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1.
Int J Mol Sci ; 23(20)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36293494

RESUMO

Patients with high-risk non-metastatic renal cell carcinoma (RCC) are at risk of metastatic relapse following nephrectomy. Cabozantinib (CZ), a potent multitarget tyrosine kinase inhibitor, interferes with angiogenesis and immunosuppression associated with surgery-induced metastasis. Here, we explored the therapeutic potential of CZ-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CZ-PLGA-NPs) as an adjuvant strategy for targeting post-nephrectomy metastasis. A clinically relevant subline recapitulating post-nephrectomy lung metastasis of high-risk human RCC, namely Renca-SRLu5-Luc, was established through in vivo serial selection of luciferase-expressing murine RCC Renca-Luc cells. CZ was encapsulated into PLGA-NPs via the conventional single emulsion technique. The multifaceted preclinical antimetastatic efficacy of CZ-PLGA-NPs was assessed in Renca-SRLu5-Luc cells. CZ-PLGA-NPs with a smooth surface displayed desirable physicochemical properties, good CZ encapsulation efficiency, as well as controlled and sustained CZ release. CZ-PLGA-NPs exhibited remarkable dose-dependent toxicity against Renca-SRLu5-Luc cells by inducing G2/M cell cycle arrest and apoptosis. CZ-PLGA-NPs attenuated in vitro colony formation, migration, and invasion by abrogating AKT and ERK1/2 activation. An intravenous injection of CZ-PLGA-NPs markedly reduced lung metastatic burden and prolonged lifespan with favorable safety in the Renca-SRLu5-Luc experimental lung metastasis model. The novel CZ-PLGA-NPs system with multifaceted antimetastatic effects and alleviating off-target toxicity potential is a promising adjunctive agent for patients with surgically resected high-risk RCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Neoplasias Pulmonares , Nanopartículas , Humanos , Camundongos , Animais , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ácido Láctico/química , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/cirurgia , Portadores de Fármacos/química , Emulsões , Proteínas Proto-Oncogênicas c-akt , Nanopartículas/química , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/cirurgia , Inibidores de Proteínas Quinases , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Tamanho da Partícula
2.
Biosens Bioelectron ; 238: 115571, 2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-37562343

RESUMO

A microneedle (MN) sensor coated with a sensing composite material was proposed for measuring glucose concentrations in interstitial fluid (ISF). The sensing composite material was prepared by blending a polymer containing glucose-responsive phenylboronic acid (PBA) moieties (i.e., polystyrene-block-poly(acrylic acid-co-acrylamidophenylboronic acid)) with conductive carbon nanotubes (CNTs). The polymer exhibited reversible swelling behavior in response to glucose concentrations, which influenced the distribution of the embedded CNTs, resulting in sensitive variations in electrical percolation, even when coated onto a confined surface of the MN in the sensor. We varied the ratio of PBA moieties and the loading amount of CNTs in the sensing composite material of the MN sensor and tested them in vitro using an ISF-mimicking gel with physiological glucose concentrations to determine the optimal sensitivity conditions. When tested in animal models with varying blood glucose concentrations, the MN sensor coated with the selected sensing material exhibited a strong correlation between the measured electrical currents and blood glucose concentrations, showing accuracy comparable to that of a glucometer in clinical use.


Assuntos
Técnicas Biossensoriais , Nanotubos de Carbono , Animais , Polímeros , Glicemia , Líquido Extracelular , Técnicas Biossensoriais/métodos , Glucose
3.
J Control Release ; 345: 1-19, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35227764

RESUMO

Inflammatory bowel diseases (IBDs) are idiopathic gastrointestinal inflammatory disorders featuring chronic intestinal inflammation. Although IBDs are increasingly becoming globally prevalent, the exact etiology of IBD remains obscure. Recently, the ability of various drugs for mucosal healing such as corticosteroids, antibiotics, and immunosuppressants has been proven. However, the delivery of free drugs is insufficient and inadequate since some patients have experienced reduced efficacy due to repeated administration and others have suffered side effects. In this regard, novel platforms based on biomaterials are required to deliver pharmaceutical agents to the damaged site with increased efficacy and reduced side effects. In this review, we summarize the most recent status of numerous biomaterials in treating IBD. This review addresses various nanoparticles, microparticles, and hydrogels recently prepared from natural polymers, lipids, synthetic polymers, and inorganic materials. These diverse biomaterials can be used as effective drug-delivery systems to promote colon-specific delivery and for the stable release of drugs in IBD treatments.


Assuntos
Portadores de Fármacos , Doenças Inflamatórias Intestinais , Materiais Biocompatíveis/uso terapêutico , Portadores de Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Polímeros/uso terapêutico
4.
Biomaterials ; 289: 121762, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36058029

RESUMO

Cancer immunotherapy is a next-generation treatment strategy; however, its side effects limit its clinical translation. Here, a novel combination of a multi-functional nano-adjuvant (M-NA) prepared with an iron oxide/gold core and a cationic polymer shell via multilayer synthesis with CpG oligodeoxynucleotide (CpG-ODN) electrostatically complexed on its surface, and irreversible electroporation (IRE) technique was developed for effective image-guided in situ cancer vaccination. The M-NA can be retained long-term in the dense tumoral extracellular matrix after intratumoral injection and internalized by antigen-presenting cells (APCs). The IRE can induce immunogenic cell death. Indeed, in a mouse tumor model, the M-NA showed longer tumor retention time than free CpG-ODN. Compared with other treatments, the combined treatment significantly inhibited tumor growth with 100% survival rate for ∼60 days. The therapy induced the activation of cytotoxic lymphocytes and the maturation of APCs in vivo. This treatment could be effective in image-guided local cancer immunotherapy.


Assuntos
Neoplasias , Oligodesoxirribonucleotídeos , Adjuvantes Imunológicos , Animais , Eletroporação/métodos , Ouro , Camundongos , Neoplasias/terapia , Polímeros , Vacinação
5.
J Mater Chem B ; 8(35): 7914-7920, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32726382

RESUMO

Brimonidine (BMD) is often prescribed as an eye drop to reduce the intraocular pressure (IOP) for glaucoma treatment. However, eye drops are limited by rapid clearance from the preocular surface, and hence a low ocular drug bioavailability. Therefore, in this study, we propose montmorillonite (MMT), as a delivery carrier, hybridized with BMD (BMD-MMT) for topical drug delivery to the eye. The BMD-MMT hybrid was prepared by intercalating the BMD molecules in the interlayer space of the MMT lattice via ion-exchange reaction; it was then formulated with polyvinyl alcohol (PVA) to produce a dry tablet (i.e., BMD-MMT@PVA). The BMD-MMT@PVA hybrid drug released BMD in a sustained manner for more than 5 h under in vitro conditions. When the hybrid drug was administered to rabbit eyes in vivo, 43% and 18.5% BMD-MMT still remained on the preocular surface for 10 and 60 min after administration, respectively. Thus, the BMD-MMT@PVA hybrid drug exhibited a prolonged decrease in IOP, that is, for 12 h, which was approximately two times longer than that observed with the commercially available BMD eye drop, Alphagan® P.


Assuntos
Bentonita/química , Tartarato de Brimonidina/administração & dosagem , Tartarato de Brimonidina/química , Olho , Administração Tópica , Animais , Tartarato de Brimonidina/metabolismo , Tartarato de Brimonidina/farmacologia , Composição de Medicamentos , Olho/efeitos dos fármacos , Olho/metabolismo , Pressão Intraocular/efeitos dos fármacos , Cinética , Masculino , Álcool de Polivinil/química , Coelhos
6.
Mater Sci Eng C Mater Biol Appl ; 109: 110565, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32228902

RESUMO

We propose an elastic net made of a biocompatible polymer to wrap silicone implants of various sizes, which also allows for the sustained release of an anti-inflammatory drug, triamcinolone, to prevent fibrosis. For this, we first prepared a strand composed of a mixture of polyurethane and triamcinolone via electrospinning, which was then assembled to prepare the elastic drug-delivery net (DDN). The DDN was prepared to just fit for wrapping the small silicone implant sample herein, but was also able to wrap a sample 7 times as large at 72% strain due to the elastic property of polyurethane. The DDN exhibited sustained drug release for 4 weeks, the profile of which was not very different between the intact and strained DDNs. When implanted in a subcutaneous pocket in living rats, the DDN-wrapped silicone implant samples showed an obvious antifibrotic effect due to the sustained release of triamcinolone. Importantly, this effect was similar for the small and large silicone samples, both wrapped with the same DDN. Therefore, we conclude that this drug-loaded net made of an elastic, biocompatible polymer has high potential for sustained drug delivery around silicone implants manufactured in various sizes.


Assuntos
Poliuretanos , Silicones , Triancinolona , Animais , Implantes de Medicamento/química , Implantes de Medicamento/farmacocinética , Implantes de Medicamento/farmacologia , Masculino , Poliuretanos/química , Poliuretanos/farmacologia , Ratos , Ratos Sprague-Dawley , Silicones/química , Silicones/farmacologia , Triancinolona/química , Triancinolona/farmacocinética , Triancinolona/farmacologia
7.
Mater Sci Eng C Mater Biol Appl ; 79: 209-215, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28629009

RESUMO

In this work, we propose a surgical suture that can sustainably release diclofenac (DF) for the local pain relief of surgical wounds. We separately fabricated a DF-loaded strand composed of a biodegradable polymer, poly(lactic-co-glycolic acid) (PLGA), which was then braided with a surgical suture already in clinical use, i.e., VICRYL™. In this way, the drug-delivery suture presented herein could release DF in a sustained manner for 10days while maintaining the mechanical strength needed for wound closure. According to the in vivo results of an induced-pain animal model, the drug-delivery suture mitigated pain throughout the period of persistent pain. The histological analysis of tissue around the sutures showed that the drug-delivery suture exhibited biocompatibility comparable to that of the VICRYL™ suture in clinical use.


Assuntos
Diclofenaco/química , Animais , Ácido Láctico , Dor , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Suturas
8.
Int J Pharm ; 522(1-2): 66-73, 2017 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-28216468

RESUMO

Dorzolamide eye drops are widely prescribed to reduce intraocular pressure (IOP) in the treatment of ocular hypertension and glaucoma. However, in an eye drop formulation, dorzolamide is rapidly cleared from the preocular space, hence requiring multiple daily administrations. Here, we sought to increase the preocular retention of dorzolamide using nanostructured, mucoadhesive microparticles (MUCO_NM) as carriers for topical delivery to the eye. MUCO_NM were prepared by freeze-milling dorzolamide-loaded, electrospun nanofibers composed of poly(lactic-co-glycolic acid) and polyethylene glycol. The microparticles were embedded in a rapidly-dissolving tablet of polyvinyl alcohol. To assess in vivo efficacy, the MUCO_NM were administered topically to the eyes of rabbits, and IOP was measured and compared to that in eyes treated with Trusopt®, a marketed eye drop of dorzolamide. The MUCO_NM showed a 35% greater maximum IOP decrease and a>2-fold increase in the duration of the IOP decrease, compared to Trusopt®. This enhanced efficacy was comparable to that obtained with a single administration of 4 drops of Trusopt® or 2 administrations of Trusopt® at a 4-h interval. Our findings suggest that this MUCO_NM preparation is a promising carrier for topical delivery of dorzolamide to the eye, with enhanced drug efficacy and the potential to reduce administration frequency.


Assuntos
Administração Oftálmica , Administração Tópica , Inibidores da Anidrase Carbônica/administração & dosagem , Sulfonamidas/administração & dosagem , Tiofenos/administração & dosagem , Adesivos , Animais , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Composição de Medicamentos , Pressão Intraocular/efeitos dos fármacos , Ácido Láctico , Masculino , Mucosa , Nanofibras , Soluções Oftálmicas , Tamanho da Partícula , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Propilenoglicol , Coelhos , Solubilidade , Sulfonamidas/química , Sulfonamidas/farmacologia , Tiofenos/química , Tiofenos/farmacologia
9.
J Microbiol ; 49(1): 141-5, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21369991

RESUMO

A metagenomic fosmid library was constructed using genomic DNA isolated from abalone intestine. Screening of a library of 3,840 clones revealed a 36 kb insert of a cellulase positive clone (pAMHElO). A shotgun clone library was constructed using the positive clone (pAMHElO) and further screening of 3,840 shotgun clones with an approximately 5 kb insert size using a Congo red overlay revealed only one cellulase positive clone (pAMHL9). The pAMHL9 consisted of a 5,293-bp DNA sequence and three open reading frames (ORFs). Among the three ORFs, cellulase activity was only shown in the recombinant protein (CelAMll) coded by ORF3, which showed 100% identity with outer membrane protein A from Vibrio alginolyticus 12G01, but no significant sequence homology to known cellulases. The expressed protein (CelAMll) has a molecular weight of approximately 37 kDa and the highest CMC hydrolysis activity was observed at pH 7.0 and 37°C. The carboxymethyl cellulase activity was determined by zymogram active staining and different degraded product profiles for CelAMll were obtained when cellotetraose and cellopentaose were used as the substrates, while no substrate hydrolysis was observed on oligosaccharides such as cellobiose and cellotriose.


Assuntos
Celulase/genética , Celulase/metabolismo , Trato Gastrointestinal/microbiologia , Gastrópodes/microbiologia , Biblioteca Gênica , Metagenoma , Animais , Carboximetilcelulose Sódica/metabolismo , Celulase/química , Celulose/análogos & derivados , Celulose/metabolismo , Clonagem Molecular , Estabilidade Enzimática , Concentração de Íons de Hidrogênio , Dados de Sequência Molecular , Peso Molecular , Oligossacarídeos/metabolismo , Fases de Leitura Aberta , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Especificidade por Substrato , Temperatura , Tetroses/metabolismo , Vibrio alginolyticus/genética
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