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1.
J Sep Sci ; 47(11): e2400181, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38863110

RESUMO

Topotecan (TPT) is used in the treatment of retinoblastoma, the most common malignant intraocular tumor in children. TPT undergoes pH-dependent hydrolysis of the lactone ring to the ring-opened carboxylate form, with the lactone form showing antitumor activity. A selective, and highly sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed for the determination of both forms of TPT in one mobile phase composition in plasma and vitreous humor matrices. The method showed an excellent linear range of 0.375-120 ng/mL for the lactone. For the carboxylate, the linear range was from 0.75 to 120 ng/mL. The matrix effect and the recovery for the lactone ranged from 98.5% to 106.0% in both matrices, for the carboxylate form, it ranged from 94.9% to 101.2%. The dynamics of the transition between TPT lactone and TPT carboxylate were evaluated at different pH environments. The stability of TPT forms was assessed in plasma and vitreous humor at 8 and 37°C and a very fast conversion of lactone to carboxylate form occurred at 37°C in both matrices. The method developed facilitates the investigation of TPT pharmacodynamics and the release kinetics in the development of the innovative local drug delivery systems.


Assuntos
Lactonas , Espectrometria de Massas em Tandem , Topotecan , Corpo Vítreo , Cromatografia Líquida de Alta Pressão , Lactonas/química , Lactonas/análise , Corpo Vítreo/química , Topotecan/química , Topotecan/análise , Humanos , Ácidos Carboxílicos/química , Ácidos Carboxílicos/análise , Estrutura Molecular
2.
Pharmaceutics ; 15(5)2023 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-37242640

RESUMO

Local chemotherapy using polymer drug delivery systems has the potential to treat some cancers, including intraocular retinoblastoma, which is difficult to treat with systemically delivered drugs. Well-designed carriers can provide the required drug concentration at the target site over a prolonged time, reduce the overall drug dose needed, and suppress severe side effects. Herein, nanofibrous carriers of the anticancer agent topotecan (TPT) with a multilayered structure composed of a TPT-loaded inner layer of poly(vinyl alcohol) (PVA) and outer covering layers of polyurethane (PUR) are proposed. Scanning electron microscopy showed homogeneous incorporation of TPT into the PVA nanofibers. HPLC-FLD proved the good loading efficiency of TPT (≥85%) with a content of the pharmacologically active lactone TPT of more than 97%. In vitro release experiments demonstrated that the PUR cover layers effectively reduced the initial burst release of hydrophilic TPT. In a 3-round experiment with human retinoblastoma cells (Y-79), TPT showed prolonged release from the sandwich-structured nanofibers compared with that from a PVA monolayer, with significantly enhanced cytotoxic effects as a result of an increase in the PUR layer thickness. The presented PUR-PVA/TPT-PUR nanofibers appear to be promising carriers of active TPT lactone that could be useful for local cancer therapy.

3.
Pharmaceutics ; 14(5)2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35631489

RESUMO

Transscleral diffusion delivery of chemotherapy is a promising way to reach the vitreal seeds of retinoblastoma, the most common intraocular malignancy in childhood. In this in vivo study, the delivery of topotecan via lens-shaped, bi-layered hydrogel implants was combined with transconjunctival cryotherapy to assess whether cryotherapy leads to higher concentrations of topotecan in the vitreous. The study included 18 New Zealand albino rabbits; nine rabbits received a topotecan-loaded implant episclerally and another nine rabbits received transconjunctival cryotherapy superotemporally 2 weeks before implant administration. Median vitreous total topotecan exposures (area under the curve, AUC) were 455 ng·h/mL for the cryotherapy group and 281 ng·h/mL for the non-cryotherapy group, and were significantly higher in the cryotherapy group, similar to maximum levels. Median plasma AUC were 50 ng·h/mL and 34 ng·h/mL for the cryotherapy and non-cryotherapy groups, respectively, with no statistically significant differences between them. In both groups, AUC values in the vitreous were significantly higher than in plasma, with plasma exposure at only approximately 11-12% of the level of vitreous exposure. The results confirmed the important role of the choroidal vessels in the pharmacokinetics of topotecan during transscleral administration and showed a positive effect of cryotherapy on intravitreal penetration, resulting in a significantly higher total exposure in the vitreous.

4.
Int J Pharm ; 606: 120832, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34175379

RESUMO

Treatment of retinoblastoma (Rb) has greatly improved in recent years in terms of survival and eye salvage rates, using mainly intra-arterial or intravitreal chemotherapy. However, the treatment of vitreous tumor seeding still represents a challenge and it is of great interest to develop new strategies to deliver pharmacologically sufficient drug amounts to the vitreous humor. In the present work, we present a lens-shaped bi-layered hydrogel implant for delivery of topotecan (TPT) via transscleral diffusion. The implant consists of an inner TPT-loaded poly(2-hydroxyethyl methacrylate) (pHEMA) layer adjacent to the sclera and an outer covering poly(2-ethoxyethyl methacrylate) (pEOEMA) layer impermeable to TPT. TPT-loaded pHEMA samples exhibit long-lasting in vitro cytotoxicity against the Rb cell line Y79. In an in vivo experiment, pHEMA/pEOEMA implants are successfully surgically administered to the posterior segment of rabbit eyes. The determination of TPT pharmacokinetics demonstrates the attainment of promising levels of TPT (10 ng/ml) in vitreous humor 8 h after implant placement. The results from the pilot experiment constitute the proof of principle for the use of the proposed implants as a drug delivery system for the local treatment of intraocular diseases.


Assuntos
Neoplasias da Retina , Retinoblastoma , Animais , Hidrogéis , Coelhos , Topotecan , Corpo Vítreo
5.
Mater Sci Eng C Mater Biol Appl ; 115: 111068, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32600692

RESUMO

Chronic wounds and their associated bacterial infections are major issues in modern health care systems. Therefore, antimicrobial resistance (AMR), treatment costs, and number of disability-adjusted life-years have gained more interest. Recently, photodynamic therapy emerged as an effective approach against resistant and naïve bacterial strains with a low probability of creating AMR. In this study, needleless electrospinning was used to produce an indocyanine green (ICG) loaded poly(d,l-lactide) nanofibrous mesh as a photoresponsive wound dressing. The non-woven mesh had a homogeneous nanofibrous structure and showed long-term hydrolytic stability at different pH values. The antimicrobial activity was tested against several bacterial strains, namely Staphylococcus saprophyticus subsp. bovis, Escherichia coli DH5 alpha, and Staphylococcus aureus subsp. aureus. Upon irradiation with a laser of a specific wavelength (λ = 810 nm), the bacterial viability was significantly reduced by 99.978% (3.66 log10), 99.699% (2.52 log10), and 99.977% (3.64 log10), respectively. The nanofibrous mesh showed good biocompatibility, which was confirmed by the proliferation of mouse fibroblasts (L929) on the surface and into deeper parts of the mesh. Furthermore, a favorable proangiogenic effect was observed in ovo using the chorioallantoic membrane assay. In general, it can be concluded that ICG loaded nanofibers as an innovative wound dressing represent a promising strategy against chronic wounds associated with skin infections.


Assuntos
Materiais Biocompatíveis/farmacologia , Verde de Indocianina/farmacologia , Viabilidade Microbiana/efeitos dos fármacos , Poliésteres/química , Animais , Bandagens , Materiais Biocompatíveis/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Verde de Indocianina/química , Camundongos , Nanofibras , Fotoquimioterapia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus saprophyticus/efeitos dos fármacos , Staphylococcus saprophyticus/crescimento & desenvolvimento
6.
Mater Sci Eng C Mater Biol Appl ; 103: 109799, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349439

RESUMO

Retinoblastoma (Rb) is the most common primary malignant intraocular tumor in children which develops from the retinal stem cells. Systemic chemotherapy is the typical therapeutic treatment and though most children survive Rb, they often lose their vision, or the eye needs to be enucleated. Regarding to the pure availability of the target tumor by systemic chemotherapy, the local anticancer drug administration would be advantageous to increase the local drug concentration and minimize adverse side effects of chemotherapy. The present paper describes a new hydrogel implant enabled to deliver therapeutically active doses of low molecular weight hydrophilic antitumor drugs topotecan and vincristine. The hydrogel implant is proposed as bi-layered with an inner hydrophilic layer from 2-hydroxyethyl methacrylate (HEMA) serving as a reservoir of the chemotherapeutic agent and an outer hydrophobic layer from 2-ethoxyethyl methacrylate (EOEMA) acting as a barrier to protect the surrounding vascularized tissue against cytotoxicity of the delivered chemotherapeutics. The experiments with enucleated pig eyes demonstrated the ability of tested drugs to diffuse through sclera and reach the vitreous humor. HEMA-based hydrogels were examined in terms of sorption, release and transport properties, showing the possibility of adjusting the loading capacity and diffusion of the drugs by the degree of crosslinking. The EOEMA-based gels proved to be an inert for drug sorption and diffusion. A chorioallantoic membrane assay demonstrated excellent biocompatibility of unloaded hydrogels, and in vitro experiments confirmed significant cytotoxicity of drug-loaded hydrogels against a Rb cell line; 2 days for those topotecan-loaded and a minimum of 6 days for vincristine-loaded hydrogels. The bi-layered hydrogel implant can be considered promising for local administration of active agents to eye-globe for the treatment of Rb and also other ocular disorders.


Assuntos
Portadores de Fármacos/química , Hidrogéis/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Olho/efeitos dos fármacos , Olho/metabolismo , Humanos , Cinética , Metacrilatos/química , Próteses e Implantes , Retinoblastoma/metabolismo , Retinoblastoma/patologia , Suínos , Topotecan/química , Topotecan/metabolismo , Topotecan/farmacologia , Vincristina/química , Vincristina/metabolismo , Vincristina/farmacologia
7.
Polymers (Basel) ; 11(7)2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31247964

RESUMO

Self-inflating soft tissue expanders represent a valuable modality in reconstructive surgery. For this purpose, particularly synthetic hydrogels that increase their volume by swelling in aqueous environment are used. The current challenge in the field is to deliver a material with a suitable protracted swelling response, ideally with an induction period (for sutured wound healing) followed by a linear increase in volume lasting several days for required tissue reconstruction. Here, we report on synthesis, swelling, thermal, mechanical and biological properties of novel hydrogel tissue expanders based on poly(styrene-alt-maleic anhydride) copolymers covalently crosslinked with p-divinylbenzene. The hydrogels exerted hydrolysis-driven swelling response with induction period over the first two days with minimal volume change and gradual volume growth within 30 days in buffered saline solution. Their final swollen volume reached more than 14 times the dry volume with little dependence on the crosslinker content. The mechanical coherence of samples during swelling and in their fully swollen state was excellent, the compression modulus of elasticity being between 750 and 850 kPa. In vitro cell culture experiments and in vivo evaluation in mice models showed excellent biocompatibility and suitable swelling responses meeting thus the application requirements as soft tissue expanders.

8.
Artigo em Inglês | MEDLINE | ID: mdl-30967685

RESUMO

Cancer despite the introduction of new targeted therapy remains for many patients a fatal disease. Nanotechnology in cancer medicine has emerged as a promising approach to defeat cancer. Targeted delivery of anti-cancer drugs by different nanosystems promises enhanced drug efficacy, selectivity, better safety profile and reduced systemic toxicity. The article presents an overview of recent developments in cancer nanomedicine. We focus on approved anti-cancer medical products and on the results of clinical studies, highlighting that liposomal and micellar cytostatics or albumin-based nanoparticles have less side effects and are more efficient than "free" drugs. In addition, we discuss results of in vitro and in vivo preclinical studies with lipid, inorganic and polymer nanosystems loaded by anticancer drugs which according to our meaning are important for development of new nanodrugs. Pharmacokinetic characteristics of nanodrugs are discussed and characterization of major nanotechnology systems used for cancer nanomedicine is presented.


Assuntos
Antineoplásicos/administração & dosagem , Nanotecnologia , Neoplasias/tratamento farmacológico , Albuminas , Sistemas de Liberação de Medicamentos , Humanos , Lipossomos , Micelas
9.
Mater Sci Eng C Mater Biol Appl ; 98: 982-993, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30813105

RESUMO

Poly(d,l-lactide)/polyethylene glycol (PLA/PEG) micro/nanofibers loaded with paclitaxel (PTX, 10 wt%) were prepared by needless electrospinning technology, which allows large scale production for real medicinal practice. The fiber structure and properties were investigated by several methods including scanning electron microscopy, nitrogen adsorption/desorption isotherm measurements, differential scanning calorimetry, and X-ray diffraction measurements to examine their morphology (fiber diameter distribution, specific surface area, and total pore volume), composition, drug-loading efficiency, and physical state. An HPLC-UV method was optimized and validated to quantify in vitro PTX release into PBS. The results showed that the addition of PEG into PLA fibers promoted the release of higher amounts of hydrophobic PTX over prolonged time periods compared to fibers without PEG. An in vitro cell assay demonstrated the biocompatibility of PLA/PEG fibrous materials and showed significant cytotoxicity of PTX-loaded PLA/PEG fibers against a human fibrosarcoma HT1080 cell line. The chick chorioallantoic membrane assay proved that PTX-loaded fibers exhibited antiangiogenic activity, with a pronounced effect in the case of the PEG-containing fibers. In vivo evaluation of PTX-loaded PLA/PEG fibers in a human fibrosarcoma recurrence model showed statistically significant inhibition in tumor incidence and growth after primary tumor resection compared to other treatment groups.


Assuntos
Inibidores da Angiogênese/farmacologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Nanofibras/química , Recidiva Local de Neoplasia/prevenção & controle , Paclitaxel/farmacologia , Poliésteres/química , Polietilenoglicóis/química , Animais , Peso Corporal , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Galinhas , Humanos , Masculino , Camundongos Nus , Nanofibras/ultraestrutura , Recidiva Local de Neoplasia/patologia , Temperatura , Carga Tumoral/efeitos dos fármacos , Difração de Raios X
10.
Int J Pharm ; 558: 268-283, 2019 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-30611748

RESUMO

Currently, chemotherapy is the most common treatment for oncological diseases. Systemic administration of chemotherapeutics provides an easy and effective distribution of the active agents throughout the patient's body, however organs may be severely impaired by serious life-threatening side effects. In many oncological diseases, particularly solid tumors, the local application of chemotherapeutics would be advantageous. Recently, nanofibrous materials as local drug delivery systems have attracted much attention. They have considerable potential in the treatment of various cancers as they can provide a high concentration of the drug at the target site for a prolonged time, thereby lowering total exposure and adverse effects. The present review describes the specifics of drug delivery to the tumor microenvironment, basic characteristics of nanofibrous materials and their preparation, and comprehensively summarizes recent scientific reports concerning in vivo experiments with drug-loaded electrospun nanofibrous systems designed for local anticancer therapy.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanofibras/administração & dosagem , Neoplasias/tratamento farmacológico , Animais , Humanos , Microambiente Tumoral
11.
Macromol Biosci ; 18(6): e1800011, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29688614

RESUMO

Local application of anticancer agents prolongs the presence time and increases the concentration of drug in the target place and therefore may reduce serious side effects compared to drug systemic administration. The preparation of fibrous materials of polylactide (PLA) and polyethylene glycol (PEG) loaded with paclitaxel (PTX, 1 or 10 wt%) is presented. Scanning electron microscopy proves that PTX is homogeneously incorporated into the fibers. The addition of PEG of various molecular weights (6, 20, or 35 kDa) ensures the release of significantly higher amounts of hydrophobic PTX in a prolonged release time compared to the fibers containing PTX only. Present PLA-PEG fibrous carriers can serve as a drug depot for PTX since they exhibit significant toxicity for cancer cell lines in several-day experiment. They are promising for local recurrence therapy, where the initial release is efficient to kill tumor cells and continued release can prevent their subsequent proliferation.


Assuntos
Antineoplásicos , Portadores de Fármacos , Neoplasias/tratamento farmacológico , Paclitaxel , Poliésteres , Polietilenoglicóis , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Humanos , Células MCF-7 , Neoplasias/metabolismo , Neoplasias/patologia , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Poliésteres/química , Poliésteres/farmacocinética , Poliésteres/farmacologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia
12.
Eur J Med Chem ; 144: 300-317, 2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-29275230

RESUMO

Polymeric bile acid sequestrants (BAS) have recently attracted much attention as lipid-lowering agents. These non-absorbable materials specifically bind bile acids (BAs) in the intestine, preventing bile acid (BA) reabsorption into the blood through enterohepatic circulation. Therefore, it is important to understand the structure-property relationships between the polymer sequestrant and its ability to bind specific BAs molecules. In this review, we describe pleiotropic effects of bile acids, and we focus on BAS with various molecular architectures that result in different mechanisms of BA sequestration. Here, we present 1) amphiphilic polymers based on poly(meth)acrylates, poly(meth)acrylamides, polyalkylamines and polyallylamines containing quaternary ammonium groups, 2) cyclodextrins, and 3) BAS prepared via molecular imprinting methods. The synthetic approaches leading to individual BAS preparation, as well as results of their in vitro BA binding activities and in vivo lipid-lowering activities, are discussed.


Assuntos
Anticolesterolemiantes/farmacologia , Ácidos e Sais Biliares/farmacologia , Desenho de Fármacos , Hipercolesterolemia/tratamento farmacológico , Polímeros/farmacologia , Animais , Anticolesterolemiantes/síntese química , Anticolesterolemiantes/química , Ácidos e Sais Biliares/síntese química , Ácidos e Sais Biliares/química , Sítios de Ligação/efeitos dos fármacos , Humanos , Estrutura Molecular , Polímeros/síntese química , Polímeros/química
13.
Pharm Res ; 34(7): 1391-1401, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28405914

RESUMO

PURPOSE: The present study aims to prepare poly(D,L-lactic acid) (PLA) nanofibers loaded by the immunosuppressant cyclosporine A (CsA, 10 wt%). Amphiphilic poly(ethylene glycol)s (PEG) additives were used to modify the hydrophobic drug release kinetics. METHODS: Four types of CsA-loaded PLA nanofibrous carriers varying in the presence and molecular weight (MW) of PEG (6, 20 and 35 kDa) were prepared by needleless electrospinning. The samples were extracted for 144 h in phosphate buffer saline or tissue culture medium. A newly developed and validated LC-MS/MS method was utilized to quantify the amount of released CsA from the carriers. In vitro cell experiments were used to evaluate biological activity. RESULTS: Nanofibers containing 15 wt% of PEG showed improved drug release characteristics; significantly higher release rates were achieved in initial part of experiment (24 h). The highest released doses of CsA were obtained from the nanofibers with PEG of the lowest MW (6 kDa). In vitro experiments on ConA-stimulated spleen cells revealed the biological activity of the released CsA for the whole study period of 144 h and nanofibers containing PEG with the lowest MW exhibited the highest impact (inhibition). CONCLUSIONS: The addition of PEG of a particular MW enables to control CsA release from PLA nanofibrous carriers. The biological activity of CsA-loaded PLA nanofibers with PEG persists even after 144 h of previous extraction. Prepared materials are promising for local immunosuppression in various medical applications.


Assuntos
Ciclosporina/química , Imunossupressores/química , Nanofibras/química , Poliésteres/química , Polietilenoglicóis/química , Linhagem Celular , Meios de Cultura , Ciclosporina/administração & dosagem , Portadores de Fármacos , Liberação Controlada de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Imunossupressores/administração & dosagem , Cinética , Tamanho da Partícula , Baço/citologia , Propriedades de Superfície , Técnicas de Cultura de Tecidos
14.
J Mater Sci Mater Med ; 28(1): 12, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27995490

RESUMO

In order to create a soft tissue surplus, implantable volume expanders are often utilized in dental surgery. Implanted tissue expanders should gradually increase their volume, exerting a constant pressure on the surrounding tissue for weeks. Current tissue expanders are based predominantly on externally inflatable balloons or on osmotically active tissue expanders that use soft hydrogels wrapped in perforated plastic coatings, which limit fluid entry and swelling. We have designed and examined tissue expanders based on the controlled rate expansive hydrogels synthesized from copolymers of selected methacrylates and N-vinylpyrrolidone, cross-linked with a combination of non-degradable (glycol dimethacrylates) and hydrolytically degradable (N,O-dimethacryloylhydroxylamine) cross-linkers. These copolymers have close-to-linear volume expansion rates (up to 6-9 times their original volume) and exert an increasing swelling pressure in vitro. The anesthetic benzocaine has been incorporated into the hydrogels, and kinetic release experiments have shown that most of the drug (90%) was released within 48 h. Our proposed hydrogel expanders are homogeneous and have suitable mechanical properties, thus simplifying the surgical manipulations required. Further studies will be needed to completely evaluate their biocompatibility and tissue response to the implants.


Assuntos
Hidrogéis/química , Metacrilatos/química , Medicina Bucal/métodos , Polímeros/química , Dispositivos para Expansão de Tecidos , Anestésicos/administração & dosagem , Materiais Biocompatíveis/química , Reagentes de Ligações Cruzadas/química , Humanos , Hidroxilaminas/química , Cinética , Pressão
15.
Acta Pharm ; 66(4): 449-469, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27749252

RESUMO

Niacin was the first hypolipidemic drug to significantly reduce both major cardiovascular events and mortality in patients with cardiovascular disease. Niacin favorably influences all lipoprotein classes, including lipoprotein[a],and belongs to the most potent hypolipidemic drugs for increasing HDL-C. Moreover, niacin causes favorable changes to the qualitative composition of lipoprotein HDL. In addition to its pronounced hypolipidemic action, niacin exerts many other, non-hypolipidemic effects (e.g., antioxidative, anti-inflammatory, antithrombotic), which favorably influence the development and progression of atherosclerosis. These effects are dependent on activation of the specific receptor HCA2. Recent results published by the two large clinical studies, AIM-HIGH and HPS2-THRIVE, have led to the impugnation of niacin's role in future clinical practice. However, due to several methodological flaws in the AIM-HIGH and HPS2-THRIVE studies, the pleiotropic effects of niacin now deserve thorough evaluation. This review summarizes the present and possible future use of niacin in clinical practice in light of its newly recognized pleiotropic effects.


Assuntos
Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Modelos Biológicos , Niacina/uso terapêutico , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Vasodilatadores/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/efeitos adversos , Antioxidantes/uso terapêutico , Aterosclerose/induzido quimicamente , Aterosclerose/etiologia , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Progressão da Doença , Quimioterapia Combinada/efeitos adversos , Fibrinolíticos/efeitos adversos , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/metabolismo , Hiperlipidemias/fisiopatologia , Hipolipemiantes/efeitos adversos , Hipolipemiantes/farmacologia , Niacina/efeitos adversos , Niacina/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismo , Vasodilatadores/efeitos adversos , Vasodilatadores/farmacologia
16.
Beilstein J Nanotechnol ; 6: 1939-45, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26665065

RESUMO

Nanofibers were prepared from polycaprolactone, polylactide and polyvinyl alcohol using Nanospider(TM) technology. Polyethylene glycols with molecular weights of 2 000, 6 000, 10 000 and 20 000 g/mol, which can be used to moderate the release profile of incorporated pharmacologically active compounds, served as model molecules. They were terminated by aromatic isocyanate and incorporated into the nanofibers. The release of these molecules into an aqueous environment was investigated. The influences of the molecular length and chemical composition of the nanofibers on the release rate and the amount of released polyethylene glycols were evaluated. Longer molecules released faster, as evidenced by a significantly higher amount of released molecules after 72 hours. However, the influence of the chemical composition of nanofibers was even more distinct - the highest amount of polyethylene glycol molecules released from polyvinyl alcohol nanofibers, the lowest amount from polylactide nanofibers.

17.
Photochem Photobiol ; 89(2): 474-82, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23106573

RESUMO

Solar UVB radiation evokes photokeratitis, accompanied by increased corneal hydration and changes in corneal transparency, resulting in increased light absorption. Corneal optical properties are disturbed and visual acuity decreased. The aim of this study was to investigate the reversibility of these UVB-induced changes. Rabbit corneas were irradiated with UVB doses of 0.5 J cm(-2) or 1.01 J cm(-2) during 4 days. Some rabbits were sacrificed after the last irradiation and some 2 months later. Corneas were investigated spectrophotometrically for light absorption, and corneal hydration was evaluated by central corneal thickness with an ultrasonic pachymeter. Corneal impression cytologies were examined immunohistochemically for proinflammatory cytokines and malondialdehyde. The increased corneal light absorption, hydration and the staining of immunohistochemical markers found in corneas after irradiation returned to normal values during 2 months in corneas irradiated with the lower UVB dose. In contrast, in corneas irradiated with the higher UVB dose, a moderate but statistically significant increase in corneal light absorption, hydration and positive immunohistochemical stainings remained as residual changes. This was in contrast to normal corneas, where the staining of proinflammatory cytokines as well as malondialdehyde was negative. In conclusion, the reversibility of UVB-induced disturbances was dependent on UVB dose.


Assuntos
Lesões da Córnea , Ceratite/patologia , Lesões Experimentais por Radiação , Recuperação de Função Fisiológica/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Animais , Córnea/metabolismo , Paquimetria Corneana , Citocinas/biossíntese , Relação Dose-Resposta à Radiação , Ceratite/etiologia , Ceratite/metabolismo , Peroxidação de Lipídeos , Malondialdeído/metabolismo , Estresse Oxidativo , Coelhos , Doses de Radiação , Recuperação de Função Fisiológica/fisiologia , Água/metabolismo
18.
Int J Nanomedicine ; 7: 5315-25, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23071393

RESUMO

Polyvinyl alcohol nanofibers incorporating the wide spectrum antibiotic gentamicin were prepared by Nanospider™ needleless technology. A polyvinyl alcohol layer, serving as a drug reservoir, was covered from both sides by polyurethane layers of various thicknesses. The multilayered structure of the nanofibers was observed using scanning electron microscopy, the porosity was characterized by mercury porosimetry, and nitrogen adsorption/desorption measurements were used to determine specific surface areas. The stability of the gentamicin released from the electrospun layers was proved by high-performance liquid chromatography (HPLC) and inhibition of bacterial growth. Drug release was investigated using in vitro experiments with HPLC/MS quantification, while the antimicrobial efficacy was evaluated on Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa. Both experiments proved that the released gentamicin retained its activity and showed that the retention of the drug in the nanofibers was prolonged with the increasing thickness of the covering layers.


Assuntos
Antibacterianos/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Gentamicinas/administração & dosagem , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/fisiologia , Nanocápsulas/química , Nanocápsulas/ultraestrutura , Antibacterianos/química , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/química , Difusão , Eletroquímica/métodos , Teste de Materiais , Tamanho da Partícula , Rotação
19.
J Mater Sci Mater Med ; 23(4): 931-41, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22331377

RESUMO

Electrospun gelatin and poly-ε-caprolactone (PCL) nanofibers were prepared using needleless technology and their biocompatibility and therapeutic efficacy have been characterized in vitro in cell cultures and in an experimental model of a skin wound. Human dermal fibroblasts, keratinocytes and mesenchymal stem cells seeded on the nanofibers revealed that both nanofibers promoted cell adhesion and proliferation. The effect of nanofibers on wound healing was examined using a full thickness wound model in rats and compared with a standard control treatment with gauze. Significantly faster wound closure was found with gelatin after 5 and 10 days of treatment, but no enhancement with PCL nanofibers was observed. Histological analysis revealed enhanced epithelialisation, increased depth of granulation tissue and increased density of myofibroblasts in the wound area with gelatin nanofibers. The results show that gelatin nanofibers produced by needleless technology accelerate wound healing and may be suitable as a scaffold for cell transfer and skin regeneration.


Assuntos
Materiais Biocompatíveis , Nanofibras , Cicatrização , Humanos
20.
J Control Release ; 156(3): 406-12, 2011 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-21802460

RESUMO

Cyclosporine A (CsA), a potent immunosuppressive drug with low water solubility, was dissolved in poly(L-lactic acid) (PLA) solution, and nanofibers were fabricated from this mixture by electrospinning technology. The addition of CsA into the PLA solution and the conditions of the electrospinning process did not influence the structure of the nanofibers nor affect the pharmacological activity of CsA. Study of the CsA release behavior in culture medium showed a release for at least 96 h. After the topical application of CsA-loaded nanofibers on skin allografts in vivo, the release was significantly slower and about 35% of the drug was still retained in the nanofibers on day 8. The addition of CsA-loaded nanofibers into cultures of mouse spleen cells stimulated with Concanavalin A selectively inhibited T cell functions; the activity of stimulated macrophages or the growth of non-T-cell populations was not suppressed in the presence of CsA-loaded nanofibers. The covering of skin allografts with CsA-loaded nanofibers significantly attenuated the local production of the proinflammatory cytokines IL-2, IFN-γ and IL-17. These results suggest that CsA-loaded electrospun nanofibers can serve as effective drug carriers for the local/topical suppression of an inflammatory reaction and simultaneously could be used as scaffolds for cell-based therapy.


Assuntos
Ciclosporina/administração & dosagem , Portadores de Fármacos/química , Imunossupressores/administração & dosagem , Ácido Láctico/química , Nanofibras/química , Polímeros/química , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ciclosporina/farmacocinética , Ciclosporina/farmacologia , Citocinas/imunologia , Imunossupressores/farmacocinética , Imunossupressores/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanofibras/ultraestrutura , Poliésteres , Transplante de Pele , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
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