhibited tumor growth both in vitro and in vivo and relieved pain and bone resorption in vivo by inducing apoptosis in cancer cells and improving the bone microenvironment. This single nanoplatform combines ZOL and PTT to provide an exciting strategy for treating breast cancer bone metastasis.

10.
Biotechnol Adv ; 37(5): 801-825, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31034960

RESUMO

Recently, United States Food and Drug Administration (FDA) and European Commission (EC) approved Alnylam Pharmaceuticals' RNA interference (RNAi) therapeutic, ONPATTRO™ (Patisiran), for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. This is the first RNAi therapeutic all over the world, as well as the first FDA-approved treatment for this indication. As a milestone event in RNAi pharmaceutical industry, it means, for the first time, people have broken through all development processes for RNAi drugs from research to clinic. With this achievement, RNAi approval may soar in the coming years. In this paper, we introduce the basic information of ONPATTRO and the properties of RNAi and nucleic acid therapeutics, update the clinical and preclinical development activities, review its complicated development history, summarize the key technologies of RNAi at early stage, and discuss the latest advances in delivery and modification technologies. It provides a comprehensive view and biotechnological insights of RNAi therapy for the broader audiences.

11.
Adv Healthc Mater ; 8(13): e1900160, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30969015

RESUMO

Cancer stem cells (CSCs) are responsible for malignant tumor initiation, recurrences, and metastasis. Therefore, targeting CSCs is a promising strategy for the development of cancer therapies. A big challenge for CSC-based cancer therapy is the overexpression of therapeutic stress protein, heat shock protein 90 (Hsp90), which protects CSCs from further therapeutic-induced damage, leading to the failure of treatment. Thus, efficient strategies to target CSCs are urgently needed for cancer therapy. To this end, a multifunctional nanoparticle (MNP) for CSC-based combined thermotherapy and chemotherapy is reported. This strategy dramatically suppresses tumor growth in breast CSC xenograft-bearing mice. Furthermore, a new mechanism is present that the MNP exerts its striking effects on CSCs by inhibiting the secretion of extracellular Hsp90 (eHsp90), resulting in the interruption of several key signaling pathways. These findings open new perspectives on the use of an MNP for effective CSC-based cancer treatment by inhibiting the function of eHsp90.

12.
Nanomaterials (Basel) ; 9(2)2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30759830

RESUMO

An equiatomic TiZrHfMoNb high-entropy alloy (HEA) was developed as a solar thermal energy storage material due to its outstanding performance of hydrogen absorption. The TiZrHfMoNb alloy transforms from a body-centered cubic (BCC) structure to a face-centered cubic (FCC) structure during hydrogen absorption and can reversibly transform back to the BCC structure after hydrogen desorption. The theoretical calculations demonstrated that before hydrogenation, the BCC structure for the alloy has more stable energy than the FCC structure while the FCC structure is preferred after hydrogenation. The outstanding hydrogen absorption of the reversible single-phase transformation during the hydrogen absorption⁻desorption cycle improves the hydrogen recycling rate and the energy efficiency, which indicates that the TiZrHfMoNb alloy could be an excellent candidate for solar thermal energy storage.

13.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(1): 118-121, 2019 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-30707882

RESUMO

OBJECTIVE: To apply the concept of evidence-based nursing to the practice of non-invasive ventilation, and to introduce the method of using self-made pressure-resistant cap cotton cover and its application effect. METHODS: Fifty patients on non-invasive ventilation admitted to intensive care unit (ICU) of Harrison International Peace Hospital Affiliated to Hebei Medical University from September 2017 to April 2018 were enrolled as observation group. By retrieved the relevant literature at home and abroad to look for clinical evidence, the concept of evidence-based nursing care program was formulated and implemented, and self-made pressure-resistant cap cotton cover was used to prevent facial pressure sores in patients on non-invasive ventilation. Forty non-invasive ventilation patients admitted from January to August in 2017 were enrolled as the historical control group, and conventional nursing was conducted by using traditional hydrocolloid dressings to prevent pressure ulcers. The incidence of facial pressure ulcers, ocular complications, dressing replacement time and cost were compared between the two groups. RESULTS: All patients were enrolled in the final analysis. The incidence of pressure ulcers in the observation group was significantly lower than that in the control group [4.0% (2/50) vs. 22.5% (9/40), P < 0.05], and the incidences of ocular complications such as eyelid swelling [2.0% (1/50) vs. 5.0% (2/40)], conjunctival congestion [2.0% (1/50) vs. 5.0% (2/40)] and irritant keratitis [0% (0/50) vs. 7.5% (3/40)] were also significantly lower than those in the control group (P < 0.05). Because the pressure-resistant cap cotton cover made by ourselves was easy to be replaced at any time, the interval time of dressing change in the observation group was significantly shorter than that in the control group (minutes: 1.5±0.5 vs. 2.0±0.5, P < 0.05). In addition it could be cleaned, used alternately, and the cost was low, so the dressing cost in the observation group was significantly lower than that in the control group (Yuan: 30±10 vs. 123±20, P < 0.01). CONCLUSIONS: The application of self-made pressure-resistant cap cotton cover could obviously reduce the occurrence of complications such as facial pressure sores in patients on non-invasive ventilation.


Assuntos
Ventilação não Invasiva/instrumentação , Lesão por Pressão/prevenção & controle , Prática Clínica Baseada em Evidências , Face , Humanos , Unidades de Terapia Intensiva , Pressão/efeitos adversos , Lesão por Pressão/epidemiologia
14.
Biomaterials ; 200: 1-14, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30743049

RESUMO

Many efforts have focused on the cancer stem cell (CSC) targeting nano delivery system, however, the anticancer therapy efficacy is relative low due to the highly drug-resistance and drug efflux. Nucleus-targeted drug delivery is a promising strategy for reverse the drug resistance and drug efflux of CSCs, but in vivo nucleus-targeted drug delivery has been challenging. Herein, we designed a mesoporous silica nanoparticle (MSN)-based nucleus-targeted system, which could directly target the CSCs and further enter the nucleus by the surface modification of anti-CD133 and thermal-triggered exposure of TAT peptides under an alternating magnetic field (AMF). The nucleus-targeted drug release ultimately leads to an exhaustive apoptosis of the CSCs through combined thermotherapy and hypoxia-activated chemotherapy. In vivo, the nucleus-targeted nano delivery system efficiently inhibits the tumor growth without notable side effects during the course of treatment. Molecular mechanism study illustrates that the system effectively eliminates the CSCs by blocking the hypoxia signaling pathway. This designed nucleus-targeted nano delivery system is expected to provide new insights for developing efficient platforms for CSC-targeted cancer therapy.

15.
Methods Mol Biol ; 1880: 511-528, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30610718

RESUMO

Anucleate platelets are produced by fragmentation of megakaryocytes. Platelets circulate in the bloodstream for a finite period: upon vessel injury, they are activated to participate in hemostasis; upon senescence, unused platelets are cleared. Platelet hypofunction leads to bleeding. Conversely, pathogenic platelet activation leads to occlusive events that precipitate strokes and heart attacks. Recently, we and others have shown that autophagy occurs in platelets and is important for platelet production and normal functions including hemostasis and thrombosis. Due to the unique properties of platelets, such as their lack of nuclei and their propensity for activation, methods for studying platelet autophagy must be specifically tailored. Here, we describe useful methods for examining autophagy in both human and mouse platelets.


Assuntos
Autofagossomos/ultraestrutura , Autofagia/fisiologia , Plaquetas/fisiologia , Microscopia Intravital/métodos , Animais , Autofagossomos/fisiologia , Plaquetas/citologia , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/genética , Voluntários Saudáveis , Hemostasia/fisiologia , Humanos , Microscopia Intravital/instrumentação , Megacariócitos/fisiologia , Camundongos , Camundongos Transgênicos , Microscopia Confocal/instrumentação , Microscopia Confocal/métodos , Microscopia Eletrônica de Transmissão/instrumentação , Microscopia Eletrônica de Transmissão/métodos , Proteínas Associadas aos Microtúbulos/análise , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo
16.
ACS Nano ; 13(1): 313-323, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30571089

RESUMO

Y2O3 nanoparticles (NPs) have become great promising products for numerous applications in nanoscience especially for biomedical application, therefore increasing the probability of human exposure and gaining wide attention in biosecurity. It is well known that rare earth (RE) materials are deposited in the bone and excreted very slowly. Nevertheless, the effect of Y2O3-based NPs on bone metabolism has not been exactly known yet. In the present study, the effects of Y2O3 NPs on bone marrow stromal cells (BMSCs) and bone metabolism in mice after intravenous injection were studied. The results demonstrated that Y2O3 NPs could be taken up into BMSCs and localized in acidifying intracellular lysosomes and underwent dissolution and transformation from Y2O3 to YPO4, which could lead to a break in the intracellular phosphate balance and induce lysosomal- and mitochondrial-dependent apoptosis pathways. Furthermore, after being administered to mice, a higher concentration of yttrium occurred in bone, which caused the apoptosis of bone cells and induced the destruction of bone structure. However, the formation of a YPO4 coating on the surface of Y2O3 NPs by pretreatment of Y2O3 NPs in lysosome-simulated body fluid could observably decrease the toxicity in vivo and in vitro. This study may be useful for practical application of Y2O3 NPs in the biomedical field.


Assuntos
Células da Medula Óssea/efeitos dos fármacos , Nanopartículas/toxicidade , Fosfatos/metabolismo , Ítrio/toxicidade , Animais , Apoptose , Células da Medula Óssea/metabolismo , Catepsinas/metabolismo , Células Cultivadas , Feminino , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias/genética , Mitocôndrias/metabolismo , Nanopartículas/química , Ítrio/química , Ítrio/farmacocinética
17.
Cell Physiol Biochem ; 50(2): 679-693, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30308521

RESUMO

BACKGROUND/AIMS: Abnormal regulation of cholesterol homeostasis is associated with type 2 diabetes mellitus (T2DM) and multiple other diseases. Glucagon-like peptide-1 (GLP-1) has unique effects on modulating hepatic lipid metabolism. However, the mechanism behind these is largely unknown. The aim of this study was to investigate the effects of GLP-1 on cholesterol-induced lipotoxicity in hepatocytes and examine the underlying mechanisms. METHODS: Cell viability was determined by CCK-8. Caspase-3 detection was used to assess the effects of GLP-1 on cholesterol-induced apoptosis. TNF-α and IL-6 as the inflammatory markers were measured by ELISA. The alterations of miR-19b and ATP-binding cassette transporter A1 (ABCA1) resulting from high-fat diet/cholesterol incubation or GLP-1 were detected by real-time PCR and western blot. RESULTS: GLP-1 markedly up-regulated the expression of ABCA1 protein, but didn't affect peroxisome proliferator-activated receptor α (PPAR-α) protein. The miR-19b levels were significantly down-regulated in GLP-1-treated groups. The inhibition and overexpression of miR-19b were established to explore the effects of a GLP-1-mediated alteration in miR-19b. Cholesterol transport assays revealed that treatment with GLP-1 alone or together with miR-19b inhibitor significantly enhanced ABCA1-dependent cholesterol efflux, resulting in reduced total cholesterol. Further, histological examination was used to detect lipid accumulation. Cholesterol significantly attenuated cell viability, promoted hepatic cell apoptosis, and facilitated lipid accumulation, and these effects could be reversed by GLP-1. CONCLUSION: GLP-1 may affect cholesterol homeostasis by regulating the expression of miR-19b and ABCA1.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/metabolismo , Regulação para Baixo/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , MicroRNAs/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Antagomirs/metabolismo , Apoptose , Diabetes Mellitus Tipo 2 , Dieta Hiperlipídica , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , PPAR alfa/genética , PPAR alfa/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/sangue
18.
Bioconjug Chem ; 29(10): 3332-3343, 2018 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-30192132

RESUMO

A novel anticancer theranostic prodrug, FDU-DB-NO2, specifically activated by hypoxia for selective two-photon imaging hypoxia status, real-time tracking drug release, and solid tumor therapy was designed. The devised prodrug consists of an anticancer drug floxuridine (FDU), a fluorescence dye precursor 4'-(diethylamino)-1,1'-biphenyl-2-carboxylate (DB), and a hypoxic trigger 4-nitrobenzyl group. In normal cells, FDU-DB-NO2 is "locked". Whereas in tumor cells, the prodrug is "unlocked" by hypoxia and results in fluorescent dye 7-(diethylamino)coumarin (CM) generation along with FDU release. The amounts and rates of CM formation and FDU release were controlled by hypoxic status and increased with the decreasing of the O2 concentration. The hypoxic status, distribution of oxygen, and amount of FDU release in tumor cells, spheroids, and tumor tissue could be visualized by fluorescence. FDU-DB-NO2 showed high cytotoxicity against hypoxic MCF-7 and MCG-803 cell lines and no cytotoxicity against normoxic BRL-3A cells and exhibited effective inhibition on tumor growth of MCF-7-cell-inoculated xenograft nude mice. This strategy may provide a promising platform for selective two-photon imaging hypoxia status, real-time tracking drug release, and personalized solid tumor treatment.


Assuntos
Antineoplásicos/farmacologia , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/farmacocinética , Liberação Controlada de Fármacos , Floxuridina/farmacologia , Corantes Fluorescentes/química , Humanos , Células MCF-7 , Camundongos Nus , Imagem Óptica , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Nano Lett ; 18(10): 6301-6311, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30240228

RESUMO

Efficient small interfering RNA (siRNA) delivery in the presence of serum is of crucial importance for effective gene therapy. Fluorinated vectors are considered to be attractive candidates for siRNA-mediated gene therapy because of their delivery efficacy in serum-containing media. However, the mechanisms driving the superior gene transfection behavior of fluorinated vectors are still not well-understood, and comprehensive investigations are warranted. Herein, we fabricated a library of perfluorooctanoyl fluoride-fluorinated (PFF-fluorinated) oligoethylenimines (f xOEIs, x is the PFF:OEI feeding ratio), which can readily form nanoassemblies (f xOEI NAs) capable of efficient siRNA delivery in cells cultured in medium both devoid of and supplemented with fetal bovine serum (FBS). The gene silencing test in serum-containing medium revealed that the f0.7OEI/siRNA NAs achieved a luciferase silencing of ∼88.4% in Luc-HeLa cells cultured in FBS-containing medium, which was almost 2-fold greater than the silencing efficacy of siRNA delivered by the commercially available vector Lipo 2000 (∼48.8%). High levels of apolipoprotein B silencing were also achieved by f0.7OEI/siRNA NAs in vivo. For an assessment of the underlying mechanisms of the efficacy of gene silencing of fluorinated vectors, two alkylated OEIs, aOEI-C8 and aOEI-C12, were fabricated as controls with similar molecular structure and hydrophobicity to that of f0.7OEI, respectively. In vitro investigations showed that the superior gene delivery exhibited by f0.7OEI NAs derived from the potent endosomal disruption capability of fluorinated vectors in the presence of serum, which was essentially attributed to the serum protein adsorption resistance of the f0.7OEI NAs. Therefore, this work provides an innovative approach to siRNA delivery as well as insights into fluorine-associated serum resistance.

20.
Blood Adv ; 2(17): 2187-2198, 2018 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-30185436

RESUMO

We genetically manipulated the major platelet vesicle-associated membrane proteins (VAMP2, VAMP3, and VAMP8) to create mice with varying degrees of disrupted platelet secretion. As previously shown, loss of VAMP8 reduced granule secretion, and this defect was exacerbated by further deletion of VAMP2 and VAMP3. VAMP2Δ3Δ8-/- platelets also had reduced VAMP7. Loss of VAMP2 and VAMP3 (VAMP2Δ3Δ) had a minimal impact on secretion when VAMP7 and VAMP8 were present. Integrin αIIbß3 activation and aggregation were not affected, although spreading was reduced in VAMP2Δ3Δ8-/- platelets. Using these mice as tools, we asked how much secretion is needed for proper thrombosis and hemostasis in vivo. VAMP2Δ3Δ mice showed no deficiency, whereas VAMP8-/- mice had attenuated formation of occlusive thrombi upon FeCl3-induced arterial injury but no excessive bleeding upon tail transection. VAMP2Δ3Δ8-/- mice bled profusely and failed to form occlusive thrombi. Plasma-coagulation factors were normal in all of the strains, but phosphatidylserine exposure was reduced in VAMP2Δ3Δ and VAMP2Δ3Δ8-/- platelets. From our data, an ∼40% to 50% reduction in platelet secretion in vitro (dense and α granule) correlated with reduced occlusive thrombosis but no compromise in hemostasis. At a >50% reduction, thrombosis and hemostasis were defective in vivo. Our studies are the first systematic manipulation of platelet exocytic machinery to demonstrate a quantitative linkage between in vitro platelet secretion and hemostasis and thrombosis in vivo. The animals described will be invaluable tools for future investigations into how platelet secretion affects other vascular processes.


Assuntos
Plaquetas/metabolismo , Hemostasia/fisiologia , Trombose/etiologia , Animais , Fatores de Coagulação Sanguínea/análise , Camundongos , Fosfatidilserinas/metabolismo , Proteínas R-SNARE/genética
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