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1.
J Control Release ; 293: 183-192, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30529259

RESUMO

The effect of poly(2-ethyl-butyl cyanoacrylate) nanoparticles containing the cytotoxic drug cabazitaxel was studied in three breast cancer cell lines and one basal-like patient-derived xenograft model grown in the mammary fat pad of immunodeficient mice. Nanoparticle-encapsulated cabazitaxel had a much better efficacy than similar concentrations of free drug in the basal-like patient-derived xenograft and resulted in complete remission of 6 out of 8 tumors, whereas free drug gave complete remission only with 2 out of 9 tumors. To investigate the different efficacies obtained with nanoparticle-encapsulated versus free cabazitaxel, mass spectrometry quantification of cabazitaxel was performed in mice plasma and selected tissue samples. Nanoparticle-encapsulated drug had a longer circulation time in blood. There was approximately a three times higher drug concentration in tumor tissue 24 h after injection, and two times higher 96 h after injection of nanoparticles with drug compared to the free drug. The tissue biodistribution obtained after 24 h using mass spectrometry analyses correlates well with biodistribution data obtained using IVIS® Spectrum in vivo imaging of nanoparticles labeled with the fluorescent substance NR668, indicating that these data also are representative for the nanoparticle distribution. Furthermore, immunohistochemistry was used to estimate infiltration of macrophages into the tumor tissue following injection of nanoparticle-encapsulated and free cabazitaxel. The higher infiltration of anti-tumorigenic versus pro-tumorigenic macrophages in tumors treated with the nanoparticles might also contribute to the improved effect obtained with the nanoparticle-encapsulated drug. Tumor infiltration of pro-tumorigenic macrophages was four times lower when using nanoparticles containing cabazitaxel than when using particles without drug, and we speculate that the very good therapeutic efficacy obtained with our cabazitaxel-containing particles may be due to their ability to reduce the level of pro-tumorigenic macrophages in the tumor. In summary, encapsulation of cabazitaxel in poly(2-ethyl-butyl cyanoacrylate) nanoparticles seems promising for treatment of breast cancer.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Cianoacrilatos/administração & dosagem , Nanopartículas/administração & dosagem , Taxoides/administração & dosagem , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cianoacrilatos/farmacocinética , Feminino , Humanos , Camundongos Nus , Taxoides/sangue , Taxoides/farmacocinética , Distribuição Tecidual , Resultado do Tratamento
2.
Rev. esp. enferm. dig ; 109(2): 162-164, feb. 2017. ilus
Artigo em Inglês | IBECS | ID: ibc-159868

RESUMO

Angiography plays an important role in both diagnosis and treatment of gastrointestinal (GI) bleeding; however, the sensitivity is low for diagnosis. We report a case of a 38-year-old woman who presented with recurrent upper GI bleeding following central pancreatectomy. Multiple selective arteriograms failed to reveal any active bleeding or other common signs of bleeding. There was an abrupt occlusion of the right gastroepiploic artery initially interpreted to be a surgical ligation. Upon direct superselective injection near the occlusion, an area of frank contrast extravasation was demonstrated immediately beyond the occlusion. The underlying vessel was embolized with n-butyl cyanoacrylate without recurrent bleeding up to 3-month follow-up (AU)


No disponible


Assuntos
Humanos , Feminino , Adulto , Artéria Gastroepiploica , Artéria Gastroepiploica/lesões , Artéria Gastroepiploica , Hemorragia Gastrointestinal/complicações , Hemorragia Gastrointestinal/tratamento farmacológico , Hemorragia Gastrointestinal , Angiografia/instrumentação , Embolização Terapêutica/instrumentação , Embolização Terapêutica/métodos , Cianoacrilatos/metabolismo , Cianoacrilatos/farmacocinética , Cianoacrilatos/uso terapêutico
4.
Nat Chem Biol ; 11(7): 525-31, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26006010

RESUMO

Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo.


Assuntos
Acrilamidas/farmacocinética , Linfócitos B/efeitos dos fármacos , Cianoacrilatos/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/antagonistas & inibidores , Acrilamidas/síntese química , Tirosina Quinase da Agamaglobulinemia , Animais , Linfócitos B/enzimologia , Linfócitos B/patologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Cianoacrilatos/síntese química , Dasatinibe , Feminino , Expressão Gênica , Humanos , Ligantes , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/síntese química , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/genética , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Células Sf9 , Spodoptera , Relação Estrutura-Atividade , Especificidade por Substrato , Tiazóis/farmacocinética , Fatores de Tempo
5.
Am J Obstet Gynecol ; 202(1): 85.e1-9, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20096254

RESUMO

OBJECTIVE: This study was undertaken to test injectable surgical sealants that are biocompatible with fetal membranes and that are to be used eventually for the closure of iatrogenic membrane defects. STUDY DESIGN: Dermabond (Ethicon Inc, Norderstedt, Germany), Histoacryl (B. Braun GmbH, Tuttlingen, Germany), and Tissucol (Baxter AG, Volketwil, Switzerland) fibrin glue, and 3 types of in situ forming poly(ethylene glycol)-based polymer hydrogels were tested for acute toxicity on direct contact with fetal membranes for 24 hours. For the determination of elution toxicity, extracts of sealants were incubated on amnion cell cultures for 72 hours. Bonding and toxicity was assessed through morphologic and/or biochemical analysis. RESULTS: Extracts of all adhesives were nontoxic for cultured cells. However, only Tissucol and 1 type of poly(ethylene glycol)-based hydrogel, which is a mussel-mimetic tissue adhesive, showed efficient, nondisruptive, nontoxic bonding to fetal membranes. Mussel-mimetic tissue adhesive that was applied over membrane defects that were created with a 3.5-mm trocar accomplished leak-proof closure that withstood membrane stretch in an in vitro model. CONCLUSION: A synthetic hydrogel-type tissue adhesive that merits further evaluation in vivo emerged as a potential sealing modality for iatrogenic membrane defects.


Assuntos
Âmnio/efeitos dos fármacos , Âmnio/cirurgia , Cianoacrilatos/farmacocinética , Adesivo Tecidual de Fibrina/farmacologia , Hidrogéis/uso terapêutico , Polietilenoglicóis/farmacologia , Adesivos Teciduais/farmacologia , Âmnio/citologia , Cianoacrilatos/administração & dosagem , Cianoacrilatos/farmacologia , Embucrilato/administração & dosagem , Embucrilato/farmacologia , Feminino , Ruptura Prematura de Membranas Fetais , Fetoscopia , Adesivo Tecidual de Fibrina/administração & dosagem , Humanos , Hidrogéis/administração & dosagem , Técnicas In Vitro , Teste de Materiais , Polietilenoglicóis/administração & dosagem , Gravidez , Adesivos Teciduais/administração & dosagem
6.
Artigo em Inglês | MEDLINE | ID: mdl-20049811

RESUMO

The major problem in drug delivery to the brain is the presence of the blood-brain barrier (BBB) which limits drug penetration even if in certain pathological situations the BBB is partly disrupted. Among noninvasive techniques to overcome this barrier, the use of nanoparticles has been proposed. This review focuses on poly(alkylcyanoacrylates) (PACA)-based nanoparticles which have been developed for brain targeting. Both types of 'stealth' PACA nanoparticles with modified surface, those coated with surfactant and those with chains of polyethylene glycol (PEG) linked to the hydrophobic core of PACA are presented. The synthesis of polymers, the preparation of nanoparticles with modified surface and their physicochemical characterization are described. The review of their in vivo results evidenced their ability to enter into the brain using healthy animals or models of central nervous system (CNS) diseases. The nature of the surface modification (surfactant nature, PEG linkage, drug loading interference) seems to have a great influence on the efficacy of brain targeting which can be related to the adsorption of some apolipoproteins (Apo E, B, A-I). The mechanism of their passage through the BBB has been studied by in vitro and in vivo experiments, which suggested the implication of receptor-mediated endocytosis processes. According to these data, some antibodies (OX26) and ligands (transferrin, Apo E/B/A-I) seem to be good candidates to be coupled with 'stealth' PACA nanoparticles in order to increase their passage through the BBB and to promote active targeting to the brain.


Assuntos
Barreira Hematoencefálica/metabolismo , Cianoacrilatos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/administração & dosagem , Animais , Cianoacrilatos/farmacocinética , Humanos
7.
Acta Haematol ; 118(4): 242-3, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18087146

RESUMO

Environmental agents have long been thought to be linked to the development of malignancies. Due to the difficulty in identifying and verifying exposures to such agents, only a few chemical compounds are clearly linked to malignancies. We report here the case of a 36-year-old man with pre-B cell acute lymphoblastic leukemia. This patient was using industrial strength glue to reattach a chipped tooth for approximately 1 year, and such use was associated with chronic exposure of his oral mucosa to this glue. This case raises the possibility that chronic exposure to cyanoacrylates, the adhesive agents in industrial strength glue, may be associated with the development of acute lymphoblastic leukemia in humans.


Assuntos
Adesivos/efeitos adversos , Cianoacrilatos/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/induzido quimicamente , Autocuidado/efeitos adversos , Fraturas dos Dentes/terapia , Adesivos/farmacocinética , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/administração & dosagem , Cianoacrilatos/farmacocinética , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Dexametasona/administração & dosagem , Doxorrubicina/administração & dosagem , Humanos , Masculino , Mercaptopurina/administração & dosagem , Metotrexato/administração & dosagem , Mucosa Bucal/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Prednisona/administração & dosagem , Recidiva , Indução de Remissão , Terapia de Salvação , Vincristina/administração & dosagem
8.
Acta Pharmacol Sin ; 26(12): 1512-8, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16297352

RESUMO

AIM: To investigate the body distribution in mice of [14C]-labeled poly methoxyethyleneglycol cyanoacrylate-co-n-hexadecyl cyanoacrylate (PEG-PHDCA) nanoparticles and in situ evading of phagocytic uptake by mouse peritoneal macrophages. METHODS: PEG-PHDCA copolymers were synthesized by condensation of methoxypolyethylene glycol cyanoacetate with [14C]-hexadecyl-cyanoacetate. [14C]-nanoparticles were prepared using the nanoprecipitation/solvent diffusion method, while fluorescent nanoparticles were prepared by incorporating rhodamine B. In situ phagocytic uptake was evaluated by flow cytometry. Body distribution in mice was evaluated by determining radioactivity in tissues using a scintillation method. RESULTS: Phagocytic uptake by macrophages can be efficiently evaded by fluorescent PEG-PHDCA nanoparticles. After 48 h, 31% of the radioactivity of the stealth [14C]-PEG-PHDCA nanoparticles after iv injection was still found in blood, whereas non-stealth PHDCA nanoparticles were cleaned up from the bloodstream in a short time. The distribution of stealth PEG-PHDCA nanoparticles and non-stealth PHDCA nanoparticals in mice was poor in lung, kidney, and brain, and a little higher in hearts. Lymphatic accumulation was unusually high for both stealth and non-stealth nanoparticles, typical of lymphatic capture. The accumulation of stealth PEG-PHDCA nanoparticles in the spleen was 1.7 times as much as that of non-stealth PHDCA (P< 0.01). But the accumulation of stealth PEG-PHDCA nanoparticles in the liver was 0.8 times as much as that of non-stealth PHDCA (P< 0.05). CONCLUSION: PEGylation leads to long-circulation of nanoparticles in the bloodstream, and splenotropic accumulation opens up the potential for further development of spleen-targeted drug delivery.


Assuntos
Cianoacrilatos/farmacocinética , Portadores de Fármacos , Macrófagos Peritoneais/fisiologia , Fagocitose , Polietilenoglicóis/farmacocinética , Baço/metabolismo , Animais , Cianoacrilatos/administração & dosagem , Cianoacrilatos/síntese química , Sistemas de Liberação de Medicamentos , Camundongos , Nanopartículas , Tamanho da Partícula , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/síntese química , Distribuição Tecidual
9.
J Invest Dermatol ; 125(2): 264-9, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16098036

RESUMO

The determination of penetration pathways of topically applied substances into the skin is the subject of several investigations. Recently, follicular penetration has become a major focus of interest. To date, a direct, non-invasive quantification of the amount of topically applied substance penetrated into the follicles had not been possible. The development of such a method was the aim of this study. Therefore, the advantages of both stripping techniques, tape stripping and cyanoacrylate skin surface biopsy, were combined and evaluated. Tape stripping was used to remove the part of the stratum corneum that contained the topically applied dye. Subsequently, the follicular contents were ripped off by cyanoacrylate skin surface biopsy. The combined method termed "differential stripping" was evaluated in vitro and in vivo, and the amount of topically applied fluorescent dye penetrated into the hair follicles was quantified after different penetration times. After 30 min, 5% of the recovered concentration of sodium fluorescein was found in the follicular infundibula, where it was still detectable after 48 h. Altogether, the results of this investigation revealed that differential stripping is a new method that can be used to study the penetration of topically applied substances into the follicular infundibula non-invasively and selectively.


Assuntos
Biópsia/métodos , Cianoacrilatos/farmacocinética , Folículo Piloso/metabolismo , Administração Tópica , Adulto , Animais , Meios de Contraste/farmacocinética , Feminino , Fluoresceína/farmacocinética , Folículo Piloso/citologia , Humanos , Masculino , Absorção Cutânea , Sus scrofa
10.
Cell Mol Life Sci ; 62(12): 1400-8, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15905957

RESUMO

Poly(MePEG2000cyanoacrylate-co-hexadecylcyanoacrylate) (PEG-PHDCA) nanoparticles have demonstrated their capacity to reach the rat central nervous system after intravenous injection. For insight into the transport of colloidal systems across the blood-brain barrier (BBB), we developed a relevant in vitro rat BBB model consisting of a coculture of rat brain endothelial cells (RBECs) and rat astrocytes. The RBECs used in our model displayed and retained structural characteristics of brain endothelial cells, such as expression of P-glycoprotein, occludin and ZO-1, and immunofluorescence studies showed the specific localization of occludin and ZO1. The high values of transendothelial electrical resistance and low permeability coefficients of marker molecules demonstrated the functionality of this model. The comparative passage of polyhexadecylcyanoacrylate and PEG-PHDCA nanoparticles through this model was investigated, showing a higher passage of PEGylated nanoparticles, presumably by endocytosis. This result was confirmed by confocal microscopy. Thanks to a good in vitro/in vivo correlation, this rat BBB model will help in understanding the mechanisms of nanoparticle translocation and in designing new types of colloidal carriers as brain delivery systems.


Assuntos
Transporte Biológico , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Cianoacrilatos/farmacocinética , Modelos Biológicos , Polietilenoglicóis/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Astrócitos/metabolismo , Permeabilidade Capilar , Sistemas de Liberação de Medicamentos , Células Endoteliais/metabolismo , Imunofluorescência , Técnicas In Vitro , Proteínas de Membrana/metabolismo , Nanotecnologia , Ocludina , Ratos , Ratos Sprague-Dawley
11.
Int J Pharm ; 288(2): 289-93, 2005 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-15620869

RESUMO

Dispersions of insulin poly(isobutylcyanoacrylate) nanoparticles were obtained by anionic in situ polymerization using aqueous pluronic acid solution. Results showed a decrease in particle size diameter by increasing the pluronic acid concentration. Nanoparticles prepared in the presence of 2.5% pluronic acid resulted in particles of 85 nm average diameter and 59% intra-particular insulin load without the use of the oily core [Damge, C., Michel, M., Aprahamian, M., Couveur, P., 1988. New approach for oral administration with polycyanoacrylate nanocapsules as drug carrier. Diabetes 37, 246-251]. In vivo testing was performed on streptozocin induced diabetic rats. The subcutaneous injection of insulin nanoparticles was able to prolong its duration of hypoglycemic effect from 6 to 72 h. Effective oral absorption of the entrapped insulin was significantly better (p<0.01) when compared with non-encapsulated insulin or the control experiments.


Assuntos
Cianoacrilatos/administração & dosagem , Cianoacrilatos/farmacocinética , Insulina/administração & dosagem , Insulina/farmacocinética , Nanoestruturas , Polímeros/administração & dosagem , Polímeros/farmacocinética , Absorção , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Embucrilato , Humanos , Injeções Subcutâneas , Masculino , Ratos , Ratos Wistar , Tela Subcutânea/efeitos dos fármacos , Tela Subcutânea/metabolismo
12.
Eur J Drug Metab Pharmacokinet ; 29(2): 77-81, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15230333

RESUMO

The aim of this study was to investigate absorption of ethyl 2-cyanoacrylate glue when used as a tissue adhesive. Ethyl 2-cyanoacrylate was applied subcutaneously to four rats; its presence in blood and urine was investigated by using High Pressure Liquid Chromatography. Blood samples were drawn at baseline and after 2, 4, 6, 24, 48, 54, 78, 96 hours following application. Urine samples were obtained at baseline and after 4, 24, 48, 72, 96 hours. Administration of ethyl 2-cyanoacrylate resulted in its absorption of unchanged ethyl 2-cyanoacrylate and unknown metabolites, in plasma and urine.


Assuntos
Cianoacrilatos/farmacocinética , Adesivos Teciduais/farmacocinética , Absorção , Animais , Biotransformação , Cromatografia Líquida de Alta Pressão , Masculino , Ratos , Ratos Sprague-Dawley , Espectrofotometria Ultravioleta
13.
Biochem Biophys Res Commun ; 318(2): 562-70, 2004 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-15120637

RESUMO

PURPOSE: Nanoparticles are able to enhance drug or DNA stability for purposes of optimised deposition to targeted tissues. Surface modifications can mediate drug targeting. The suitability of nanoparticles synthesised out of porcine gelatin, human serum albumin, and polyalkylcyanoacrylate as drug and gene carriers for pulmonary application was investigated in vitro on primary airway epithelium cells and the cell line 16HBE14o-. METHODS: The uptake of nanoparticles into these cells was examined by confocal laser scan microscopy (CLSM) and flow cytometry (FACS). Further the cytotoxicity of nanoparticles was evaluated by an LDH-release-test and the inflammatory potential of the nanoparticles was assessed by measuring IL-8 release. RESULTS: CLSM and FACS experiments showed that the nanoparticles were incorporated into bronchial epithelial cells provoking little or no cytotoxicity and no inflammation as measured by IL-8 release. CONCLUSIONS: Based on their low cytotoxicity and the missing inflammatory potential in combination with an efficient uptake in human bronchial epithelial cells, protein-based nanoparticles are suitable drug and gene carriers for pulmonary application.


Assuntos
Brônquios/metabolismo , Cianoacrilatos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Gelatina/farmacocinética , Albumina Sérica/farmacocinética , Biodegradação Ambiental , Brônquios/citologia , Brônquios/efeitos dos fármacos , Separação Celular , Células Cultivadas , Cianoacrilatos/química , Cianoacrilatos/toxicidade , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Citometria de Fluxo , Gelatina/química , Gelatina/toxicidade , Técnicas de Transferência de Genes , Humanos , Interleucina-8/biossíntese , L-Lactato Desidrogenase/biossíntese , Microscopia Confocal , Nanotecnologia/métodos , Tamanho da Partícula , Albumina Sérica/química , Albumina Sérica/toxicidade
14.
J Control Release ; 93(2): 151-60, 2003 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-14636721

RESUMO

Simultaneous cellular resistance to multiple lipophilic drugs represents a major problem in cancer chemotherapy. This drug resistance may appear clinically either as a lack of tumor size reduction or as the occurrence of clinical relapse after an initial positive response to antitumor treatment. The resistance mechanism can have different origins either directly linked to specific mechanisms developed by the tumor tissue or connected to the more general problem of distribution of a drug towards its targeted tissue. The purpose of this paper is to summarize the results of the use of poly(alkyl cyanoacrylate) nanoparticles to overcome multidrug resistance (MDR) phenomena at both the cellular and the non-cellular level.


Assuntos
Cianoacrilatos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Animais , Cianoacrilatos/administração & dosagem , Cianoacrilatos/química , Cianoacrilatos/uso terapêutico , Previsões , Humanos , Nanotecnologia/métodos , Nanotecnologia/tendências
15.
J Control Release ; 92(1-2): 19-26, 2003 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-14499182

RESUMO

We report a molecular simulation study of doxorubicin interacting within a frame of n-butyl polycyanoacrylate, one of the most commonly encountered polymers in the production of nanoparticles. Emphasis is put on the tetrameric, hexameric and octameric oligomers (PACA's). Log P was calculated for all interacting species. Molecular dynamics along with energy minimization processes (molecular mechanics MM2, semi-empirical quantum mechanics PM3) were employed to probe the conformational behavior of doxorubicin and polyalkylcyanoacrylate both as isolated species and interacting with each other. A docked structure of protonated doxorubicin with two octamers of n-butyl polycyanoacrylate is described. Among the main stability factors of the assembly was the charge-dipole interaction representing a stabilizing contribution of -33 kcal/mol. The mechanism of aggregation and desegregation (doxorubicin release) can be summarized as follows: oligomeric PACA's are lipophilic entities that scavenge amphiphilic doxorubicin already during the polymerization process by extraction of the protonated species from the aqueous environment to the increasingly lipophilic phase of the growing PACA's. The establishment of hydrogen bonds between the ammonium N-H function and the cyano groups is noteworthy. The cohesion in PACA nanoparticle comes therefore from a blend of dipole-charge interaction, H bonds, and hydrophobic forces,


Assuntos
Cianoacrilatos/química , Doxorrubicina/química , Modelos Moleculares , Cianoacrilatos/farmacocinética , Doxorrubicina/farmacocinética , Interações Medicamentosas/fisiologia , Nanotecnologia/métodos
16.
J Pharmacol Exp Ther ; 303(3): 928-36, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12438511

RESUMO

The aim of the present study was to evaluate the tumor accumulation of radiolabeled long-circulating poly(ethylene glycol) (PEG)-coated hexadecylcyanoacrylate nanospheres and non-PEG-coated hexadecylcyanoacrylate nanospheres (used as control), after intravenous injection in Fischer rats bearing intracerebrally well established 9L gliosarcoma. Both types of nanospheres showed an accumulation with a retention effect in the 9L tumor. However, long-circulating nanospheres concentrated 3.1 times higher in the gliosarcoma, compared with non-PEG-coated nanospheres. The tumor-to-brain ratio of pegylated nanospheres was found to be 11, which was in accordance with the ratios reported for other carriers tested for brain tumor targeting such as long-circulating liposomes or labels for magnetic resonance imaging. In addition, a 4- to 8-fold higher accumulation of the PEG-coated carriers was observed in normal brain regions, when compared with control nanospheres. Using a simplified pharmacokinetic model, two different mechanisms were proposed to explain this higher concentration of PEG-coated nanospheres in a tumoral brain. 1) in the 9L tumor, the preferential accumulation of pegylated nanospheres was attributable to their slower plasma clearance, relative to control nanospheres. Diffusion/convection was the proposed mechanism for extravasation of the nanospheres in the 9L interstitium, across the altered blood-brain barrier. 2) In addition, PEG-coated nanospheres displayed an affinity with the brain endothelial cells (normal brain region), which may not be considered as the result of a simple diffusion/convection process. The exact underlying mechanism of such affinity deserves further investigation, since it was observed to be as important as specific interactions described for immunoliposomes with the blood-brain barrier.


Assuntos
Neoplasias Encefálicas/metabolismo , Cianoacrilatos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Gliossarcoma/metabolismo , Nanotecnologia/métodos , Polietilenoglicóis/farmacocinética , Animais , Neoplasias Encefálicas/tratamento farmacológico , Cianoacrilatos/administração & dosagem , Gliossarcoma/tratamento farmacológico , Masculino , Microesferas , Polietilenoglicóis/administração & dosagem , Ratos , Ratos Endogâmicos F344 , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
17.
Int J Pharm ; 235(1-2): 237-46, 2002 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-11879758

RESUMO

The effect of several formulation variables on some of the physico-chemical characteristics of poly (ethyl cyanoacrylate) (PECA) nanocapsules prepared by the interfacial polymerisation of biocompatible water-in-oil microemulsions was investigated. In all cases, yields were high (>90%) and the polydispersity in size of nanocapsules was narrow. The molecular weight of the nanocapsules formed was influenced by the pH of the aqueous component of the microemulsion, increasing with increasing pH. The size of the nanocapsules formed (ranging from around 130 to 180 nm) was a function of the ratio of the mass of monomer used to the water weight fraction of the microemulsion, increasing as this ratio was increased. This is due to the formation of a thicker polymer wall resulting from the increased mass of monomer available per unit interfacial area as this ratio is increased. The rate of release of insulin from nanocapsules was also influenced by this ratio, in agreement with its effect on wall thickness. This study demonstrates that many pharmaceutically relevant physico-chemical properties of poly (alkyl cyanoacrylate) (PACA) nanocapsules prepared by interfacial polymerisation of microemulsions can readily be manipulated by changing either the pH of the aqueous component, the water weight fraction of the microemulsion or the mass of monomer used for polymerisation.


Assuntos
Cianoacrilatos/química , Nanotecnologia/métodos , Cápsulas , Química Farmacêutica , Cianoacrilatos/farmacocinética , Emulsões , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Insulina/química , Insulina/farmacocinética , Adesivos Teciduais/química , Adesivos Teciduais/farmacocinética
18.
J Neurosci Methods ; 111(2): 151-5, 2001 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-11595281

RESUMO

PEGylated polymeric nanoparticles are hereby presented as a potential efficient drug carrier for the delivery of active therapeutic molecules in prion experimental diseases. Based on their blood long-circulating characteristics, these PEGylated particles made by the amphiphilic copolymer poly [methoxy poly(ethylene glycol) cyanoacrylate-co-hexadecyl cyanoacrylate] (PEG-PHDCA), showed comparatively conventional non-PEGylated nanoparticles, a higher uptake by the spleen and the brain which are both the target tissues of PrPres accumulation in scrapie infected animals.


Assuntos
Materiais Biocompatíveis , Cianoacrilatos , Polietilenoglicóis , Scrapie/tratamento farmacológico , Animais , Materiais Biocompatíveis/farmacocinética , Sangue/metabolismo , Encéfalo/metabolismo , Cianoacrilatos/farmacocinética , Portadores de Fármacos , Injeções Intravenosas , Masculino , Concentração Osmolar , Tamanho da Partícula , Polietilenoglicóis/farmacocinética , Ratos , Scrapie/fisiopatologia , Distribuição Tecidual
19.
Pharm Res ; 18(4): 467-73, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11451033

RESUMO

PURPOSE: The aim of the studv was to evaluate the capacity of poly(isohexylcyanoacrylate) nanospheres to concentrate 3'-azido 3'-deoxythymidine (AZT) in the intestinal epithelium and associated immunocompetent cells, which are known to be one of the major reservoirs of the human immunodeficiency virus (HIV). METHODS: The tissue concentration of 3H-radiolabeled AZT in the gastrointestinal (GI) tract was obtained 30 and 9() minutes after intragastric administration to rats at a dose of 0.25 mg AZT/100 g of body weight. The distribution along the intestine was determined. AZT concentrations in the lymph were obtained by lymphatic duct cannulation. RESULTS: Unlike the solution. nanoparticles did concentrate AZT very cfficiently in the intestinal mucosa, as well as in the Peyer's patches, and could simultaneously control the release of free AZT. Concentration in Peyer's patches was 4 times higher for nanoparticles, compared with the control solution. The tissue concentration was 30-45 microM, which was much higher than the reported IC50 of AZT (0.06-1.36 microM) and was regularly distributed along the gastrointestinal tract. CONCLUSIONS: Nanoparticles have been shown to be efficient in concentrating AZT in the intestinal epithelium and gut-associated lymphoid tissues, supporting the view that these particles may represent a promising carrier to treat specifically the GI reservoir of HIV.


Assuntos
Fármacos Anti-HIV/farmacocinética , Cianoacrilatos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Mucosa Intestinal/metabolismo , Tecido Linfoide/metabolismo , Zidovudina/farmacocinética , Animais , Fármacos Anti-HIV/administração & dosagem , Cianoacrilatos/administração & dosagem , Mucosa Intestinal/efeitos dos fármacos , Tecido Linfoide/efeitos dos fármacos , Microesferas , Ratos , Ratos Wistar , Zidovudina/administração & dosagem
20.
Adv Drug Deliv Rev ; 47(1): 55-64, 2001 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-11251245

RESUMO

Much effort has been made to achieve lymphatic targeting of drugs using colloidal carriers. This paper reviews the recent progress in the development of biodegradable nanoparticulate systems, including nanospheres, emulsions, and liposomes. The major purpose of lymphatic targeting is to provide an effective anticancer chemotherapy to prevent the metastasis of tumor cells by accumulating the drug in the regional lymph node via subcutaneous administration. The objectives of lymph targeting also involve the localization of diagnostic agents to the regional lymph node to visualize the lymphatic vessels before surgery, and the improvement of peroral bioavailability of macromolecular drugs, like polypeptides or proteins, which are known to be selectively taken up from the Peyer's patch in the intestine. Nanocapsules, which are ultrafine oily droplet-coated polymeric substances, are probably one of the most promising candidates of colloidal carriers. Surface engineering by the interfacial deposition method can provide a suitable size distribution and necessary surface characteristics to the nanocapsules. Our recent in vivo study proved that polyisobutylcyanoacrylate nanocapsules showed enhanced accumulation of drug in the lymph node, compared with other carriers such as emulsions and liposomes.


Assuntos
Portadores de Fármacos/administração & dosagem , Composição de Medicamentos/métodos , Metástase Linfática/prevenção & controle , Animais , Disponibilidade Biológica , Cápsulas , Cianoacrilatos/administração & dosagem , Cianoacrilatos/química , Cianoacrilatos/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Emulsões , Embucrilato , Lipossomos , Polímeros/administração & dosagem , Polímeros/química , Polímeros/farmacocinética , Ratos , Ácidos Esteáricos/administração & dosagem , Ácidos Esteáricos/química , Ácidos Esteáricos/farmacocinética
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