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1.
Biochem Biophys Res Commun ; 509(1): 268-274, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30583860

RESUMO

PURPOSE: Cancer stem cells (CSCs), also known as tumor-initiating cells, are involved in tumor progression, metastasis, and drug resistance. Hybrid liposomes (HLs) are nano-sized liposomal particles that can be easily prepared by ultrasonicating a mixture of vesicular and micellar molecules in buffer solutions. In this study, we investigated the inhibitory effects of HL on the growth of CSC subpopulations in liver cancer cells (HepG2) in vitro. METHODS: HLs composed of 90 mol% L-α-dimyristoylphosphatidylcholine and 10 mol% polyoxyethylene(23) dodecyl ether were prepared by sonication. Cell viability was determined by the trypan blue exclusion assay. In liver cancer cells, CSCs were identified by the presence of the cell surface marker proteins CD133 and EpCAM by flow cytometry. A soft agar colony formation assay was performed using HepG2 cells pretreated with HLs. RESULTS: HLs selectively inhibited liver cancer cell growth without affecting normal hepatocytes. Additionally, HLs induced apoptosis of HepG2 cells by a"ctivating caspase-3. Notably, the CD133(+)/EpCAM(+) CSC sub-population of liver cancer cells treated with HLs was reduced. Furthermore, HLs markedly decreased the number of colony-forming cells. Finally, we confirmed the fusion and accumulation of HLs into the cell membranes of CSCs using a fluorescently labeled lipid (NBDPC). Significant accumulation of HL/NBDPC into the CSCs (particularly EpCAM(+) cells) occurred in a dose-dependent manner. CONCLUSION: These results suggest that HLs are a novel nanomedical therapeutic agent for targeting CSCs in liver cancer therapy.


Assuntos
Dimiristoilfosfatidilcolina/farmacologia , Lipossomos/farmacologia , Neoplasias Hepáticas/terapia , Células-Tronco Neoplásicas/patologia , Polietilenoglicóis/farmacologia , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dimiristoilfosfatidilcolina/química , Doxorrubicina/farmacologia , Células Hep G2 , Humanos , Lipossomos/química , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Polietilenoglicóis/química
2.
Nanomedicine (Lond) ; 12(8): 845-863, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28351228

RESUMO

AIM: To fabricate PEGylated liposomes which preserve the activity of hydrophobic Wnt3A protein, and to demonstrate their efficacy in promoting expansion of osteoprogenitors from human bone marrow. METHODS: PEGylated liposomes composed of several synthetic lipids were tested for their ability to preserve Wnt3A activity in reporter and differentiation assays. Single-molecule microspectroscopy was used to test for direct association of protein with liposomes. RESULTS: Labeled Wnt3A protein directly associated with all tested liposome preparations. However, Wnt3A activity was preserved or enhanced in PEGylated 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) liposomes but not in PEGylated 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes. PEGylated Wnt3A liposomes associated with skeletal stem cell populations in human bone marrow and promoted osteogenesis. CONCLUSION: Active Wnt protein-containing PEGylated liposomes may have utility for systemic administration for bone repair.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Lipossomos/farmacologia , Osteogênese/efeitos dos fármacos , Proteína Wnt3A/farmacologia , Células da Medula Óssea/efeitos dos fármacos , Dimiristoilfosfatidilcolina/química , Dimiristoilfosfatidilcolina/farmacologia , Humanos , Lipossomos/química , Fosfatidilcolinas/química , Fosfatidilcolinas/farmacologia , Polietilenoglicóis/química , Células-Tronco/efeitos dos fármacos , Proteína Wnt3A/química
3.
J Biomed Mater Res B Appl Biomater ; 105(7): 1799-1807, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-27192551

RESUMO

In this article, liposome-based coatings aiming to control drug release from therapeutic soft contact lenses (SCLs) materials are analyzed. A PHEMA based hydrogel material loaded with levofloxacin is used as model system for this research. The coatings are formed by polyelectrolyte layers containing liposomes of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and DMPC + cholesterol (DMPC + CHOL). The effect of friction and temperature on the drug release is investigated. The aim of the friction tests is to simulate the blinking of the eyelid in order to verify if the SCLs materials coated with liposomes are able to keep their properties, in particular the drug release ability. It was observed that under the study conditions, friction did not affect significantly the drug release from the liposome coated PHEMA material. In contrast, increasing the temperature of release leads to an increase of the drug diffusion rate through the hydrogel. This phenomenon is recorded both in the control and in the coated samples. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1799-1807, 2017.


Assuntos
Piscadela , Colesterol , Materiais Revestidos Biocompatíveis , Lentes de Contato Hidrofílicas , Dimiristoilfosfatidilcolina , Colesterol/química , Colesterol/farmacocinética , Colesterol/farmacologia , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacocinética , Materiais Revestidos Biocompatíveis/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Dimiristoilfosfatidilcolina/química , Dimiristoilfosfatidilcolina/farmacocinética , Dimiristoilfosfatidilcolina/farmacologia , Temperatura Alta , Humanos , Lipossomos
4.
Colloids Surf B Biointerfaces ; 140: 121-127, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26752208

RESUMO

In a previous investigation, cationic liposomes formulated with new 5-FU derivatives, differing for the length of the polyoxyethylenic spacer that links the N(3) position of 5-FU to an alkyl chain of 12 carbon atoms, showed a higher cytotoxicity compared to free 5-FU, the cytotoxic effect being directly related to the length of the spacer. To better understand the correlation of the spacer length with toxicity, we carried out initial rate studies to determine inhibition, equilibrium and kinetic constants (KI, KM, kcat), and get inside inhibition activity of the 5-FU derivatives and their mechanism of action, a crucial information to design structural variations for improving the anticancer activity. The experimental investigation was supported by docking simulations based on the X-ray structure of thymidine phosphorylase (TP) from Escherichia coli complexed with 3'-azido-2'-fluoro-dideoxyuridin. Theoretical and experimental results showed that all the derivatives exert the same inhibition activity of 5-FU either as monomer and when embedded in lipid bilayer.


Assuntos
Proteínas de Escherichia coli/metabolismo , Fluoruracila/metabolismo , Timidina Fosforilase/metabolismo , Timidina/metabolismo , Antimetabólitos/química , Antimetabólitos/metabolismo , Antimetabólitos/farmacologia , Sítios de Ligação , Ligação Competitiva , Dimiristoilfosfatidilcolina/química , Dimiristoilfosfatidilcolina/metabolismo , Dimiristoilfosfatidilcolina/farmacologia , Escherichia coli/enzimologia , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Escherichia coli/química , Fluoruracila/química , Fluoruracila/farmacologia , Cinética , Lipossomos/química , Lipossomos/metabolismo , Lipossomos/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Timidina/química , Timidina Fosforilase/antagonistas & inibidores , Timidina Fosforilase/química
5.
J Clin Invest ; 126(1): 254-65, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26650179

RESUMO

Sphingolipids make up a family of molecules associated with an array of biological functions, including cell death and migration. Sphingolipids are often altered in cancer, though how these alterations lead to tumor formation and progression is largely unknown. Here, we analyzed non-small-cell lung cancer (NSCLC) specimens and cell lines and determined that ceramide synthase 6 (CERS6) is markedly overexpressed compared with controls. Elevated CERS6 expression was due in part to reduction of microRNA-101 (miR-101) and was associated with increased invasion and poor prognosis. CERS6 knockdown in NSCLC cells altered the ceramide profile, resulting in decreased cell migration and invasion in vitro, and decreased the frequency of RAC1-positive lamellipodia formation while CERS6 overexpression promoted it. In murine models, CERS6 knockdown in transplanted NSCLC cells attenuated lung metastasis. Furthermore, combined treatment with l-α-dimyristoylphosphatidylcholine liposome and the glucosylceramide synthase inhibitor D-PDMP induced cell death in association with ceramide accumulation and promoted cancer cell apoptosis and tumor regression in murine models. Together, these results indicate that CERS6-dependent ceramide synthesis and maintenance of ceramide in the cellular membrane are essential for lamellipodia formation and metastasis. Moreover, these results suggest that targeting this homeostasis has potential as a therapeutic strategy for CERS6-overexpressing NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Proteínas de Membrana/fisiologia , Esfingosina N-Aciltransferase/fisiologia , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Ceramidas/metabolismo , Dimiristoilfosfatidilcolina/farmacologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Camundongos , MicroRNAs/fisiologia , Metástase Neoplásica , Fenótipo , Esfingosina N-Aciltransferase/antagonistas & inibidores , Esfingosina N-Aciltransferase/genética
6.
Drug Deliv ; 22(5): 619-26, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-24344811

RESUMO

Hybrid liposomes (HLs) can be prepared by simply sonicating a mixture of vesicular and micellar molecules in buffer solutions. This study aims to demonstrate inhibitory effects of HLs on the growth of fibroblast-like synoviocytes along with apoptosis and therapeutic effects of HLs in a mouse model with rheumatoid arthritis (RA). HLs composed of 95 mol% L-α-dimyristoylphosphatidylcholine (DMPC) and 5 mol% polyoxyethylene(23)dodecyl ether (C12(EO)23) were prepared by the sonication method. The inhibitory effects of HLs on the growth of human fibroblast-like synoviocytes-RA (HFLS-RA) cells in vitro and their inhibitory mechanism were examined. High inhibitory effects of HLs on the growth of HFLS-RA cells were observed. The induction of apoptosis by HLs was revealed on the basis of flow cytometric analysis. Furthermore, therapeutic effects of HLs in the mouse model with RA were examined in vivo. Our results demonstrate that HLs showed inhibitory effects on the growth of HFLS-RA cells in vitro along with apoptosis and therapeutic effects in mouse models of RA in vivo.


Assuntos
Apoptose/efeitos dos fármacos , Artrite Experimental , Artrite Reumatoide , Proliferação de Células/efeitos dos fármacos , Dimiristoilfosfatidilcolina/farmacologia , Fibroblastos/efeitos dos fármacos , Lipossomos/farmacologia , Polietilenoglicóis/farmacologia , Membrana Sinovial/efeitos dos fármacos , Animais , Linhagem Celular , Modelos Animais de Doenças , Humanos , Técnicas In Vitro , Camundongos , Membrana Sinovial/citologia
7.
Anticancer Res ; 34(9): 4701-8, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25202047

RESUMO

AIM: We examined the therapeutic effects of hybrid liposomes (HL) composed of L-α-dimyristylphosphati-dylcholine (DMPC) and polyoxyethylene (25) dodecyl ether (C12(EO)25) on the growth of human colorectal cancer (WiDr) cells in vitro and in vivo. MATERIALS AND METHODS: HL composed of 95 mol% DMPC and 5 mol% C12(EO)25 were prepared by the sonication method and their therapeutic effects in xenograft mouse models of colorectal cancer liver metastases were examined in vivo. RESULTS: The inhibitory effects of HL-25 on the growth of WiDr cells along with apoptosis were assessed in vitro. Remarkable inhibitory effects of HL-25 for the liver metastasis of colorectal cancer cells along with apoptosis were revealed on the basis of histological analysis. Prolonged survival was attained for the xenograft mouse model of colorectal cancer after treatment with HL-25 in vivo. CONCLUSION: Therapeutic effects of HL-25 without any drugs on the liver metastasis of human colorectal cancer were obtained for the first time in vivo.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Dimiristoilfosfatidilcolina , Lipossomos/farmacologia , Polietilenoglicóis , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Dimiristoilfosfatidilcolina/química , Dimiristoilfosfatidilcolina/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Lipossomos/química , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Camundongos , Nanomedicina , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Biomaterials ; 35(11): 3688-96, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24462362

RESUMO

Liposomes are becoming increasingly important as drug delivery systems, to target a drug to specific cells and tissues and thereby protecting the recipient from toxic effects of the contained drug. Liposome preparations have been described to activate complement. In this study, we have investigated complement activation triggered by neutral dimyristoyl-phosphocholine (DMPC) liposomes in human plasma and whole-blood systems. Incubation in plasma led to the generation of complement activation products (C3a and sC5b-9). Unexpectedly, investigations of surface-bound C3 revealed contact activated, conformationally changed C3 molecules on the liposomes. These changes were characterized by Western blotting with C3 monoclonal antibodies, and by incubating liposomes with purified native C3 and factors I and H. Quartz crystal microbalance analysis confirmed binding of C3 to planar DMPC surfaces. In addition, we demonstrated that DMPC liposomes bound to or were phagocytized by granulocytes in a complement-dependent manner, as evidenced by the use of complement inhibitors. In summary, we have shown that C3 is activated both by convertase-dependent cleavage, preferentially in the fluid phase, by mechanisms which are not well elucidated, and also by contact activation into C3(H2O) on the DMPC surface. In particular, this contact activation has implications for the therapeutic regulation of complement activation during liposome treatment.


Assuntos
Ativação do Complemento/efeitos dos fármacos , Complemento C3/metabolismo , Lipossomos/metabolismo , Fosfolipídeos/farmacologia , Adsorção , Sistemas Computacionais , Dimiristoilfosfatidilcolina/farmacologia , Eletroforese em Gel de Poliacrilamida , Citometria de Fluxo , Humanos , Modelos Biológicos , Fagocitose/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Técnicas de Microbalança de Cristal de Quartzo
9.
J Chem Phys ; 139(6): 065102, 2013 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-23947892

RESUMO

We present a molecular dynamics (MD) study of the water molecules in a hydrated lipid bilayer. Due to the interactions at the surface of a solvated lipid membrane, the dynamics of the water and lipid molecules are to some degree correlated. In spite of previous efforts reported in the literature, little is known about the time and length scales of these correlations. Here, by employing a 0.1 µs long equilibrium MD simulation of a dimyristoylphosphatidylcholine (DMPC) lipid bilayer, we show that the waters in a hydrated lipid bilayer can be classified into four dynamically connected water layers, and provide a detailed analysis of the water dynamics within these four regions. We also show that there exists a cooperative molecular motion between the hydration waters and the DMPC lipid molecules, and determine the corresponding characteristic time and length scales.


Assuntos
Bicamadas Lipídicas/química , Simulação de Dinâmica Molecular , Animais , Difusão , Dimiristoilfosfatidilcolina/química , Dimiristoilfosfatidilcolina/farmacologia , Camundongos , Água/química
10.
Cancer Med ; 2(3): 267-76, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23930203

RESUMO

Antitumor effects of hybrid liposomes (HL) composed of l-α-dimyristoylphosphatidylcholine (DMPC) and polyoxyethylene(23) dodecyl ether (C12(EO)23) on the metastatic growth of murine osteosarcoma (LM8) cells were investigated in vitro and in vivo. Remarkable inhibitory effects of HL-23 on the growth of LM8 cells were obtained through the induction of apoptotic cell death in vitro. It was also indicated that HL-23 should dramatically suppress the invasion of LM8 cells and the formation of filopodia on the cell surface in vitro. Furthermore, significantly high therapeutic effects were observed in the homograft mouse models of LM8 cells with lung metastasis after the treatment with HL-23 in vivo. That is, the histological analysis demonstrated that the primary tumor growth of LM8 cells implanted subcutaneously into the mice was inhibited along with the induction of apoptosis. In addition, it was found that HL-23 significantly decreased the lung metastasis of LM8 cells in the mouse models through the inhibition of primary tumor invasion. These results suggest that HL-23 could be a novel agent for the chemotherapy of osteosarcoma.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Dimiristoilfosfatidilcolina/farmacologia , Lipossomos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Osteossarcoma/tratamento farmacológico , Polietilenoglicóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Dimiristoilfosfatidilcolina/química , Lipossomos/química , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Osteossarcoma/patologia , Polidocanol , Polietilenoglicóis/química , Distribuição Aleatória
11.
J Clin Invest ; 123(7): 3014-24, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23934128

RESUMO

Clearance of invading pathogens is essential to preventing overwhelming inflammation and sepsis that are symptomatic of bacterial peritonitis. Macrophages participate in this innate immune response by engulfing and digesting pathogens, a process called phagocytosis. Oxidized phospholipids (OxPL) are danger-associated molecular patterns (DAMPs) generated in response to infection that can prevent the phagocytic clearance of bacteria. We investigated the mechanism underlying OxPL action in macrophages. Exposure to OxPL induced alterations in actin polymerization, resulting in spreading of peritoneal macrophages and diminished uptake of E. coli. Pharmacological and cell-based studies showed that an anchored pool of PKA mediates the effects of OxPL. Gene silencing approaches identified the A-kinase anchoring protein (AKAP) WAVE1 as an effector of OxPL action in vitro. Chimeric Wave1(-/-) mice survived significantly longer after infection with E. coli and OxPL treatment in vivo. Moreover, we found that endogenously generated OxPL in human peritoneal dialysis fluid from end-stage renal failure patients inhibited phagocytosis via WAVE1. Collectively, these data uncover an unanticipated role for WAVE1 as a critical modulator of the innate immune response to severe bacterial infections.


Assuntos
Infecções por Escherichia coli/imunologia , Macrófagos Peritoneais/imunologia , Peritonite/imunologia , Fagocitose , Fosfolipídeos/fisiologia , Família de Proteínas da Síndrome de Wiskott-Aldrich/metabolismo , Animais , Linhagem Celular , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dimiristoilfosfatidilcolina/farmacologia , Ativação Enzimática , Escherichia coli/imunologia , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Humanos , Imunidade Inata , Falência Renal Crônica/imunologia , Falência Renal Crônica/metabolismo , Falência Renal Crônica/terapia , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredução , Diálise Peritoneal , Peritonite/metabolismo , Peritonite/microbiologia , Fosfatidilcolinas/farmacologia , Fosfatidilcolinas/fisiologia , Família de Proteínas da Síndrome de Wiskott-Aldrich/genética
12.
Eur J Med Chem ; 57: 143-8, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23059544

RESUMO

Therapeutic effects of hybrid liposomes (HL) composed of l-α-dimyristoylphosphatidylcholine (DMPC) and polyoxyethylene(25) dodecyl ether (C(12)(EO)(25)) on the metastasis of human colon carcinoma (HCT116) cells were examined in vivo. Remarkably high therapeutic effects were obtained in the xenograft mouse models of colorectal cancer (CRC) liver metastases after treatment with HL-25 on the basis of relative liver weight and histological analysis of the liver tissue sections of mouse models with HE staining, and TUNEL staining for detection of apoptotic cells. The survival effects of HL-25 were obtained using xenograft mouse models of CRC liver metastases. Furthermore, with regard to pharmacokinetics, the accumulation of fluorescent labeled HL-25 was observed in the liver tissue of xenograft mouse models of CRC liver metastases for 24 h after the intravenous injection of fluorescent labeled HL-25. Therapeutic effects of HL without any drugs on the liver metastasis of human CRC were revealed for the first time in vivo.


Assuntos
Antineoplásicos/farmacologia , Carcinoma/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Dimiristoilfosfatidilcolina/farmacologia , Lipossomos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Polietilenoglicóis/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma/mortalidade , Carcinoma/secundário , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Dimiristoilfosfatidilcolina/química , Feminino , Corantes Fluorescentes , Humanos , Marcação In Situ das Extremidades Cortadas , Injeções Intravenosas , Lipossomos/química , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Camundongos , Camundongos SCID , Tamanho do Órgão/efeitos dos fármacos , Polietilenoglicóis/química , Taxa de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Bioorg Med Chem Lett ; 22(4): 1784-7, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22260774

RESUMO

Marked inhibitory effects of hybrid liposomes (HL-n; n=21, 23, 25) composed of 90 mol% l-α-dimyristoylphosphatidylcholine (DMPC) and 10 mol% polyoxyethylene(n) dodecyl ethers on the growth of two human osteosarcoma cell lines (MG-63 and U-2 OS) were obtained. Furthermore, fluorescence microscopic and flow cytometric analyses revealed the induction of apoptosis by HL-n in both cells. It is noteworthy that HL-23 could inhibit the invasion and migration of U-2 OS cells on the basis of matrigel invasion assay and scratch wound assay, respectively.


Assuntos
Apoptose/efeitos dos fármacos , Dimiristoilfosfatidilcolina/química , Lipossomos/química , Lipossomos/farmacologia , Polietilenoglicóis/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Dimiristoilfosfatidilcolina/farmacologia , Citometria de Fluxo , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Invasividade Neoplásica , Osteossarcoma/tratamento farmacológico , Polietilenoglicóis/farmacologia
14.
Pediatr Surg Int ; 27(4): 379-84, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21327948

RESUMO

PURPOSE: Hybrid liposomes composed of vesicular and micellar molecules have been used as drug-delivery systems. It has become clear that hybrid liposomes alone have an inhibitory effect against the growth of various tumor cells. The present study was designed to determine whether a drug-free hybrid liposome composed of dimyristoylphosphatidylcholine (DMPC) and polyoxyethylenealkyl ether (EO) [90 mol% DMPC/10% C(12)(EO)(21) (HL21), 90 mol% DMPC/10% C(12)(EO)(23) (HL23), or 90 mol% DMPC/10% C(12)(EO)(25) (HL25)], inhibit the liver metastasis of human neuroblastoma cells and thus increases survival. METHODS: A human neuroblastoma cell, TNB9, and BALB/C-nu/nu athymic mice were used in this study. First, we determined the inhibitory effect of the hybrid liposomes on TNB9 cells in vitro. Next, to determine the inhibitory effect of the hybrid liposomes on metastasis of neuroblastoma cells to the liver, we made a murine hepatic metastasis model by implanting TNB9 cells (2 × 106) in the spleen of the mice and compared anatomic appearance, weights, and histological findings of the livers of treated mice and control mice 60 days after the beginning of a 7-day intraperitoneal injection of a hybrid liposome. We also compared survival rates using the Kaplan-Meier method. RESULTS: In mice implanted with TNB9 neuroblastoma cells and treated with HL21 or HL25, no histological evidence of metastasis was found, the weight of the liver was normal, and survival was a mean of 88 and 87.9 days, respectively. In contrast, mice treated with HL23 and control mice had countless tumor cell masses histologically, their liver weight was increased, and their survival was 73.0 and 68.6 days, respectively. CONCLUSIONS: Two kinds of hybrid liposomes, HL21 and HL25, inhibit metastasis of human neuroblastoma cells to the liver, and thus increase survival.


Assuntos
Lipossomos/farmacologia , Neoplasias Hepáticas/prevenção & controle , Neuroblastoma/tratamento farmacológico , Análise de Variância , Animais , Divisão Celular/efeitos dos fármacos , Dimiristoilfosfatidilcolina/farmacologia , Feminino , Humanos , Hibridomas/patologia , Neoplasias Hepáticas/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Polietilenoglicóis/farmacologia , Células Tumorais Cultivadas
15.
Yakugaku Zasshi ; 130(11): 1581-7, 2010 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-21048419

RESUMO

In general, chemotherapeutic effects were low for non-small cell lung cancer (NSCLC) in the lung tumor. We examined the accumulation and antitumor effects of hybrid liposomes (HL-23) composed of phospholipid (L-α-dimyristoylphosphatidylcholine: DMPC) and PEG surfactant [polyoxyethylene(23)dodecyl ether: C12(EO)23] on NSCLC cells in vitro. Accumulation of HL-23 including a fluorescence probe [1-Palmitoyl-2-[12(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]dodecanoyl]-sn-Glycero-3-Phosphocholine: NBDPC] was observed for NSCLC cells using a confocal laser microscope, but no accumulation of HL-23 in normal lung cells was observed. Furthermore, inhibitory effects of HL-23 on the growth of NSCLC cells were obtained on the basis of a WST-1 assay. It was also clarified that HL-23 induced apoptosis for NSCLC cells on the basis of Annexin-V binding and TUNEL assay. These results suggest that HL-23 could be applied in effective chemotherapies for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Dimiristoilfosfatidilcolina/farmacologia , Lipossomos/farmacologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Polietilenoglicóis/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Divisão Celular/efeitos dos fármacos , Dimiristoilfosfatidilcolina/metabolismo , Dimiristoilfosfatidilcolina/uso terapêutico , Humanos , Lipossomos/metabolismo , Lipossomos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Fluidez de Membrana/efeitos dos fármacos , Polietilenoglicóis/metabolismo , Polietilenoglicóis/uso terapêutico , Células Tumorais Cultivadas
16.
Int J Pharm ; 394(1-2): 174-8, 2010 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-20471463

RESUMO

Therapeutic effects of hybrid liposomes (HL) composed of l-alpha-dimyristoylphosphatidylcholine (DMPC) and polyoxyethylene (23) dodecylether (C(12)(EO)(23)) on the metastasis of colon carcinoma (Colon26) cells were examined in vivo. Fluorescent labeled Colon26 cells were observed in the liver tissue of hepatic metastasis mouse models after the intrasplenic inoculation of the cells. Remarkably high therapeutic effects were obtained in the hepatic metastasis mouse models after the treatment with HL on the basis of relative liver weight and histological analysis of the liver tissue sections of mouse models with hematoxylin-eosin staining, Masson trichrome staining, and CEA immunostaining as a histochemical marker of metastatic colon carcinoma. Furthermore, no toxicity was observed in the hepatic metastasis mouse models after the intravenous injection of HL. Therapeutic effects of HL without any drugs on the hepatic metastasis were revealed on the basis of histological analysis for the first time in vivo.


Assuntos
Neoplasias do Colo/patologia , Dimiristoilfosfatidilcolina/farmacologia , Neoplasias Hepáticas/prevenção & controle , Polietilenoglicóis/farmacologia , Animais , Neoplasias da Mama , Linhagem Celular Tumoral , Dimiristoilfosfatidilcolina/administração & dosagem , Dimiristoilfosfatidilcolina/química , Feminino , Injeções Intravenosas , Lipossomos , Fígado/patologia , Neoplasias Hepáticas/secundário , Camundongos , Camundongos Endogâmicos BALB C , Tamanho do Órgão , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Baço , Coloração e Rotulagem/métodos
17.
Anticancer Res ; 30(2): 327-37, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20332436

RESUMO

Cationic hybrid liposomes (HL) can be prepared by simply ultrasonicating a mixture of L-alpha-dimyristoylphosphatidylcholine (DMPC), polyoxyethylene (21)dodecyl ether (C(12)(EO)(21)) and O,O'-ditetradecanoyl-N-(alpha-trimethylammonioacetyl) diethanolamine chloride (2C(14)ECl) in a buffer solution. The inhibitory effects of cationic HL containing 2C(14)ECl on the growth of OS-RC-2 human renal carcinoma cells in vitro and in vivo were examined. The 50% inhibitory concentration of cationic HL was remarkably reduced compared with that of DMPC liposomes. Induction of apoptosis by cationic HL in OS-RC-2 cells was verified on the basis of flow cytometric analysis and fluorescence microscopy in vitro. In addition, the effects on survival of cationic HL along with apoptosis in vivo were obtained using a mouse model of renal carcinoma. Chemotherapy with drug-free cationic HL for renal cell carcinoma was developed for the first time through the interaction between cationic HL and anionic surface region of tumor cell membranes, without any side-effects. The results obtained might be applied in chemotherapies used at present for patients with renal carcinoma.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Proliferação de Células/efeitos dos fármacos , Dimiristoilfosfatidilcolina/farmacologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Lipossomos , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Carcinoma de Células Renais/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Feminino , Citometria de Fluxo , Hemólise/efeitos dos fármacos , Humanos , Marcação In Situ das Extremidades Cortadas , Neoplasias Renais/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
18.
Langmuir ; 26(2): 1107-16, 2010 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-20014818

RESUMO

Phospholipids (PL) form the matrix of biological membranes and of the lipoprotein envelope monolayer, and are responsible for many of the unique physicochemical, biochemical, and biological properties of these supermolecular bioassemblies. It was suggested that phospholipids present in the synovial fluid (SF) and on the surface of articular cartilage have major involvement in the low friction of cartilage, which is essential for proper mobility of synovial joints. In pathologies, such as impaired biolubrication (leading to common joint disorders such as osteoarthritis), the level of phospholipids in the SF is reduced. Using a human-sourced cartilage-on-cartilage setup, we studied to what extent and how phospholipids act as highly effective cartilage biolubricants. We found that large multilamellar vesicles (MLV), >800 nm in diameter, composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) or of a mixture of DMPC and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) are superior lubricants in comparison to MLV composed of other phosphatidylcholines. Introducing cholesterol into liposomes resulted in less effective lubricants. DMPC-MLV was also superior to small unilamellar vesicles (SUV), <100 nm in diameter, composed of DMPC. MLV are superior to SUV due to MLV retention at and near (<200 microm below) the cartilage surface, while SUV penetrate deeper into the cartilage (450-730 microm). Superiority of specific PL compositions is explained by the thermotropic behavior (including compressibility) of the lipid bilayer. Correlating physicochemical properties of the MLV with the friction results suggests that MLV having lipid bilayers in the liquid-disordered phase and having a solid-ordered to liquid-disordered phase transition temperature slightly below physiological temperature are optimal for lubrication. High phospholipid headgroup hydration, high compressibility, and softness are the common denominators of all efficient PL compositions. The high efficiency of DMPC-MLV and DMPC/DPPC-MLV as cartilage lubricants combined with their resistance to degradation at 37 degrees C supports further evaluation of these MLV for treatment of joint impairments related to poor lubrication. This work also demonstrates the relevance of basic physicochemical properties of phospholipids to their activities in biological systems.


Assuntos
Lipossomos/química , Lubrificantes/química , Líquido Sinovial/química , 1,2-Dipalmitoilfosfatidilcolina/química , 1,2-Dipalmitoilfosfatidilcolina/farmacologia , Idoso , Idoso de 80 Anos ou mais , Cartilagem/efeitos dos fármacos , Cartilagem/fisiologia , Dimiristoilfosfatidilcolina/química , Dimiristoilfosfatidilcolina/farmacologia , Humanos , Técnicas In Vitro , Lipossomos/farmacologia , Lubrificantes/farmacologia , Pessoa de Meia-Idade , Modelos Teóricos , Tensoativos/química , Tensoativos/farmacologia
19.
Colloids Surf B Biointerfaces ; 72(1): 135-40, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19403276

RESUMO

The phase transitions of distearoyl- (DSPC), dipalmitoyl- (DPPC) and dimyristoyl-phosphatidylcholine (DMPC) bilayer membranes were observed by means of differential scanning calorimetry as a function of the concentration of a local anesthetic tetracaine hydrochloride (TC.HCl). The depression of both temperatures of the main- and pre-transition, which is accompanied by a decrease in enthalpy changes for both transitions, was observed initially by the addition of TC.HCl. Bilayer interdigitation, which is accompanied by an increase in enthalpy change for the main transition from the interdigitated gel phase to the liquid crystalline phase, was followed by disappearance of the pretransition. The TC.HCl concentration necessary for the bilayer interdigitation was found to be 10, 21 and 6 mmol kg(-1) for DSPC, DPPC and DMPC bilayers, respectively, which was not consistent with the order of acyl-chain length of lipids. Biphasic interactions for the interdigitation, that is, repulsive interaction between polar head groups and van der Waals attractive interaction between hydrophobic chains of lipids, were discussed. On the other hand, vesicle-to-micelle transformation, which is accompanied by a cooperative decrease in enthalpy change for the main transition, was observed at higher concentration of TC.HCl and was confirmed by the vesicle size determined by the dynamic light scattering. The longer the acyl-chain length of lipids, the higher the TC.HCl concentration necessary for the vesicle-to-micelle transformation.


Assuntos
Anestésicos Locais/farmacologia , Bicamadas Lipídicas/química , Micelas , Fosfolipídeos/química , Tetracaína/farmacologia , Lipossomas Unilamelares/química , Varredura Diferencial de Calorimetria , Dimiristoilfosfatidilcolina/farmacologia , Transição de Fase/efeitos dos fármacos , Temperatura
20.
Yakugaku Zasshi ; 128(10): 1485-92, 2008 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-18827469

RESUMO

We established cell-line (CoRa 622 G6) of gastric carcinoma using cotton rats with spontaneous malignant gastric carcinoma with hypergastrinaemia. Inhibitory effects of hybrid liposomes (HL) composed of dimyristoylphosphatidylcoline (DMPC) and polyoxyethylene (n) dodecyl ether (C(12)(EO)(n): n=21, 23, 25) on the growth of CoRa 622 G6 cells were clarified on the basis of WST-1 assay. Fusion and accumulation of HL including fluorescence probe into CoRa 622 G6 cell membrane were clarified using confocal laser microscopy and total internal reflection fluorescence microscopy. Induction of apoptosis of CoRa 622 G6 cells after the treatment with HL was observed in fluorescence micrographs on the basis of Annexin-V binding assay and TUNEL method using confocal laser microscopy. The results in this study could contribute to the chemotherapy for patients with gastric carcinoma.


Assuntos
Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Dimiristoilfosfatidilcolina/farmacologia , Lipossomos/farmacologia , Neoplasias Gástricas/patologia , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Masculino , Microscopia Confocal , Sigmodontinae , Neoplasias Gástricas/ultraestrutura
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