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1.
Chem Pharm Bull (Tokyo) ; 69(8): 727-733, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34334516

RESUMO

Recently, a novel humidifier that sprays water fine droplets equipped with a copolymer, poly(3,4-ethylene dioxythiophene)-poly(styrene sulfonate) (PEDOT/PSS) was developed. PEDOT/PSS in the humidifier absorbs water from the environment and releases fine water droplets by heating. In the present study, the effect of hydration on the skin barrier, stratum corneum, was first determined by the application of fine water droplets using the humidifier. The skin-penetration enhancement effect of a model hydrophilic drug, caffeine, was also investigated using the humidifier and compared with a conventional water-evaporative humidifier. More prolonged skin hydration effect was observed after application of the fine water droplet release humidifier using PEDOT/PSS than that using a conventional humidifier. In addition, markedly higher skin permeation of caffeine was observed in both infinite and finite dose conditions. Furthermore, higher skin permeation of caffeine from oil/water emulsion containing caffeine was observed in finite dose conditions by pretreatment with the humidifier using PEDOT/PSS. This device can provide water droplets without replenishing water, so it is more convenient for enhancing the skin permeation of chemical compounds from topical drugs and cosmetic formulations.


Assuntos
Cafeína/farmacologia , Umidificadores , Pele/efeitos dos fármacos , Administração Cutânea , Ar , Animais , Cafeína/administração & dosagem , Cafeína/química , Umidade , Interações Hidrofóbicas e Hidrofílicas , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Pelados , Absorção Cutânea/efeitos dos fármacos , Temperatura , Água/química
2.
Chem Pharm Bull (Tokyo) ; 69(8): 806-810, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34334526

RESUMO

Effect of rubbing application on the skin permeation of a hydrophilic drug caffeine (CAF) and lipophilic drug rhododendrol (RD) from lotion and cream were investigated. Skin permeation of CAF was markedly increased by rubbing action independent of the formulation type. In addition, the skin penetration-enhancement effect was affected by the rubbing direction: rubbing application against the direction of hair growth showed the highest permeation compared with rubbing applications along the direction of hair growth and in a circular pattern on the skin. On the other hand, no enhancement effect was observed by the rubbing actions on the skin permeation of RD, regardless of formulation type. Change in the infundibula orifice size of hair follicles by the rubbing and following skin stretching may be related to the higher skin permeation for CAF. In contrast, high RD distribution into the stratum corneum may be a reason why no enhancement effect was observed by the rubbing action. These results can be helpful to predict safety and effectiveness of topically applied formulations.


Assuntos
Butanóis/farmacologia , Cafeína/farmacologia , Pomadas/farmacologia , Creme para a Pele/farmacologia , Pele/efeitos dos fármacos , Animais , Butanóis/química , Cafeína/química , Interações Hidrofóbicas e Hidrofílicas , Pomadas/química , Permeabilidade/efeitos dos fármacos , Absorção Cutânea/efeitos dos fármacos , Creme para a Pele/química , Suínos
3.
Biochem Biophys Rep ; 27: 101067, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34258398

RESUMO

Antibody-modified liposomes, immuno-liposomes, can selectively deliver encapsulated drug 'cargos' to cells via the interaction of cell surface proteins with antibodies. However, chemical modification of both the antibodies and phospholipids is required for the preparation of immuno-liposomes for each target protein using conventional methods, which is time-consuming. In the present study, we demonstrated that high-affinity protein A- (Protein A-R28: PAR28) displaying liposomes prepared by the post-insertion of PAR28-conjugated phospholipid through polyethylene glycol (PEG)-linkers (PAR28-PEG-lipo) can undergo rapid modification of antibodies on their surface, and the liposomes can be delivered to cells based on their modified antibodies. Anti-CD147 and anti-CD31 antibodies could be modified with PAR28-PEG-lipo within 1 h, and each liposome was specifically taken up by CD147- and CD31-positive cells, respectively. The cellular amounts of doxorubicin delivered by anti-CD147 antibody-modified PAR28-PEG-lipo were significantly higher than those of isotype control antibody-modified liposomes. PAR28-PEG-lipo can easily and rapidly undergo modification of various antibodies on their surface, which then makes them capable of selective drug delivery dependent on the antibodies.

4.
Chem Pharm Bull (Tokyo) ; 69(7): 639-645, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34193712

RESUMO

The purpose of the present study was to evaluate whether iontophoresis (IP) accelerates the intradermal migration rate of medium molecular weight drugs. Sodium polystyrene sulfonate (PSA) and fluorescein isothiocyanate-dextran (FD) were used as model medium molecular weight acidic and non-electrolyte drugs, respectively. Low molecular weight acid and non-electrolyte drugs were also used for comparison. Drug-loaded excised split-layered skin (SL skin) was used in the experiment. SL skin was prepared using (i) whole skin was split once, (ii) the drug solution was applied on the lower skin, and (iii) the upper skin was layered onto the lower skin containing the drug solution as in the original skin. The effect of constant-current cathodal or anodal IP was applied to the SL skin, and the time course of the cumulative amount of drug migration from the SL skin through the dermis to the receiver was followed. In cases without IP and with anodal IP, the intradermal migration rates of medium molecular weight drugs were much lower than those of small molecules. The driving force for drug migration was thought to be simple diffusion through the skin layer. In contrast, cathodal IP significantly increased the intradermal migration rate of PSA not but of FD or low molecular weight drugs. This IP-facilitated migration of PSA was probably due to electrorepulsion. These results suggest that IP can be used to increase the intradermal migration of medium molecular weight charged drugs.


Assuntos
Dextranos/metabolismo , Fluoresceína-5-Isotiocianato/análogos & derivados , Iontoforese/métodos , Poliestirenos/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Dextranos/análise , Fluoresceína-5-Isotiocianato/análise , Fluoresceína-5-Isotiocianato/metabolismo , Fluorometria , Peso Molecular , Poliestirenos/análise , Absorção Cutânea , Suínos
5.
Chem Pharm Bull (Tokyo) ; 69(7): 674-680, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34193716

RESUMO

Quality by design (QbD) is an essential concept for modern manufacturing processes of pharmaceutical products. Understanding the science behind manufacturing processes is crucial; however, the complexity of the manufacturing processes makes implementing QbD challenging. In this study, structural equation modeling (SEM) was applied to understand the causal relationships between variables such as process parameters, material attributes, and quality attributes. Based on SEM analysis, we identified a model composed of the above-mentioned variables and their latent factors without including observational data. Difficulties in fitting the observed data to the proposed model are often encountered in SEM analysis. To address this issue, we adopted Bayesian estimation with Markov chain Monte Carlo simulation. The tableting process involving the wet-granulation process for acetaminophen was employed as a model case for the manufacturing process. The results indicate that SEM analysis could be useful for implementing QbD for the manufacturing processes of pharmaceutical products.


Assuntos
Análise de Classes Latentes , Comprimidos/química , Acetaminofen/química , Teorema de Bayes , Composição de Medicamentos/métodos , Cadeias de Markov , Método de Monte Carlo , Análise de Componente Principal
6.
Pharm Res ; 38(3): 503-513, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33638122

RESUMO

PURPOSE: Non-lamellar liquid crystal (NLLC)-forming lipids have gained attention as a novel component because of their ability to self-assemble upon contact with body fluids. In this study, a novel NLLC-forming lipid, mono-O-(5, 9, 13-trimethyl-4-tetradecenyl) glycerol ester (C17MGE), and a model drug with a middle molecule weight, leuprolide acetate (LA), were used to confirm the usefulness of C17MGE as an excipient for depot formulations with sustained release properties. METHODS: A self-constructed depot formulation was prepared by mixing C17MGE and different types of phospholipids. The constructed NLLC structure was evaluated using small angle X-ray analysis and cryo-transmission electron microscopy. In vitro release and blood concentration profiles of LA were investigated. RESULTS: The NLLC structure was confirmed by small angle X-ray analysis. LA release was able to be modified by adding different ratios of various phospholipids to C17MGE. Formulations containing 1, 2-dioleoyl-sn-glycero-3-phosphoglycerol sodium salt with a mixing ratio of 12% or 24% (MDOPG12 or MDOPG24, respectively) exhibited sustained release profiles of LA. In addition, the blood concentration of LA was detected over 21 days or more after administration of MDOPG12, and the absolute bioavailability was calculated to be about 100%. CONCLUSIONS: A depot formulation using C17MGE was useful to achieve sustained release of LA.

7.
Pharm Res ; 38(2): 289-299, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33515137

RESUMO

PURPOSE: Penetration enhancers are necessary to overcome a formidable barrier function of the stratum corneum in the development of topical formulations. Recently, non-lamella liquid crystal (NLLC)-forming lipids such as glycerol monooleate and phytantriol (PHY) are gaining increasing attention as a novel skin permeation enhancer. In the present study, fluorescein sodium (FL-Na) was used as a model hydrophilic drug, and acryl-base pressure-sensitive adhesive (PSA) tape containing NLLC forming lipids, mono-O-(5,9,13-trimethyl-4-tetradecenyl) glycerol ester (MGE) or PHY, was prepared to enhance drug permeation through the skin. METHODS: A PSA patch containing FL-Na was prepared by mixing FL-Na entrapped in NLLC and acrylic polymer. FL permeation through excised hairless rat skin, and also human skin, was investigated. Changes in lipid structure, folding/unfolding state of keratin in the stratum corneum, and penetration of MGE into the stratum corneum were investigated using confocal Raman microscopy. RESULTS: Enhanced FL permeation was observed by the application of a PSA patch containing MGE and PHY. Especially, dramatically enhancement effect was confirmed by 15% of MGE contained formulation. Penetration of MGE provided diminished orthorhombic crystal structure and a peak shift of the aliphatic CH3 vibration of keratin chains toward lower wavenumbers. CONCLUSION: The present results suggested that the formulation development by adding MGE may be useful for improving the skin permeation of mal-permeable drugs such as hydrophilic drugs.


Assuntos
Sistemas de Liberação de Medicamentos/instrumentação , Epiderme/metabolismo , Glicerol/farmacologia , Absorção Cutânea/efeitos dos fármacos , Adesivo Transdérmico , Adesivos/química , Administração Cutânea , Animais , Epiderme/efeitos dos fármacos , Fluoresceína/administração & dosagem , Fluoresceína/farmacocinética , Glicerol/análogos & derivados , Glicerol/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Cristais Líquidos/química , Permeabilidade/efeitos dos fármacos , Ratos
8.
Chem Pharm Bull (Tokyo) ; 68(11): 1025-1033, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33132369

RESUMO

We examined the physicochemical and biochemical properties of mono-O-(5,9,13-trimethyl-4-tetradecenyl)glycerol ester (MGE), including ease of handling, high bioadhesiveness, quick and stable in vivo self-organization (forming a non-lamellar lyotropic liquid crystal [NLLC]), and high biomembrane permeation enhancement. We prepared MGE oral mucosa-applied spray preparations containing triamcinolone acetonide (TA), which is widely used in the treatment of stomatitis, and we examined the usefulness of the MGE preparations compared with commercially available oral mucosal application preparations containing 2,3-dihydroxypropyl oleate (1-mono(cis-9-octadecenoyl)glycerol (GMO) (previously studied as an NLLC-forming lipid) preparation. As a result, the MGE preparation applied to the oral mucosa can rapidly formed an NLLC with reverse hexagonal or cubic structures, or a mixture, on contact with water. In addition, by adding hydroxypropyl cellulose to the MGE preparation, similar retention properties on the oral mucous membrane were obtained to that using marketed drug preparations. Furthermore, the MGE spray formulation on the oral mucosa showed an equivalent or higher TA release as well as oral mucous membrane permeability compared with commercial formulations. Because MGE forms a stable NLLC and is easy to handle compared with GMO, MGE was considered to be a useful pharmaceutical additive for a spray preparation applied to the oral mucosa in combination.


Assuntos
Composição de Medicamentos/métodos , Lipídeos/química , Cristais Líquidos/química , Mucosa Bucal/metabolismo , Animais , Permeabilidade da Membrana Celular/efeitos dos fármacos , Glicerol/química , Lipídeos/farmacologia , Masculino , Mucosa Bucal/efeitos dos fármacos , Ratos , Ratos Pelados , Triancinolona Acetonida/química , Triancinolona Acetonida/farmacologia
9.
Chem Pharm Bull (Tokyo) ; 68(8): 779-783, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32741920

RESUMO

Tranilast, a lipophilic drug with various ophthalmic applications, was used as a model drug to establish the possibility of delivering lipophilic drugs through the eyelid skin. Pharmacokinetics and tissue distribution studies were conducted employing three application methods (topical application onto eyelid skin, eye drops, and intravenous injection in rats) to broaden the significance of delivering drugs through the eyelids. A two-compartment open model analysis was used for intravenous route while a non-compartmental evaluation was used for topical applications to estimate the pharmacokinetic parameters. Eyelid skin application, eye drops, and intravenous administration had mean residence times (MRTs) of 8.07, 1.79, and 3.25 h in the eyeball and 10.8, 1.29, and 2.97 h in the conjunctiva, correspondingly. In the eyeball, topical application of tranilast onto the eyelids corresponded to a 4.5- and 2.5-fold higher MRT compared with eye drops and intravenous administration, respectively. An 8.4- or 3.6-fold higher MRT was observed in the conjunctiva after topical application compared with eye drops or intravenous administration, respectively. This indicated a gradual penetration of tranilast into the eyeball and conjunctiva, subsequently a slow elimination from these target tissues.


Assuntos
Pele/efeitos dos fármacos , ortoaminobenzoatos/farmacologia , Administração Intravenosa , Administração Tópica , Animais , Cromatografia Líquida de Alta Pressão , Túnica Conjuntiva/metabolismo , Portadores de Fármacos/química , Pálpebras/metabolismo , Meia-Vida , Masculino , Soluções Oftálmicas/química , Soluções Oftálmicas/farmacocinética , Soluções Oftálmicas/farmacologia , Ratos , Ratos Pelados , Pele/metabolismo , Espectrometria de Massas em Tandem , Distribuição Tecidual , ortoaminobenzoatos/sangue , ortoaminobenzoatos/farmacocinética
10.
J Control Release ; 325: 1-9, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32598958

RESUMO

Intranasal administration is poised as a competent method in delivering drugs to the brain, because the nasal route has a direct link with the central nervous system bypassing the formidable blood-brain barrier. C17-monoglycerol ester (MGE) and glyceryl monooleate (GMO) as liquid crystal (LC)-forming lipids possess desirable formulation characteristics as drug carriers for intranasally administered drugs. This study investigated the effect of LC formulations on the pharmacokinetics of tranilast (TL), a lipophilic model drug, and its distribution in the therapeutic target regions of the brain in rats. The anatomical biodistribution of LC formulations was monitored using micro-computed tomography tandem in vivo imaging systems. MGE and GMO effectively formed LC with suitable particle size, zeta potential, and viscosity supporting the delivery of TL to the brain. MGE and GMO LC formulations enhanced brain uptake by 10- to 12-fold and 2- to 2.4- fold, respectively, compared with TL solution. The olfactory bulb had the highest TL concentration and fluorescent signals among all the brain regions, indicating a direct nose-to-brain delivery pathway of LC formulations. LC-forming lipids, MGE and GMO, are potential biomaterials in formulations intended for intranasal administration.


Assuntos
Cristais Líquidos , Administração Intranasal , Animais , Encéfalo/diagnóstico por imagem , Sistemas de Liberação de Medicamentos , Ratos , Distribuição Tecidual , Microtomografia por Raio-X , ortoaminobenzoatos
11.
Pharmaceutics ; 12(5)2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32384778

RESUMO

: A highly viscous substance was prepared by evaporating an ethanol solution containing two hydrophilic vitamins; vitamin C, and vitamin B6. The viscous substance and physical mixture of the two vitamins were tested using a differential scanning calorimeter and an X-ray diffractometer. The highly viscous substance was found to be a liquid crystal (LC) made of these two hydrophilic vitamins. Determination by proton nuclear magnetic resonance measurement suggested that intramolecular hydrogen bonding in vitamin B6 was eliminated by the LC formation. This LC compound showed high solubility in 1,3-butanediol (almost 87%). Much higher skin permeation of both vitamin C and B6 was also observed from the LC compound than that from the physical mixture. The present LC compound containing vitamin C and vitamin B6 may be useful for pharmaceutical and cosmeceutical applications.

12.
Int J Pharm ; 578: 119186, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32112931

RESUMO

Finite dose experiments represent clinical use wherein depletion of dose, evaporation of excipients, and gradual change in vehicle composition may occur. In the present study, we attempted a mathematical approach for predicting skin permeation and concentration of a cosmetic active, rhododendrol (RD), from complex vehicle-based formulations applied in finite dose. In vitro skin permeation and concentration studies of RD were conducted from formulations containing water and polyols with concentrations ranging from 10 to 100% under infinite and finite dose conditions using vertical Franz diffusion cells. Observed data for skin permeation and the viable epidermis and dermis (VED) concentration of RD were estimated by the differential equations under Fick's second law of diffusion together with water evaporation kinetics and changes in the partition coefficient from vehicles to the stratum corneum. As a result, a goodness-of-fit was observed allowing accurate estimation of skin permeation and VED concentration of RD. This mathematical approach could become a useful tool to estimate the skin permeation and concentration of actives from topical formulation applied in finite dose conditions likened in actual use.


Assuntos
Butanóis/metabolismo , Cosméticos/metabolismo , Derme/metabolismo , Epiderme/metabolismo , Administração Cutânea , Animais , Química Farmacêutica/métodos , Difusão/efeitos dos fármacos , Cinética , Permeabilidade , Polímeros/metabolismo , Absorção Cutânea/fisiologia , Suínos , Água/metabolismo
13.
Pharmaceutics ; 12(2)2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32092954

RESUMO

The ban on the use of animals in testing cosmetic products has led to the development of animal-free in vitro methods. Strat-M® is an artificial membrane engineered to mimic human skin and is recommended as a replacement for skin. However, its usefulness in the assessment of the permeation of cosmetics in in-use conditions remains unverified. No data have been published on its comparative performance with the membrane of choice, porcine skin. The comparative permeability characteristics of Strat-M® and porcine skin were investigated using Franz diffusion cells. Caffeine (CF) and rhododendrol (RD) in complex vehicles with varying concentrations of polyols were applied as finite and infinite doses. Good rank orders of permeation from finite dose experiments were observed for RD. High correlations were observed in RD permeation between Strat-M® and porcine skin under finite and infinite dose conditions, whereas only finite dose conditions for CF were associated with good correlations. Permeation from formulations with high polyol content and residual formulations was enhanced due to the disruption of the integrity of the Strat-M® barrier. The usefulness of Strat-M® in the assessment of dermal permeation may be limited to finite dose conditions and not applicable to infinite dose conditions or formulations applied in layers.

14.
Int J Pharm ; 577: 118944, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31870952

RESUMO

Skin offers an easily accessible and convenient site for the administration of drugs. Therefore, the development of injectable formulations with controlled drug release properties are now expected to deliver middle- and large-size biomolecules. In the present study, formulations mainly composed of a novel polyol ester with an isoprenoid side chain; mono-O-(5,9,13-trimethyl-4-tetradecenyl) glycerol ester (MGE), that was capable of forming a non-lamellar liquid crystal (NLLC), were prepared with different types of phospholipid. Then, factors that affected the release of a model entrapped drug, fluorescein-isothiocyanate dextran (FD-4, M.W. 4,000), from the MGE formulations were analyzed with multi-regression analysis. In addition, self-assembly of the NLLC structure was investigated using small-angle X-ray scattering analysis after contacting the MGE formulations with water. NLLC-forming ability of the formulations after s.c. injection into rats was also confirmed using microscopic observations. FD-4 concentrations in blood were determined after s.c. injection of the MGE formulations. The injectable MGE formulations successfully constructed NLLC structures to form a sponge-like gel after contact with water in vitro and in vivo (in rats) as well. In in vitro conditions, the amount of FD-4 released from the formulations was altered by changing the type and concentration of phospholipid in the MGE formulations and can be expressed with parameters such as MGE content and interplanar spacing of the NLLC. A significantly sustained FD-4 level in the blood was observed after s.c. injection of the formulations. These results suggested that injectable MGE formulations may have the potential to achieve controlled release profiles of drugs after s.c. injection.


Assuntos
Ésteres/química , Glicerol/química , Cristais Líquidos/química , Fosfolipídeos/química , Animais , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Fluoresceínas/administração & dosagem , Fluoresceínas/química , Interações Hidrofóbicas e Hidrofílicas , Injeções Subcutâneas , Masculino , Ratos
15.
J Clin Monit Comput ; 32(1): 63-72, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28074417

RESUMO

Two types of Planecta™ ports are commonly used as sampling ports in blood pressure transducer kits: a flat-type port (FTP) and a port with a three-way stopcock (PTS). Recently, a new type of three-way stopcock (Marvelous™) has been released as a Planecta™ counterpart, but its effects on the frequency characteristics and reliability of blood pressure monitoring have not been investigated. We assessed the influence of the Marvelous™ stopcock on the frequency characteristics of the pressure transducer kit. The basic pressure transducer kit, DT4812J, was modified by replacing one or two of the original three-way stopcocks with Marvelous™ stopcocks. The frequency characteristics (i.e., natural frequency and damping coefficient) of each kit were determined using wave parameter analysis software, and subsequently evaluated on a Gardner chart. Replacement of the original blood pressure transducer kit stopcocks with Marvelous™ stopcocks decreased the natural frequency (48.3 Hz) to 46.3 Hz or 44.8 Hz, respectively; the damping coefficient was not significantly changed. Plotting the data on a Gardner chart revealed that the changes fell within the adequate dynamic response region, indicating they were within the allowable range. Insertion of Marvelous™ stopcocks slightly affects the natural frequency of the pressure transducer kit, similar to inserting a PTS. The results indicate that the Marvelous™ stopcock is useful for accurate monitoring of arterial blood pressure, and may be recommended when insertion of two or more closed-loop blood sampling systems is necessary.


Assuntos
Determinação da Pressão Arterial/instrumentação , Determinação da Pressão Arterial/métodos , Transdutores de Pressão , Pressão Sanguínea , Desenho de Equipamento , Humanos , Oscilometria/instrumentação , Oscilometria/métodos , Reprodutibilidade dos Testes , Processamento de Sinais Assistido por Computador , Software
16.
Biomacromolecules ; 18(2): 535-543, 2017 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-28055201

RESUMO

Delivery of anticancer drugs into tumor cores comprised of malignant cancer cells can result in potent therapeutic effects. However, conventional nanoparticle-based drug delivery systems used for cancer therapy often exhibit inefficient tumor-penetrating properties, thus, suggesting the need to improve the functional design of such systems. Herein, we focus on the interactions between cancer cells and the extracellular matrix (ECM) and demonstrate that liposomes modified with slightly acidic pH-sensitive peptide (SAPSp-lipo) can penetrate in vivo tumor tissue and in vitro spheroids comprised of cancer cells and ECM. We previously reported SAPSp-lipo, tumor microenvironment-sensitive liposomes, are effectively delivered to tumor tissue (Hama et al. J Control Release 2015, 206, 67-74). Compared with conventional liposomes, SAPSp-lipo could be delivered to deeper regions within both spheroids and tumor tissues. Furthermore, tumor penetration was found to be promoted at regions where actin depolymerization was induced by SAPSp-lipo and inhibited by the polymerization of actin. In addition, SAPSp-lipo attenuated the interaction between cancer cells and ECM, contributing to the penetration of SAPSp-lipo. These results suggest that SAPSp-lipo penetrates tumors via the interspace route and is accompanied by actin depolymerization. Taken together, SAPSp-lipo demonstrates potential as a novel tumor-penetrable drug carrier for induction of therapeutic effects against malignant cells that comprise tumor cores.


Assuntos
Actinas/metabolismo , Sistemas de Liberação de Medicamentos , Matriz Extracelular/metabolismo , Lipossomos/administração & dosagem , Melanoma Experimental/tratamento farmacológico , Nanopartículas/administração & dosagem , Fragmentos de Peptídeos/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Matriz Extracelular/efeitos dos fármacos , Lipossomos/química , Masculino , Melanoma Experimental/metabolismo , Camundongos , Camundongos Pelados , Nanopartículas/química , Fragmentos de Peptídeos/administração & dosagem , Polimerização , Células Tumorais Cultivadas , Microambiente Tumoral
17.
J Oleo Sci ; 65(11): 949-954, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27803494

RESUMO

Conjugated linoleic acid (CLA) has several beneficial biological properties. Specifically, trans10, cis12-CLA, one of the CLA isomers, has strong physiologic activity against cancer and obesity. However, compared with cis9, trans11-CLA, a naturally occurring CLA isomer, trans10, cis12-CLA tends to be easily metabolized. Therefore, to make efficient use of its biological properties, it is necessary to overcome the rapid clearance of trans10, cis12-CLA from the blood. Here, we employed premix membrane emulsification to prepare two oil-in-water CLA microemulsions (CLA-ME), 100 nm CLA-ME and 200 nm CLA-ME, and investigated their pharmacokinetics in a mouse model. We report that 100 nm CLA-ME contributed to the concentration of blood CLA for longer than 200 nm CLA-ME, indicating that small CLA microparticles were more suitable for maintaining blood trans10, cis12-CLA levels in vivo. However, both CLA-ME could be hardly detected in blood and other tissues 24 h after administration, suggesting that additional strategies for prolonging CLA-ME half-life are required.


Assuntos
Ácidos Linoleicos Conjugados/sangue , Ácidos Linoleicos Conjugados/farmacocinética , Animais , Emulsões/análise , Emulsões/síntese química , Emulsões/química , Emulsões/farmacocinética , Ácidos Linoleicos Conjugados/síntese química , Ácidos Linoleicos Conjugados/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Tecidual
18.
Nanoscale ; 8(20): 10649-58, 2016 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-27145993

RESUMO

Condensing siRNA with cationic polymers is a major strategy used in the development of siRNA carriers that can avoid degradation by nucleases and achieve effective delivery of siRNA into the cytoplasm. However, ineffective release of siRNA from such condensed forms into the cytoplasm is a limiting step for induction of RNAi effects, and can be attributed to tight condensation of siRNA with the cationic polymers, due to potent electrostatic interactions. Here, we report that siRNA condensed with a slightly acidic pH-sensitive peptide (SAPSP), whose total charge is inverted from positive to negative in response to cytoplasmic pH, is effectively released via electrostatic repulsion of siRNA with negatively charged SAPSP at cytoplasmic pH (7.4). The condensed complex of siRNA and positively-charged SAPSP at acidic pH (siRNA/SAPSP) was found to result in almost complete release of siRNA upon charge inversion of SAPSP at pH 7.4, with the resultant negatively-charged SAPSP having no undesirable interactions with endogenous mRNA. Moreover, liposomes encapsulating siRNA/SAPSP demonstrated knockdown efficiencies comparable to those of commercially available siRNA carriers. Taken together, SAPSP may be very useful as a siRNA condenser, as it facilitates effective cytoplasmic release of siRNA, and subsequent induction of specific RNAi effects.


Assuntos
Citoplasma/química , Lipossomos/química , Peptídeos/química , RNA Interferente Pequeno/administração & dosagem , Animais , Feminino , Concentração de Íons de Hidrogênio , Melanoma Experimental , Camundongos , Camundongos Nus , Interferência de RNA
19.
J Control Release ; 206: 67-74, 2015 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-25770398

RESUMO

Modification with polyethylene glycol (PEG) is currently considered an important strategy for anti-cancer drug delivery, because PEGylated-nanoparticles would be effectively delivered to tumor tissue by enhanced permeation and retention effects. However, PEGylation suppresses the cellular uptake of nanoparticles (NPs) to target cells (known as the PEG dilemma). Here, we propose a novel strategy, namely conferring a pathological environment-sensitive property of nanoparticles for overcoming the PEG dilemma. Specifically, although nanoparticles have an overall negative surface charge to avoid interactions with biogenic substances in blood circulation, inversion of surface charge (to positive) at the pH of the tumor microenvironment may allow the nanoparticles to be taken up by cancer cells. To prove this concept, charge-invertible nanoparticles modified with novel slightly acidic pH-sensitive peptide (SAPSP-NPs) were developed. The negatively-charged SAPSP-NPs were delivered to tumor tissue, and were successfully taken up by cancer cells upon inversion of the surface charge to positive at intratumoral pH. SAPSP-NPs may serve as an alternative carrier to the PEGylated NP for anti-cancer drug delivery.


Assuntos
Portadores de Fármacos/metabolismo , Nanopartículas/metabolismo , Neoplasias/metabolismo , Peptídeos/metabolismo , Polietilenoglicóis/metabolismo , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Peptídeos/química , Polietilenoglicóis/química , Propriedades de Superfície
20.
FEBS J ; 282(1): 142-52, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25315678

RESUMO

Antibodies against cytoplasmic proteins are useful tools that can control cellular function and clarify signaling mechanisms. However, it is difficult to capture proteins inside living cells, and thus appropriate methods for antibody delivery to the cytoplasm of living cells are required. Cell-penetrating materials, such as the TAT-peptide, have received attention for their ability to deliver various cargos into living cells. However, the direct modification of cargos with cell-penetrating materials is time-consuming and lacks versatility. Therefore, we conceived that protein A, which can bind to the fragment crystallizable region of an antibody, could indirectly link antibodies with cell-penetrating materials, creating an efficient and simple antibody delivery system. Here, we constructed a novel antibody delivery system using a cell-penetrating polymer-modified protein A derivative (CPP-pAd). Living cells treated with CPP-pAd/antibody complexes showed significantly higher antibody levels than those achieved with the commercially available reagent HVJ-E. Pre-treatment with sucrose prevented cellular uptake of the CPP-pAd/antibody complex, suggesting that the CPP-pAd/antibody internalization mechanism occurs through clathrin-dependent endocytosis. Interestingly, intracellularly delivered antibodies did not colocalize with endosome/lysosome markers, further suggesting that antibodies were delivered to the cytoplasm by escape from endosome/lysosome. Moreover, we observed that anti-nuclear pore complex antibodies, delivered to cells using CPP-pAd, localized to the nuclear membrane and inhibited nuclear factor κB dependent luciferase activity. Together, these results suggest that the antibodies delivered by CPP-pAd captured functional proteins, making CPP-pAd a promising strategy for effective capture of proteins inside living cells.


Assuntos
Anticorpos/administração & dosagem , Peptídeos Penetradores de Células/administração & dosagem , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína Estafilocócica A/administração & dosagem , Peptídeos Penetradores de Células/química , Citoplasma/metabolismo , Sistemas de Liberação de Medicamentos , Endocitose , Endossomos/metabolismo , Células HeLa , Humanos , Estrutura Molecular , Complexo de Proteínas Formadoras de Poros Nucleares/imunologia , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Polímeros/administração & dosagem , Polímeros/química , Proteína Estafilocócica A/química
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