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1.
J Control Release ; 360: 496-513, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37423524

RESUMO

CRISPR/Cas9-based genome editing is promising for therapy of cervical cancer by precisely targeting human papillomavirus (HPV). To develop CRISPR/Cas9-based genome editing nanotherapies, a pH-responsive hybrid nonviral nanovector was constructed for co-delivering Cas9 mRNA and guide RNAs (gRNAs) targeting E6 or E7 oncogenes. The pH-responsive nanovector was fabricated using an acetalated cyclic oligosaccharide (ACD), in combination with low molecular weight polyethyleneimine. Thus obtained hybrid ACD nanoparticles (defined as ACD NP) showed efficient loading for both Cas9 mRNA and E6 or E7 gRNA, giving rise to two pH-responsive genome editing nanotherapies E6/ACD NP and E7/ACD NP, respectively. Cellularly, ACD NP exhibited high transfection but low cytotoxicity in HeLa cervical carcinoma cells. Also, efficient genome editing of target genes was achieved in HeLa cells, with minimal off-target effects. In mice bearing HeLa xenografts, treatment with E6/ACD NP or E7/ACD NP afforded effective editing of target oncogenes and considerable antitumor activities. More importantly, treatment with E6/ACD NP or E7/ACD NP notably promoted CD8+ T cell survival by reversing the immunosuppressive microenvironment, thereby leading to synergistic antitumor effects by combination therapy using the gene editing nanotherapies and adoptive T-cell transfer. Consequently, our pH-responsive genome editing nanotherapies deserve further development for the treatment of HPV-associated cervical cancer, and they can also serve as promising nanotherapies to improve efficacies of other immune therapies against different advanced cancers by regulating the immunosuppressive tumor microenvironment.


Assuntos
Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Camundongos , Animais , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/patologia , Edição de Genes , Células HeLa , RNA Mensageiro/genética , Imunossupressores , Terapia Baseada em Transplante de Células e Tecidos , Proteínas E7 de Papillomavirus/genética , Microambiente Tumoral
2.
Acta Pharm Sin B ; 13(1): 390-409, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36815041

RESUMO

Uncontrolled and persistent inflammation is closely related to numerous acute and chronic diseases. However, effective targeting delivery systems remain to be developed for precision therapy of inflammatory diseases. Herein we report a novel strategy for engineering inflammation-accumulation nanoparticles via phenolic functionalization. Different phenol-functionalized nanoparticles were first developed, which can undergo in situ aggregation upon triggering by the inflammatory/oxidative microenvironment. Phenolic compound-decorated poly (lactide-co-glycolide) nanoparticles, in particular tyramine (Tyr)-coated nanoparticles, showed significantly enhanced accumulation at inflammatory sites in mouse models of colitis, acute liver injury, and acute lung injury, mainly resulting from in situ cross-linking and tissue anchoring of nanoparticles triggered by local myeloperoxidase and reactive oxygen species. By combining a cyclodextrin-derived bioactive material with Tyr decoration, a multifunctional nanotherapy (TTN) was further developed, which displayed enhanced cellular uptake, anti-inflammatory activities, and inflammatory tissue accumulation, thereby affording amplified therapeutic effects in mice with colitis or acute liver injury. Moreover, TTN can serve as a bioactive and inflammation-targeting nanoplatform for site-specifically delivering a therapeutic peptide to the inflamed colon post oral administration, leading to considerably potentiated in vivo efficacies. Preliminary studies also revealed good safety of orally delivered TTN. Consequently, Tyr-based functionalization is promising for inflammation targeting amplification and therapeutic potentiation of nanotherapies.

3.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-940709

RESUMO

ObjectiveThe law of fertilizer requirement serves as the basis for the fertilization of medicinal plants, development of special fertilizer, and high-quality medicinal materials. MethodThis study aims to explore the optimal potassium application rate for Panax ginseng to achieve high yield and quality of the medicinal material and targeted management of potassium fertilizer. To be specific, 6 concentration gradients (0, 2, 4, 8, 10, and 12 mmol·L-1) of potassium sulfate (potassium fertilizer) were designed and applied to the 4-year-old P. ginseng in CK, C1, C2, C3, C4, and C5 treatments, respectively. Thereby, the influence of potassium concentration on P. ginseng was observed. ResultWhen potassium sulfate was applied at 8 mmol·L-1, P. ginseng had the chlorophyll content of 32.13%, net photosynthetic rate of 2.548 8 µmol·m-2·s-1, and activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) significantly higher than those in the CK, C1, C4, and C5 treatments (P<0.05). The average fresh weight of P. ginseng roots was 6.25 g, 134% up from the CK, and the content of ginsenoside Rg1 (5.24 mg·g-1) and Re (4.17 mg·g-1) and total saponins (12.33 mg·g-1) was significantly higher than that in CK and other treatments (P<0.05). Thus, 8 mmol·L-1 potassium sulfate was most favorable for the growth and effective component accumulation of four-year-old P. ginseng. ConclusionThis study expounds the effect of potassium fertilizer on the yield and quality of P. ginseng, which is expected to help guide the precise application of potassium fertilizer in P. ginseng production in the field and lay a theoretical basis for the development of special fertilizer for P. ginseng and the optimization of fertilization technology.

4.
Nanotechnology ; 32(39)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34153956

RESUMO

Currently, a single treatment is less effective for triple-negative breast cancer (TNBC) therapy. Additionally, there are some limitations to the use of siRNA alone as a new method to treat breast cancer, such as its effective delivery into cells. In this study, we proposed a strategy that combines a siRNA-loaded DNA nanostructure and genistein for TNBC therapy. Both CD36 siRNA-loaded self-assembled DNA nanoprisms (NP-siCD36) and genistein knocked down CD36, resulting in enhanced anticancer efficacy through phosphorylation of the p38 MAPK pathway.In vitrostudies showed that combination therapy could effectively enhance cell apoptosis and reduce cell proliferation, achieving an antitumor effect in TNBC cells. The current study suggests that NP-siCD36 combined with genistein might be a promising strategy for breast cancer and treatment.


Assuntos
Antineoplásicos , Antígenos CD36/genética , Nanoestruturas/química , RNA Interferente Pequeno/genética , Neoplasias de Mama Triplo Negativas , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antígenos CD36/metabolismo , Linhagem Celular Tumoral , DNA/química , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Feminino , Genisteína/metabolismo , Genisteína/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
J Control Release ; 327: 641-666, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-32911014

RESUMO

Inflammation is intimately related to the pathogenesis of numerous acute and chronic diseases like cardiovascular disease, inflammatory bowel disease, rheumatoid arthritis, and neurodegenerative diseases. Therefore anti-inflammatory therapy is a very promising strategy for the prevention and treatment of these inflammatory diseases. To overcome the shortcomings of existing anti-inflammatory agents and their traditional formulations, such as nonspecific tissue distribution and uncontrolled drug release, bioresponsive drug delivery systems have received much attention in recent years. In this review, we first provide a brief introduction of the pathogenesis of inflammation, with an emphasis on representative inflammatory cells and mediators in inflammatory microenvironments that serve as pathological fundamentals for rational design of bioresponsive carriers. Then we discuss different materials and delivery systems responsive to inflammation-associated biochemical signals, such as pH, reactive oxygen species, and specific enzymes. Also, applications of various bioresponsive drug delivery systems in the treatment of typical acute and chronic inflammatory diseases are described. Finally, crucial challenges in the future development and clinical translation of bioresponsive anti-inflammatory drug delivery systems are highlighted.


Assuntos
Sistemas de Liberação de Medicamentos , Doenças Inflamatórias Intestinais , Liberação Controlada de Fármacos , Humanos , Inflamação/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Distribuição Tecidual
6.
ACS Nano ; 14(9): 11083-11099, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32790342

RESUMO

Liver injury can result in different hepatic diseases such as fatty liver, liver fibrosis, hepatitis, and liver failure, which are mainly responsible for global mortality and morbidity. Early diagnosis is critical for the treatment of liver diseases. Herein we report luminescence imaging of neutrophil-mediated acute liver injury, including alcoholic liver injury (ALI) and acute liver failure (ALF). To this purpose, a biodegradable luminescent material was developed by chemical functionalization of a cyclic oligosaccharide, which can be produced into nanoprobes (defined as LaCD NPs). Luminescence of LaCD NPs was dependent on the level of reactive oxygen species and myeloperoxidase (MPO). Correspondingly, activated neutrophils could be specifically imaged by LaCD NPs, and the luminescent signal was positively associated with the neutrophil count. In mouse models of ALI and ALF, LaCD NPs enabled precise quantification and tracking of neutrophils in livers. In both cases, changes in the luminescence intensity are consistent with time-dependent profiles of neutrophils, MPO, and other parameters relevant to the pathogenesis of liver injury. Moreover, the luminescence imaging capacity of LaCD NPs can be additionally improved by surface functionalization with a neutrophil-targeting peptide. In addition, preliminary in vitro and in vivo studies demonstrated good safety of LaCD NPs. Consequently, LaCD NPs can be further developed as an effective and biocompatible luminescent nanoprobe for in vivo dynamic detection of the development of neutrophil-mediated acute liver injury. It is also promising for diagnosis of other neutrophil-associated liver diseases.


Assuntos
Falência Hepática Aguda , Luminescência , Animais , Modelos Animais de Doenças , Fígado/diagnóstico por imagem , Falência Hepática Aguda/diagnóstico por imagem , Camundongos , Neutrófilos
7.
Adv Mater ; 31(46): e1904607, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31583783

RESUMO

Inflammation is a common cause of many acute and chronic inflammatory diseases. A major limitation of existing anti-inflammatory therapeutics is that they cannot simultaneously regulate pro-inflammatory cytokine production, oxidative stress, and recruitment of neutrophils and macrophages. To overcome this limitation, nanoparticles (NPs) with multiple pharmacological activities are synthesized, using a chemically modified cyclic oligosaccharide. The manufacture of this type of bioactive, saccharide material-based NPs (defined as LCD NP) is straightforward, cost-effective, and scalable. Functionally, LCD NP effectively inhibits inflammatory response, oxidative stress, and cell migration for both neutrophils and macrophages, two major players of inflammation. Therapeutically, LCD NP shows desirable efficacies for the treatment of acute and chronic inflammatory diseases in mouse models of peritonitis, acute lung injury, and atherosclerosis. Mechanistically, the therapeutic benefits of LCD NP are achieved by inhibiting neutrophil-mediated inflammatory macrophage recruitment and by preventing subsequent pro-inflammatory events. In addition, LCD NP shows good safety profile in a mouse model. Thus, LCD NP can serve as an effective anti-inflammatory nanotherapy for the treatment of inflammatory diseases mainly associated with neutrophil and macrophage infiltration.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Nanopartículas/química , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacologia , Doença Aguda , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/uso terapêutico , Transporte Biológico , Doença Crônica , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Células RAW 264.7 , beta-Ciclodextrinas/metabolismo , beta-Ciclodextrinas/uso terapêutico
8.
Theranostics ; 9(13): 3732-3753, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281510

RESUMO

Colitis-associated colon cancer (CAC) is a widely recognized cancer, while treatment with the existing chemotherapeutic drugs affords limited clinical benefits. Herein we proposed a site-specific, combination nanotherapy strategy for targeted treatment of CAC by the oral route. Methods: A reactive oxygen species (ROS)-responsive and hydrogen peroxide-eliminating material OCD was synthesized, which was further produced into a functional nanoparticle (OCD NP). The antioxidative stress and anti-inflammatory effects of OCD NP were examined by in vitro and in vivo experiments. By packaging an anticancer drug camptothecin-11 (CPT-11) into OCD NP, a ROS-responsive nanotherapy CPT-11/OCD NP was obtained, and its antitumor activity was evaluated by both in vitro and in vivo studies. Preliminary safety studies were also performed for CPT-11/OCD NP in mice. Results: OCD NP significantly attenuated oxidative stress and inhibited inflammatory response in different cells and mice with induced colitis. CPT-11/OCD NP could selectively release drug molecules under intestinal pH conditions and at high levels of ROS. In C26 murine colon carcinoma cells, this nanotherapy showed significantly higher antitumor activity compared to free CPT-11 and a non-responsive CPT-11 nanotherapy. Correspondingly, oral delivery of CPT-11/OCD NP notably inhibited tumorigenesis and tumor growth in mice with induced CAC. By combination therapy with the nanovehicle OCD NP in the inflammatory phase, more desirable therapeutic effects were achieved. Furthermore, CPT-11/OCD NP displayed excellent safety profile for oral administration at a dose that is 87.3-fold higher than that employed in therapeutic studies. Conclusions: Anticancer nanotherapies derived from intrinsic anti-inflammatory nanocarriers are promising for targeted combination treatment of inflammation-associated tumors by simultaneously shaping pro-inflammatory microenvironment toward a relatively normal niche sensitive to chemotherapy.


Assuntos
Neoplasias do Colo/patologia , Neoplasias do Colo/terapia , Nanopartículas Multifuncionais/química , Microambiente Tumoral , Administração Oral , Animais , Anti-Inflamatórios/farmacologia , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Colite/complicações , Neoplasias do Colo/etiologia , Progressão da Doença , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/química , Hidrólise , Inflamação/patologia , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Distribuição Tecidual/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
9.
Sci Adv ; 5(1): eaat2953, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30662940

RESUMO

Nanoparticles have been extensively used for inflammation imaging and photodynamic therapy of cancer. However, the major translational barriers to most nanoparticle-based imaging and therapy applications are the limited depth of tissue penetration, inevitable requirement of external irradiation, and poor biocompatibility of the nanoparticles. To overcome these critical limitations, we synthesized a sensitive, specific, biodegradable luminescent nanoparticle that is self-assembled from an amphiphilic polymeric conjugate with a luminescent donor (luminol) and a fluorescent acceptor [chlorin e6 (Ce6)] for in vivo luminescence imaging and photodynamic therapy in deep tissues. Mechanistically, reactive oxygen species (ROS) and myeloperoxidase generated in inflammatory sites or the tumor microenvironment trigger bioluminescence resonance energy transfer and the production of singlet oxygen (1O2) from the nanoparticle, enabling in vivo imaging and cancer therapy, respectively. This self-illuminating nanoparticle shows an excellent in vivo imaging capability with suitable tissue penetration and resolution in diverse animal models of inflammation. It is also proven to be a selective, potent, and safe antitumor nanomedicine that specifically kills cancer cells via in situ 1O2 produced in the tumor microenvironment, which contains a high level of ROS.


Assuntos
Antineoplásicos/uso terapêutico , Substâncias Luminescentes/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/terapia , Fotoquimioterapia/métodos , Nanomedicina Teranóstica/métodos , Células A549 , Animais , Clorofilídeos , Humanos , Inflamação/diagnóstico por imagem , Luminescência , Luminol/química , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Nanopartículas/química , Polímeros/química , Porfirinas/química , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Neuroscience Bulletin ; (6): 434-446, 2019.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wpr-775427

RESUMO

The obstacle to successful remyelination in demyelinating diseases, such as multiple sclerosis, mainly lies in the inability of oligodendrocyte precursor cells (OPCs) to differentiate, since OPCs and oligodendrocyte-lineage cells that are unable to fully differentiate are found in the areas of demyelination. Thus, promoting the differentiation of OPCs is vital for the treatment of demyelinating diseases. Shikimic acid (SA) is mainly derived from star anise, and is reported to have anti-influenza, anti-oxidation, and anti-tumor effects. In the present study, we found that SA significantly promoted the differentiation of cultured rat OPCs without affecting their proliferation and apoptosis. In mice, SA exerted therapeutic effects on experimental autoimmune encephalomyelitis (EAE), such as alleviating clinical EAE scores, inhibiting inflammation, and reducing demyelination in the CNS. SA also promoted the differentiation of OPCs as well as their remyelination after lysolecithin-induced demyelination. Furthermore, we showed that the promotion effect of SA on OPC differentiation was associated with the up-regulation of phosphorylated mTOR. Taken together, our results demonstrated that SA could act as a potential drug candidate for the treatment of demyelinating diseases.


Assuntos
Animais , Feminino , Ratos , Apoptose , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Doenças Desmielinizantes , Encefalite , Encefalomielite Autoimune Experimental , Camundongos Endogâmicos C57BL , Proteína Básica da Mielina , Metabolismo , Fármacos Neuroprotetores , Células Precursoras de Oligodendrócitos , Metabolismo , Remielinização , Ácido Chiquímico , Serina-Treonina Quinases TOR , Metabolismo
11.
J Am Coll Cardiol ; 72(21): 2591-2605, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30466517

RESUMO

BACKGROUND: Abdominal aortic aneurysm (AAA) is a leading cause of mortality and morbidity in the elderly. Currently, there remain no effective drugs that can prevent the growth of aneurysms and delay aneurysm rupture in the clinical setting. OBJECTIVES: The aim of this study was to develop a nanotherapy that can target aneurysms and release drug molecules in response to the inflammatory microenvironment. METHODS: Using a reactive oxygen species (ROS)-responsive nanoparticle and a candidate drug rapamycin, in combination with a peptide ligand for integrin and biomimetic cloaking with macrophage cell membrane, a nanotherapy was developed. Its effectiveness was demonstrated by in vitro and in vivo studies. RESULTS: Based on a facile and translational method, a rapamycin-loaded responsive nanotherapy was successfully prepared, which could release drug molecules upon triggering by the high level of ROS. In cells associated with the development of AAAs, the nanotherapy significantly inhibited calcification and attenuated ROS-mediated oxidative stress and apoptosis. By passively targeting aneurysms and releasing drug molecules in response to the inflammatory microenvironment, the intravenously injected ROS-responsive nanotherapy more effectively prevented aneurysm expansion in AAA rats than a nonresponsive control nanotherapy. After decoration with a peptide ligand cRGDfK and macrophage cell membrane, the aneurysmal targeting capability and therapeutic effects of a ROS-responsive nanotherapy with a mean diameter of 190 nm were further enhanced. Moreover, the nanotherapy showed a good safety profile in a preliminary safety test. CONCLUSIONS: The multifunctional nanotherapy can be further studied as a promising targeted drug for treatment of aneurysms. The underlying design principles enable the development of a broad range of nanomedicines for targeted therapy of other vascular diseases.


Assuntos
Aneurisma da Aorta Abdominal/tratamento farmacológico , Aneurisma da Aorta Abdominal/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Imunossupressores/administração & dosagem , Nanopartículas/administração & dosagem , Sirolimo/administração & dosagem , Animais , Aneurisma da Aorta Abdominal/patologia , Células Cultivadas , Masculino , Camundongos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Células RAW 264.7 , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
12.
ACS Nano ; 12(9): 8943-8960, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30114351

RESUMO

Atherosclerosis is a leading cause of vascular diseases worldwide. Whereas antioxidative therapy has been considered promising for the treatment of atherosclerosis in view of a critical role of reactive oxygen species (ROS) in the pathogenesis of atherosclerosis, currently available antioxidants showed considerably limited clinical outcomes. Herein, we hypothesize that a broad-spectrum ROS-scavenging nanoparticle can serve as an effective therapy for atherosclerosis, taking advantage of its antioxidative stress activity and targeting effects. As a proof of concept, a broad-spectrum ROS-eliminating material was synthesized by covalently conjugating a superoxide dismutase mimetic agent Tempol and a hydrogen-peroxide-eliminating compound of phenylboronic acid pinacol ester onto a cyclic polysaccharide ß-cyclodextrin (abbreviated as TPCD). TPCD could be easily processed into a nanoparticle (TPCD NP). The obtained nanotherapy TPCD NP could be efficiently and rapidly internalized by macrophages and vascular smooth muscle cells (VSMCs). TPCD NPs significantly attenuated ROS-induced inflammation and cell apoptosis in macrophages, by eliminating overproduced intracellular ROS. Also, TPCD NPs effectively inhibited foam cell formation in macrophages and VSMCs by decreasing internalization of oxidized low-density lipoprotein. After intravenous (i.v.) administration, TPCD NPs accumulated in atherosclerotic lesions of apolipoprotein E-deficient (ApoE-/-) mice by passive targeting through the dysfunctional endothelium and translocation via inflammatory cells. TPCD NPs significantly inhibited the development of atherosclerosis in ApoE-/- mice after i.v. delivery. More importantly, therapy with TPCD NPs afforded stabilized plaques with less cholesterol crystals, a smaller necrotic core, thicker fibrous cap, and lower macrophages and matrix metalloproteinase-9, compared with those treated with control drugs previously developed for antiatherosclerosis. The therapeutic benefits of TPCD NPs mainly resulted from reduced systemic and local oxidative stress and inflammation as well as decreased inflammatory cell infiltration in atherosclerotic plaques. Preliminary in vivo tests implied that TPCD NPs were safe after long-term treatment via i.v. injection. Consequently, TPCD NPs can be developed as a potential antiatherosclerotic nanotherapy.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Aterosclerose/tratamento farmacológico , Nanopartículas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Anti-Inflamatórios não Esteroides/química , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Apoptose/efeitos dos fármacos , Aterosclerose/metabolismo , Ácidos Borônicos/química , Ácidos Borônicos/farmacologia , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/farmacologia , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nanopartículas/química , Polissacarídeos/química , Polissacarídeos/farmacologia , Marcadores de Spin , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacologia
13.
Biomaterials ; 143: 93-108, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28778000

RESUMO

Atherosclerosis is the leading cause of many fatal cardiovascular and cerebrovascular diseases. Whereas nanomedicines are promising for targeted therapy of atherosclerosis, great challenges remain in development of effective, safe, and translational nanotherapies for its treatment. Herein we hypothesize that non-proinflammatory nanomaterials sensitive to low pH or high reactive oxygen species (ROS) may serve as effective platforms for triggerable delivery of anti-atherosclerotic therapeutics in cellular and tissue microenvironments of inflammation. To demonstrate this hypothesis, an acid-labile material of acetalated ß-cyclodextrin (ß-CD) (Ac-bCD) and a ROS-sensitive ß-CD material (Ox-bCD) were separately synthesized by chemical modification of ß-CD, which were formed into responsive nanoparticles (NPs). Ac-bCD NP was rapidly hydrolyzed in mildly acidic buffers, while hydrolysis of Ox-bCD NP was selectively accelerated by H2O2. Using an anti-atherosclerotic drug rapamycin (RAP), we found stimuli-responsive release of therapeutic molecules from Ac-bCD and Ox-bCD nanotherapies. Compared with non-responsive poly(lactide-co-glycolide) (PLGA)-based NP, Ac-bCD and Ox-bCD NPs showed negligible inflammatory responses in vitro and in vivo. By endocytosis in cells and intracellularly releasing cargo molecules in macrophages, responsive nanotherapies effectively inhibited macrophage proliferation and suppressed foam cell formation. After intraperitoneal (i.p.) delivery in apolipoprotein E-deficient (ApoE-/-) mice, fluorescence imaging showed accumulation of NPs in atherosclerotic plaques. Flow cytometry analysis indicated that the lymphatic translocation mediated by neutrophils and monocytes/macrophages may contribute to atherosclerosis targeting of i.p. administered NPs, in addition to targeting via the leaky blood vessels. Correspondingly, i.p. treatment with different nanotherapies afforded desirable efficacies. Particularly, both pH and ROS-responsive nanomedicines more remarkably delayed progression of atherosclerosis and significantly enhanced stability of atheromatous lesions, in comparison to non-responsive PLGA nanotherapy. Furthermore, responsive nanovehicles displayed good safety performance after long-term administration in mice. Consequently, for the first time our findings demonstrated the therapeutic advantages of nanomedicines responsive to mildly acidic or abnormally high ROS microenvironments for the treatment of atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Preparações de Ação Retardada/química , Imunossupressores/administração & dosagem , Nanopartículas/química , Sirolimo/administração & dosagem , beta-Ciclodextrinas/química , Acetilação , Animais , Aterosclerose/imunologia , Aterosclerose/patologia , Preparações de Ação Retardada/efeitos adversos , Sistemas de Liberação de Medicamentos , Concentração de Íons de Hidrogênio , Imunossupressores/uso terapêutico , Inflamação/induzido quimicamente , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/efeitos adversos , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/imunologia , Placa Aterosclerótica/patologia , Células RAW 264.7 , Espécies Reativas de Oxigênio/imunologia , Sirolimo/uso terapêutico , beta-Ciclodextrinas/efeitos adversos
14.
Nano Lett ; 17(2): 1056-1064, 2017 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-28075596

RESUMO

Targeting of nanoparticles to distant diseased sites after oral delivery remains highly challenging due to the existence of many biological barriers in the gastrointestinal tract. Here we report targeted oral delivery of diverse nanoparticles in multiple disease models, via a "Trojan horse" strategy based on a bioinspired yeast capsule (YC). Diverse charged nanoprobes including quantum dots (QDs), iron oxide nanoparticles (IONPs), and assembled organic fluorescent nanoparticles can be effectively loaded into YC through electrostatic force-driven spontaneous deposition, resulting in different diagnostic YC assemblies. Also, different positive nanotherapies containing an anti-inflammatory drug indomethacin (IND) or an antitumor drug paclitaxel (PTX) are efficiently packaged into YC. YCs containing either nanoprobes or nanotherapies may be rapidly endocytosed by macrophages and maintained in cells for a relatively long period of time. Post oral administration, nanoparticles packaged in YC are first transcytosed by M cells and sequentially endocytosed by macrophages, then transported to neighboring lymphoid tissues, and finally delivered to remote diseased sites of inflammation or tumor in mice or rats, all through the natural route of macrophage activation, recruitment, and deployment. For the examined acute inflammation model, the targeting efficiency of YC-delivered QDs or IONPs is even higher than that of control nanoprobes administered at the same dose via intravenous injection. Assembled IND or PTX nanotherapies orally delivered via YCs exhibit remarkably potentiated efficacies as compared to nanotherapies alone in animal models of inflammation and tumor, which is consistent with the targeting effect and enhanced accumulation of drug molecules at diseased sites. Consequently, through the intricate transportation route, nanoprobes or nanotherapies enveloped in YC can be preferentially delivered to desired targets, affording remarkably improved efficacies for the treatment of multiple diseases associated with inflammation.


Assuntos
Anti-Inflamatórios/administração & dosagem , Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Indometacina/química , Nanopartículas/química , Paclitaxel/química , Saccharomyces cerevisiae/química , Administração Oral , Animais , Anti-Inflamatórios/química , Antineoplásicos/química , Cápsulas , Carcinoma 256 de Walker/diagnóstico por imagem , Carcinoma 256 de Walker/tratamento farmacológico , Linhagem Celular , Liberação Controlada de Fármacos , Humanos , Indometacina/administração & dosagem , Inflamação/diagnóstico por imagem , Inflamação/tratamento farmacológico , Camundongos Endogâmicos BALB C , Paclitaxel/administração & dosagem , Ratos Sprague-Dawley , Eletricidade Estática
15.
Int J Mol Sci ; 17(7)2016 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-27399689

RESUMO

BACKGROUND: Atherosclerosis is a fundamental pathological process responded to some serious cardiovascular events. Although the cholesterol-lowering drugs are widely prescribed for atherosclerosis therapy, it is still the leading cause of death in the developed world. Here we measured the effects of compound K in atherosclerosis formation and investigated the probably mechanisms of the anti-antherosclerosis roles of compound K. METHODS: We treated the atherosclerotic model animals (apoE(-/-) mice on western diet) with compound K and measured the size of atherosclerotic lesions, inflammatory cytokine levels and serum lipid profile. Peritoneal macrophages were collected in vitro for the foam cell and inflammasome experiments. RESULTS: Our results show that treatment with compound K dose-dependently attenuates the formation of atherosclerotic plaques by 55% through activation of reverse cholesterol transport pathway, reduction of systemic inflammatory cytokines and inhibition of local inflammasome activity. Compound K increases the cholesterol efflux of macrophage-derived foam cells, and reduces the inflammasome activity in cholesterol crystal stimulated macrophages. The activation of LXRα may contribute to the athero-protective effects of compound K. CONCLUSION: These observations provide evidence for an athero-protective effect of compound K via LXRα activation, and support its further evaluation as a potential effective modulator for the prevention and treatment of atherosclerosis.


Assuntos
Apolipoproteínas E/genética , Aterosclerose/tratamento farmacológico , Ginsenosídeos/uso terapêutico , Receptores X do Fígado/metabolismo , Animais , Aterosclerose/patologia , Caspase 1/metabolismo , Colesterol/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Fígado Gorduroso/tratamento farmacológico , Células Espumosas/metabolismo , Células Espumosas/patologia , Ginsenosídeos/farmacologia , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fator de Transcrição RelA/metabolismo , Triglicerídeos/sangue
16.
J Control Release ; 235: 48-62, 2016 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-27235978

RESUMO

Increasing evidence has demonstrated special advantages of the nanomedicinal approach for the management of cardiovascular disease. We hypothesize that sustained delivery of rapamycin (RAP) may provide more desirable therapeutic effects than traditional oral administration by selectively inhibiting mammalian target of rapamycin complex 1 (mTORC1) signaling. To evidence this assumption and develop an effective, safe, and translational nanotherapy for atherosclerosis, this study was designed to examine antiatherosclerotic efficacy of a RAP nanotherapy based on an acetalated ß-cyclodextrin (Ac-bCD) material in apolipoprotein E-deficient (ApoE(-/-)) mice. First, biodegradable and biocompatible materials of Ac-bCDs were synthesized by kinetically controlled acetalation, giving rise to carrier materials that may not generate acidic byproducts after hydrolysis. Then RAP-loaded nanoparticles base on various Ac-bCDs were prepared by a nanoemulsion technique, which can sustain drug release for different periods of time, depending on the composition of Ac-bCDs. For a RAP/Ac-bCD180-derived nanotherapy (RAP-NP) that may continue RAP release for up to 20days in vitro, it afforded constant drug levels in both the blood and aortic tissue after subcutaneous injection, while orally administered free RAP showed typical peak-valley profiles with remarkably high peak concentrations. Therapeutic studies conducted in an experimental model of atherosclerosis established in ApoE(-/-) mice revealed that RAP-NP significantly reduced the formation of atherosclerotic lesions and dramatically enhanced the stability of plaques, which was more efficacious than orally delivered free RAP. Moreover, rupture-prone proinflammatory factors in both serum and aortas were significantly decreased after treatment. Whereas oral administration of RAP simultaneously inhibited mTORC1 and mTORC2 in the aorta, sustained delivery by RAP-NP selectively suppressed mTORC1, agreeing with in vitro results in smooth muscle cells. These findings demonstrated that antiatherosclerotic activity of RAP may be considerably improved by sustained release via the Ac-bCD material-derived nanocarrier, which was achieved through selectively inhibiting mTORC1.


Assuntos
Aterosclerose/tratamento farmacológico , Portadores de Fármacos/administração & dosagem , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Nanopartículas/administração & dosagem , Sirolimo/administração & dosagem , beta-Ciclodextrinas/administração & dosagem , Animais , Aorta/metabolismo , Aorta/patologia , Aterosclerose/metabolismo , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/uso terapêutico , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/uso terapêutico , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Nanopartículas/uso terapêutico , Sirolimo/farmacocinética , Sirolimo/uso terapêutico , Distribuição Tecidual , beta-Ciclodextrinas/química , beta-Ciclodextrinas/uso terapêutico
17.
Guang Pu Xue Yu Guang Pu Fen Xi ; 36(10): 3114-8, 2016 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-30222254

RESUMO

In this paper, an Nd∶YAG laser with 10ns pulse width and output wavelength of 1 064 nm was employed to ablate Gd metal target and Gd-doped glass target for plasma generation. The out-of-band (OOB) radiation of extreme ultraviolet sources with the two target configurations was comparatively studied. It has been found that the continuous radiation emitted by the plasma is the main component of the out-of-band radiation. The spectral distribution of the continuum emission matches that of blackbody radiation with a temperature of about 5 eV. And it is also found that the intensity of OOB radiation can be considerably decreased by using Gd-doped glass target. Optical Emission Spectroscopy (OES) has been used to analyze the temporal and spatial behaviors of electron temperature (Te) and density (Ne) of the Gd-doped glass target plasma, and experimental results show that temporal evolution of electron temperature and density of the plasma are found to be decayed exponentially with the increasing of delay time. At 125 ns after laser irradiation, electron temperature and density were 4 eV and 1.2×1018 cm-3 respectively, and then decreased to 1.5 eV and 8×1017 cm-3 with delaying time of 250 ns. On the other hand, spatial evolution of electron temperature and density show that both of them first increase and then decrease in the region of 1~10 mm from the target surface. The electron temperature and electron density achieves the maximum of 2.6 eV and 8.5×1017 cm-3, respectively, when the probe location away from the target surface 6 mm.

18.
Beilstein J Nanotechnol ; 6: 1781-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26425430

RESUMO

This study investigates near-infrared region Ag2S quantum dots (QDs) and their nonlinear optical response under 532 nm nanosecond laser pulses. Our experimental result shows that nonlinear transmission is reduced from 0.084 to 0.04. The observed narrowing behavior of the output pulse width shows superior optical limiting. We discuss the physical mechanisms responsible for the nonlinear optical response of the QDs. The average size of the nanocrystals was 5.5 nm. Our results suggest the possibility of using these Ag2S QDs for photoelectric, biosensor, optical ranging, and self-adaptive technologies.

19.
Guang Pu Xue Yu Guang Pu Fen Xi ; 35(1): 44-7, 2015 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-25993817

RESUMO

Extreme ultraviolet lithography is one of the most promising technologies on the next generation of high-capacity integrated circuit manufacturing. However, techniques for ion debris mitigation have to be considered in the application of extreme ultraviolet source for lithography. In our paper the dynamics of ion debris from Sn plasma by using dual ns laser pulses were investigated. The results show that debris from plasma greatly depends on the energy of pre-pulse and the delay time between the two laser pulses. The energy of Sn ions debris was efficiently mitigated from 2. 47 to 0. 40 keV in the case of dual laser pulses, up to 6. 1 times lower than that by using single laser pulse. We also found that Sn ions debris can be mitigated at all angles by using the dual laser pulses method.

20.
J Mater Chem B ; 3(37): 7355-7365, 2015 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-32262762

RESUMO

Atherosclerosis may cause life-threatening coronary artery disease, carotid artery disease, stroke, and peripheral vascular disease, while its effective therapy remains challenging thus far. With the aim of facilely constructing efficacious and translational oral delivery systems for an anti-atherosclerotic drug of rapamycin (RAP), an all-in-one approach was created. This strategy involves a carboxyl-bearing compound (serves as a guest molecule) mediated self-assembly of a structurally simple host polymer of poly(N-isopropylacrylamide) (PNIPAm). The formation of microspheres and highly efficient packaging of RAP could be simultaneously achieved by this host-guest self-assembly, affording cost-effective therapeutic assemblies with particularly robust drug loading capacity, desirable drug dissolution, relative manufacturing simplicity, good lyophilization-reconstitution character, and facile scalability. Besides these pharmaceutical characteristics superior over control microspheres based on poly(lactide-co-glycolide) or a enteric coating material, therapeutic RAP microspheres fabricated by this assembly approach had high oral bioavailability. More importantly, assembled RAP microspheres displayed significant therapeutic advantages upon treatment of atherosclerosis in an apolipoprotein E-deficient mouse model. In addition, a long-term treatment with either RAP-containing assemblies or the carrier material PNIPAm revealed a good safety profile in mice post oral delivery. Accordingly, RAP microspheres developed herein are promising and translational therapeutics for atherosclerotic diseases. This study also provides new insights into the design of effective carrier materials for various lipophilic therapeutics.

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