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1.
PLoS One ; 17(8): e0268307, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36001584

RESUMO

Peripheral artery disease (PAD) is a systemic vascular disease of the legs that results in a blockage of blood flow from the heart to the lower extremities. Now one of the most common causes of mortality in the U.S., the first line of therapy for PAD is to mechanically open the blockages using balloon angioplasty. Coating the balloons with antiproliferative agents can potentially reduce vessel re-narrowing, or restenosis after surgical intervention, but current drug-coated balloons releasing chemotherapy agents like paclitaxel have in some cases shown increased mortality long-term. Our aim was to design a novel drug-coated balloon using a polymeric nanodelivery system for a sustained release of polyphenols that reduce restenosis but with reduced toxicity compared to chemotherapy agents. Poly (lactic-co-glycolic acid) (PLGA) nanoparticles with entrapped quercetin, a dimethoxy quercetin (rhamnazin), as well as quercetin covalently attached to PLGA, were developed. Balloon catheters were coated with polymeric nanoparticles using an ultrasonic method, and nanoparticle characteristics, drug loading, coating uniformity and drug release were determined. The adhesion of nanoparticles to vascular smooth muscle cells and the antiproliferative effect of nano-delivered polyphenols were also assessed. Of the nanoparticle systems tested, those with covalently attached quercetin provided the most sustained release over a 6-day period. Although these particles adhered to cells to a smaller extent compared to other nanoparticle formulations, their attachment was resistant to washing. These particles also exhibited the greatest anti-proliferative effect. In addition, their attachment was not altered when the cells were grown in calcifying conditions, and in PAD tissue calcification is typically a condition that impedes drug delivery. Moreover, the ultrasonic coating method generated a uniform balloon coating. The polymeric nanoparticle system with covalently attached quercetin developed herein is thus proposed as a promising platform to reduce restenosis post-angioplasty.


Assuntos
Angioplastia com Balão , Nanopartículas , Doença Arterial Periférica , Angioplastia com Balão/métodos , Materiais Revestidos Biocompatíveis , Preparações de Ação Retardada , Humanos , Paclitaxel/farmacologia , Doença Arterial Periférica/terapia , Polímeros , Quercetina/farmacologia
2.
Vet Comp Orthop Traumatol ; 35(5): 347-350, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35732181

RESUMO

OBJECTIVES: The aim of this study was to describe how the addition of contrast-enhanced low-field magnetic resonance imaging sequences can confirm or change the initially planned surgical approach for canine intervertebral disc extrusions. STUDY DESIGN: Magnetic resonance imagings of 20 dogs diagnosed with intervertebral disc extrusions were retrospectively reviewed by a board-certified neurologist for the location of extradural disc material, contrast enhancement, and whether enhancement reinforced or changed the initially planned surgical approach. RESULTS: Extradural compressive material contrast-enhanced in 17/20 dogs. In 14/20 dogs, enhancement was considered to increase the confidence level of the location for surgery including two cases where the surgical approach was altered. CONCLUSION: Gadolinium-based contrast agents in low-field magnetic resonance imaging can aid the surgical planning of intervertebral disc extrusions in dogs by improving the confidence level of location and extent of extradural material and occasionally altering the surgical approach.


Assuntos
Doenças do Cão , Deslocamento do Disco Intervertebral , Disco Intervertebral , Cães , Animais , Meios de Contraste , Gadolínio , Estudos Retrospectivos , Doenças do Cão/diagnóstico por imagem , Doenças do Cão/cirurgia , Deslocamento do Disco Intervertebral/diagnóstico por imagem , Deslocamento do Disco Intervertebral/cirurgia , Deslocamento do Disco Intervertebral/veterinária , Imageamento por Ressonância Magnética/veterinária , Imageamento por Ressonância Magnética/métodos , Disco Intervertebral/diagnóstico por imagem , Disco Intervertebral/cirurgia , Disco Intervertebral/patologia
3.
Phys Chem Chem Phys ; 22(20): 11197-11218, 2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32393957

RESUMO

Compartmentalization is a fundamental principle in biology that is needed for the temporal and spatial separation of chemically incompatible reactions and biomolecules. Nano- or micro-sized compartments made of synthetic polymers are used to mimick this principle. The self-assembly of these polymers into vesicular objects is highly compatible with the integration of biomolecules, either into the lumen, the membrane or onto the surface of the vesicles. Thus, a great variety of biohybrid nano- and microscaled compartments has been developed exploiting the specific function and properties of targeting peptides, antibodies, enzymes, nucleic acids or lipids. Such biohybrid compartments have moved from simple systems encapsulating e.g. a model protein into complex multicompartmentalized structures that are able to combine the activity of different biomolecular cargos getting closer to the realization of artifical organelles or cells. Encapsulation of medically relevant cargos combined with careful design of the polymeric scaffold and specific surface functionalization have led to a significant progress in therapeutical applications such as targeted drug delivery or enzyme replacement therapy.


Assuntos
Células Artificiais/química , Polímeros/química , Ácidos Nucleicos/química , Peptídeos/química , Proteínas/química , Lipossomas Unilamelares/química
4.
Nanoscale ; 12(17): 9786-9799, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32328600

RESUMO

DNA has been widely used as a key tether to promote self-organization of super-assemblies with emergent properties. However, control of this process is still challenging for compartment assemblies and to date the resulting assemblies have unstable membranes precluding in vitro and in vivo testing. Here we present our approach to overcome these limitations, by manipulating molecular factors such as compartment membrane composition and DNA surface density, thereby controlling the size and stability of the resulting DNA-linked compartment clusters. The soft, flexible character of the polymer membrane and low number of ssDNA remaining exposed after cluster formation determine the interaction of these clusters with the cell surface. These clusters exhibit in vivo stability and lack of toxicity in a zebrafish model. To display the breadth of therapeutic applications attainable with our system, we encapsulated the medically established enzyme laccase within the inner compartment and demonstrated its activity within the clustered compartments. Most importantly, these clusters can interact selectively with different cell lines, opening a new strategy to modify and expand cellular functions by attaching such pre-organized soft DNA-mediated compartment clusters on cell surfaces for cell engineering or therapeutic applications.


Assuntos
DNA/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Animais , Catálise , Linhagem Celular Tumoral , Membrana Celular/metabolismo , DNA/metabolismo , Células HEK293 , Humanos , Lacase/química , Lacase/metabolismo , Nanopartículas/metabolismo , Nanopartículas/toxicidade , Polímeros/química , Polímeros/metabolismo , Polímeros/farmacocinética , Polímeros/toxicidade , Receptores Depuradores/antagonistas & inibidores , Receptores Depuradores/metabolismo , Distribuição Tecidual , Peixe-Zebra
5.
Biomacromolecules ; 18(11): 3471-3480, 2017 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-28776980

RESUMO

The design of functional systems with sizes in the nanometer range is a key challenge in fields such as biomedicine, nanotechnology, and engineering. Some of the most promising materials nowadays consist of self-assembling peptides or peptide-polymer hybrid materials because of their versatility and the resulting properties that can be achieved with these structures. Self-assembly of pure amphiphilic peptides or in combination with block copolymers results in a large variety of nanostructures (micelles, nanoparticles (NPs), compartments, planar membranes) each with different characteristics and tunable properties. Here, we describe such novel peptide- or peptide-polymer-based supramolecular nanostructures and emphasize their functionality and various promising applications.


Assuntos
Nanotecnologia/tendências , Peptídeos/química , Polímeros/química , Tensoativos/química , Nanoestruturas/química
6.
Glycobiology ; 26(7): 701-709, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26850997

RESUMO

The balance between neutrophil serine proteases (NSPs) and protease inhibitors (PIs) in the lung is a critical determinant for a number of chronic inflammatory lung diseases such as chronic obstructive pulmonary disease, cystic fibrosis and acute lung injury. During activation at inflammatory sites, excessive release of NSPs such as human neutrophil elastase (HNE), proteinase 3 (Pr3) and cathepsin G (CatG), leads to destruction of the lung matrix and continued propagation of acute inflammation. Under normal conditions, PIs counteract these effects by inactivating NSPs; however, in chronic inflammatory lung diseases, there are insufficient amounts of PIs to mitigate damage. Therapeutic strategies are needed to modulate excessive NSP activity for the clinical management of chronic inflammatory lung diseases. In the study reported here, a panel of N-arylacyl O-sulfonated aminoglycosides was screened to identify inhibitors of the NSPs. Dose-dependent inhibitors for each individual serine protease were identified. Select compounds were found to inhibit multiple NSPs, including one lead structure that is shown to inhibit all three NSPs. Two lead compounds identified during the screen for each individual NSP were further characterized as partial mixed inhibitors of CatG. Concentration-dependent inhibition of protease-mediated detachment of lung epithelial cells is demonstrated.


Assuntos
Aminoglicosídeos/metabolismo , Catepsina G/metabolismo , Elastase de Leucócito/metabolismo , Mieloblastina/metabolismo , Proteínas Secretadas Inibidoras de Proteinases/metabolismo , Lesão Pulmonar Aguda/metabolismo , Aminoglicosídeos/isolamento & purificação , Catepsina G/antagonistas & inibidores , Fibrose Cística/metabolismo , Humanos , Inflamação/metabolismo , Elastase de Leucócito/antagonistas & inibidores , Mieloblastina/antagonistas & inibidores , Doença Pulmonar Obstrutiva Crônica/metabolismo
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