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The aim of this study is to validate an in vitro skin irritation test (SIT) using three-dimensional reconstructed human epidermal (RhE) skin equivalents prepared by layer-by-layer (LbL) method (LbL-3D Skin) in a series of interlaboratory studies. The goal of these validation studies is to evaluate the ability of this in vitro test to reliably discriminate skin irritant from nonirritant chemicals, as defined by OECD and UN GHS. This me-too validation study is to assess the within- and between-laboratory reproducibility, as well as the predictive capacity, of the LbL-3D Skin SIT in accordance with performance standards for OECD TG 439. The developed skin model, LbL-3D Skin had a highly differentiated epidermis and dermis, similar to the validated reference methods (VRM) and native human skin. The quality parameters (cell survival in controls, tissue integrity, and barrier function) were similar to VRM and in accordance with OECD TG 439. The LbL-3D Skin SIT validation study was performed by three participating laboratories and consisted of three independent tests using 20 reference chemicals. The results obtained with the LbL-3D Skin demonstrated high within-laboratory and between-laboratory reproducibility, as well as high accuracy for use as a stand-alone assay to distinguish skin irritants from nonirritants. The predictive potency of LbL-3D Skin SIT using total 54 test chemicals were comparable to those in other RhE models in OECD TG 439. The validation study demonstrated that LbL-3D Skin has proven to be a robust and reliable method for predicting skin irritation.
Asunto(s)
Irritantes , Pruebas de Irritación de la Piel , Humanos , Animales , Reproducibilidad de los Resultados , Pruebas de Irritación de la Piel/métodos , Irritantes/toxicidad , Piel , Epidermis , Técnicas In Vitro , Alternativas a las Pruebas en AnimalesRESUMEN
A small library of amphiphilic prodrugs has been synthesized by conjugation of gemcitabine (Gem) (a hydrophilic nucleoside analogue) to a series of lipid moieties and investigated for their capacity to spontaneously self-assemble into nanosized objects by simple nanoprecipitation. Four of these conjugates formed stable nanoparticles (NPs), while with the others, immediate aggregation occurred, whatever the tested experimental conditions. Whether such capacity could have been predicted based on the prodrug physicochemical features was a matter of question. Among various parameters, the hydrophilic-lipophilic balance (HLB) value seemed to hold a predictive character. Indeed, we identified a threshold value which well correlated with the tendency (or not) of the synthesized prodrugs to form stable nanoparticles. Such a hypothesis was further confirmed by broadening the analysis to Gem and other nucleoside prodrugs already described in the literature. We also observed that, in the case of Gem prodrugs, the lipid moiety affected not only the colloidal properties but also the in vitro anticancer efficacy of the resulting nanoparticles. Overall, this study provides a useful demonstration of the predictive potential of the HLB value for lipid prodrug NP formulation and highlights the need of their opportune in vitro screening, as optimal drug loading does not always translate in an efficient biological activity.
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Desoxicitidina/análogos & derivados , Lípidos/química , Nanopartículas/química , Profármacos/química , Antineoplásicos/química , Línea Celular Tumoral , Coloides/química , Desoxicitidina/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Difracción de Polvo , Profármacos/síntesis química , GemcitabinaRESUMEN
Intracellular distribution of doxorubicin (DOX) and its squalenoylated (SQ-DOX) nanoparticles (NPs) form in murine lung carcinoma M109 and human breast carcinoma MDA-MB-231 cells was investigated by Raman microspectroscopy. Pharmacological data showed that DOX induced higher cytotoxic effect than SQ-DOX NPs. Raman data were obtained using single-point measurements and imaging on the whole cell areas. These data showed that after DOX treatment at 1⯵M, the spectral features of DOX were not detected in the M109 cell cytoplasm and nucleus. However, the intracellular distribution of SQ-DOX NPs was higher than DOX in the same conditions. In addition, SQ-DOX NPs were localized into both cell cytoplasm and nucleus. After 5⯵M treatment, Raman bands of DOX at 1211 and 1241â¯cm-1 were detected in the nucleus. Moreover, the intensity ratio of these bands decreased, indicating DOX intercalation into DNA. However, after treatment with SQ-DOX NPs, the intensity of these Raman bands increased. Interestingly, with SQ-DOX NPs, the intensity of 1210/1241â¯cm-1 ratio was higher suggesting a lower fraction of intercalated DOX in DNA and higher amount of non-hydrolyzed SQ-DOX. Raman imaging data confirm this subcellular localization of these drugs in both M109 and MDA-MB-231 cells. These finding brings new insights to the cellular characterization of anticancer drugs at the molecular level, particularly in the field of nanomedicine.
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Neoplasias de la Mama , Doxorrubicina , Neoplasias Pulmonares , Nanopartículas , Análisis de la Célula Individual , Escualeno , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Nanopartículas/química , Nanopartículas/uso terapéutico , Espectrometría Raman , Escualeno/química , Escualeno/farmacocinética , Escualeno/farmacologíaRESUMEN
" Drug-initiated" nitroxide-mediated synthesis of two well-defined, heterotelechelic polymer prodrugs ( Mn = 1960-5260 g·mol-1, D = 1.31-1.37) was performed by using the newly developed nitroxide exchange reaction. These polymers comprised, at the chain end, gemcitabine (Gem) as anticancer drug and either cyanine 7.5 (Cy7.5) as a near-infrared (NIR) dye suitable for in vivo imaging or biotin (Biot) for cancer cell targeting. These materials were co-nanoprecipitated into fluorescently labeled polymer prodrug nanoparticles of average diameter in the 100-180 nm range with narrow particle size distribution and variable surface amounts of biotin. Nanoparticles containing 15 wt % biotinylated polymer showed superior uptake and the highest cytotoxicity in vitro on A549 human lung cancer cells. In vivo, on A549 tumor bearing mice, biotinylated nanoparticles showed significantly higher efficacy than free Gem and maintained the same anticancer activity than nontargeted nanoparticles without inducing prohibitive body weight loss. Biotinylated polymer prodrug nanoparticles did not result in an improved anticancer activity or significant increase in tumor accumulation, which may be the result of a nonoptimal biotin surface display and/or insufficient affinity toward the target. They however displayed delayed liver accumulation compared to nonbiotinylated counterparts, suggesting the premise of a stealth property likely due to the hydrophilic tetraethylene glycol-Biot positioned at the nanoparticle surface. This work showed for the first time the applicability of this simple construction method to in vivo imaging and cancer cell targeting and might stimulate the design of new functional materials for biomedical applications.
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Antineoplásicos , Desoxicitidina/análogos & derivados , Sistemas de Liberación de Medicamentos , Neoplasias Pulmonares , Nanopartículas , Imagen Óptica , Profármacos , Células A549 , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Desoxicitidina/química , Desoxicitidina/farmacología , Xenoinjertos , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Nanopartículas/química , Nanopartículas/uso terapéutico , Profármacos/química , Profármacos/farmacología , GemcitabinaRESUMEN
We have studied the interaction of three clinically promising squalenoylated drugs (gemcitabine-squalene, adenine-squalene, and doxorubicin-squalene) with low-density lipoproteins (LDL) by means of atomistic molecular dynamics simulations. It is shown that all studied squalenoylated drugs accumulate inside the LDL particles. This effect is promoted by the squalene moiety, which acts as an anchor and drives the hydrophilic drugs into the hydrophobic core of the LDL lipid droplet. Our data suggest that LDL particles could be a universal carriers of squalenoylated drugs in the bloodstream. Interaction of gemcitabine-squalene with human serum albumin (HSA) was also studied by ensemble of docking simulations. It is shown that HSA could also act as a passive carrier of this bioconjugate. It should be noted that the binding of squalene moiety to HSA was unspecific and did not occur in the binding pockets devoted to fatty acids.
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Portadores de Fármacos/química , Composición de Medicamentos/métodos , Lipoproteínas LDL/química , Albúmina Sérica Humana/química , Escualeno/química , Adenina/administración & dosificación , Adenina/química , Sitios de Unión , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Nanopartículas/química , Unión Proteica , Albúmina Sérica Humana/metabolismo , GemcitabinaRESUMEN
Selective delivery of anticancer drugs to rapidly growing cancer cells can be achieved by taking advantage of their high receptor-mediated uptake of low-density lipoproteins (LDLs). Indeed, we have recently discovered that nanoparticles made of the squalene derivative of the anticancer agent gemcitabine (SQGem) strongly interacted with the LDLs in the human blood. In the present study, we showed both in vitro and in vivo that such interaction led to the preferential accumulation of SQGem in cancer cells (MDA-MB-231) with high LDL receptor expression. As a result, an improved pharmacological activity has been observed in MDA-MB-231 tumor-bearing mice, an experimental model with a low sensitivity to gemcitabine. Accordingly, we proved that the use of squalene moieties not only induced the gemcitabine insertion into lipoproteins, but that it could also be exploited to indirectly target cancer cells in vivo.
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Adenocarcinoma/terapia , Neoplasias de la Mama/terapia , Regulación Neoplásica de la Expresión Génica , Lipoproteínas LDL/metabolismo , Nanopartículas/administración & dosificación , Receptores de LDL/genética , Escualeno/química , Adenocarcinoma/genética , Adenocarcinoma/patología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/farmacología , Portadores de Fármacos , Femenino , Humanos , Lipoproteínas LDL/química , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Ratones SCID , Nanopartículas/química , Receptores de LDL/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder related, in part, to the accumulation of amyloid-ß peptide (Aß) and especially the Aß peptide 1-42 (Aß1-42). The aim of this study was to design nanocarriers able to: (i) interact with the Aß1-42 in the blood and promote its elimination through the "sink effect" and (ii) correct the memory defect observed in AD-like transgenic mice. To do so, biodegradable, PEGylated nanoparticles were surface-functionalized with an antibody directed against Aß1-42. Treatment of AD-like transgenic mice with anti-Aß1-42-functionalized nanoparticles led to: (i) complete correction of the memory defect; (ii) significant reduction of the Aß soluble peptide and its oligomer level in the brain and (iii) significant increase of the Aß levels in plasma. This study represents the first example of Aß1-42 monoclonal antibody-decorated nanoparticle-based therapy against AD leading to complete correction of the memory defect in an experimental model of AD.
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Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/inmunología , Anticuerpos Monoclonales/química , Modelos Animales de Enfermedad , Trastornos de la Memoria/terapia , Nanopartículas/administración & dosificación , Polímeros/administración & dosificación , Animales , Anticuerpos Monoclonales/inmunología , Humanos , Masculino , Ratones , Ratones Transgénicos , Nanopartículas/química , Nanopartículas/metabolismo , Polímeros/química , Polímeros/metabolismo , Recuperación de la FunciónRESUMEN
The synthesis of ω-di-(trideuteromethyl)-trisnorsqualenic acid has been achieved from natural squalene. The synthesis features the use of a Shapiro reaction of acetone-d 6 trisylhydrazone as a key step to implement the terminal isopropylidene-d 6 moiety. The obtained squalenic acid-d 6 has been coupled to gemcitabine to provide the deuterated analogue of squalenoyl gemcitabine, a powerful anticancer agent endowed with self-assembling properties. The Raman spectra of both deuterated and non-deuterated squalenoyl gemcitabine nanoparticles displayed significant Raman scattering signals. They revealed no differences except from the deuterium peak patterns in the silent spectral region of cells. This paves the way for label-free intracellular trafficking studies of squalenoyl nanomedicines.
RESUMEN
Spurred by recent progress in materials chemistry and drug delivery, stimuli-responsive devices that deliver a drug in spatial-, temporal- and dosage-controlled fashions have become possible. Implementation of such devices requires the use of biocompatible materials that are susceptible to a specific physical incitement or that, in response to a specific stimulus, undergo a protonation, a hydrolytic cleavage or a (supra)molecular conformational change. In this Review, we discuss recent advances in the design of nanoscale stimuli-responsive systems that are able to control drug biodistribution in response to specific stimuli, either exogenous (variations in temperature, magnetic field, ultrasound intensity, light or electric pulses) or endogenous (changes in pH, enzyme concentration or redox gradients).
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Portadores de Fármacos , Nanoestructuras , Animales , Ensayos Clínicos como Asunto , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Humanos , Nanoestructuras/química , NanotecnologíaRESUMEN
We report herein a detailed study concerning the impact of different bioconjugation and nanoformulation strategies on the in vitro targeting ability of peptide-decorated squalenoyl gemcitabine (SQdFdC) nanoparticles (NPs). NPs have been functionalized with the CKAAKN peptide, previously identified as an efficient homing device within the pancreatic pathological microenvironment. Two approaches have been followed: (i) either the CKAAKN peptide was directly conjugated at the surface of preformed SQdFdC nanoparticles (conjugation after NP formation) or (ii) it was first reacted with a maleimide squalenoyl derivative before the resulting bioconjugate was co-nanoprecipitated with SQdFdC to form the peptide-decorated NPs (conjugation before NP formation). NPs were characterized with respect to mean diameter, zeta potential, and stability over time. Then, their specific interaction with the sFRP-4 protein was evaluated by surface plasmon resonance. Although both synthetic strategies allowed us to formulate NPs able to interact with the corresponding receptor, enhanced target binding and better specific avidity were observed with CKAAKN-NPs functionalized before NP formation. These NPs displayed the highest cell uptake and cytotoxicity in an in vitro model of human MIA Paca-2 pancreatic cancer cells.
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Portadores de Fármacos/química , Nanopartículas/química , Oligopéptidos/química , Secuencia de Aminoácidos , Animales , Línea Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Portadores de Fármacos/metabolismo , Diseño de Fármacos , Humanos , Ligandos , Ratones , Células 3T3 NIH , Nanopartículas/metabolismo , Tamaño de la Partícula , Proteínas Proto-Oncogénicas/metabolismo , GemcitabinaRESUMEN
Design and functionalization strategies for multifunctional nanocarriers (e.g., nanoparticles, micelles, polymersomes) based on biodegradable/biocompatible polymers intended to be employed for active targeting and drug delivery are reviewed. This review will focus on the nature of the polymers involved in the preparation of targeted nanocarriers, the synthesis methods to achieve the desired macromolecular architecture, the selected coupling strategy, the choice of the homing molecules (vitamins, hormones, peptides, proteins, etc.), as well as the various strategies to display them at the surface of nanocarriers. The resulting morphologies and the main colloidal features will be given as well as an overview of the biological activities, with a special focus on the main in vivo achievements.
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Materiales Biocompatibles/química , Portadores de Fármacos/química , Nanopartículas/química , Polímeros/química , Materiales Biocompatibles/síntesis química , Portadores de Fármacos/síntesis química , Humanos , Micelas , Modelos Moleculares , Polímeros/síntesis químicaRESUMEN
A better understanding of the molecular and cellular events involved in the inflammation process has opened novel perspectives in the treatment of inflammatory diseases, particularly through the development of well-designed nanomedicines. Here we describe the design of a novel class of anti-inflammatory nanomedicine (denoted as Au@MIL) synthesized through a one-pot, cost-effective and green approach by coupling a benchmark mesoporous iron(III) carboxylate metal organic framework (MOF) (i.e. MIL-100(Fe)) and glutathionate protected gold nanoclusters (i.e. Au25SG18 NCs). This nano-carrier exhibits low toxicity and excellent colloidal stability combined with the high loading capacity of the glucocorticoid dexamethasone phosphate (DexP) whose pH-dependent delivery was observed. The drug loaded Au@MIL nanocarrier shows high anti-inflammatory activity due to its capacity to specifically hinder inflammatory cell growth, scavenge intracellular reactive oxygen species (ROS) and downregulate pro-inflammatory cytokine secretion. In addition, this formulation has the capacity to inhibit the Toll-like receptor (TLR) signaling cascade namely the nuclear factor kappa B (NF-κB) and the interferon regulatory factor (IRF) pathways. This not only provides a new avenue for the nanotherapy of inflammatory diseases but also enhances our fundamental knowledge of the role of nanoMOF based nanomedicine in the regulation of innate immune signaling.
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Antiinflamatorios , Dexametasona , Oro , Inflamación , Nanopartículas del Metal , Estructuras Metalorgánicas , Transducción de Señal , Receptores Toll-Like , Oro/química , Ratones , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Transducción de Señal/efectos de los fármacos , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Animales , Receptores Toll-Like/metabolismo , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Inflamación/tratamiento farmacológico , Dexametasona/química , Dexametasona/farmacología , Especies Reactivas de Oxígeno/metabolismo , Células RAW 264.7 , Portadores de Fármacos/química , Humanos , FN-kappa B/metabolismoRESUMEN
A new paclitaxel (Ptx) prodrug was designed by coupling a single terpene unit (MIP) to the hydroxyl group in position 2' of the drug molecule. Using a squalene derivative of polyethylene glycol (SQ-PEG) as surface active agent, the resulting bioconjugate (PtxMIP) self-assembled in water leading to the formation of stable nanoparticles (PtxMIP_SQ-PEG NPs) with an impressively high drug loading (82%). In vivo, the anticancer activity of this novel Ptx nanoassembled prodrug was compared to the conventional Cremophor-containing formulation (Taxol) on a murine model of breast cancer lung metastasis induced by intravenous injection of 4T1 tumor cells, genetically modified to stably express firefly luciferase. Cell growth was assessed noninvasively by bioluminescence imaging (BLI) which enabled monitoring tumor metastatic burden in the same animals. PtxMIP_SQ-PEG nanoparticles slowed metastatic spread and were better tolerated than the Cremophor-containing formulation (i.e., free drug), thus demonstrating the potential of terpene-based nanoassembled prodrugs in the improvement of the therapeutic index of Ptx in balb/c mice.
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Antineoplásicos/metabolismo , Butadienos/química , Sistemas de Liberación de Medicamentos , Hemiterpenos/química , Nanopartículas/química , Paclitaxel/metabolismo , Pentanos/química , Profármacos/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Concentración 50 Inhibidora , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Paclitaxel/farmacología , Profármacos/síntesis química , Profármacos/farmacología , Células Tumorales CultivadasRESUMEN
Three cyclic ketene acetals, 2-methylene-1,3-dioxepane (MDO), 5,6-benzo-2-methylene-1,3-dioxepane (BMDO), and 2-methylene-4-phenyl-1,3-dioxolane (MPDL), have been copolymerized with oligo(ethylene glycol) methyl ether methacrylate and a small amount of acrylonitrile (or styrene) at 90 °C by nitroxidemediated radical ring-opening polymerization, as a convenient way to prepare degradable PEG-based copolymers for biomedical applications. MPDL was the best candidate, enabling high monomer conversions to be reached and well-defined PEG-based copolymers with adjustable amount of ester groups in the main chain to be synthesized, leading to nearly complete hydrolytic degradation (5% KOH aqueous solution, ambient temperature). The noncytotoxicity of the obtained copolymers was shown on three different cell lines (i.e., fibroblasts, endothelial cells and macrophages), representing a promising approach for the design of degradable precursors for PEGylation and bioconjugation via the NMP technique.
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Óxidos de Nitrógeno/química , Polietilenglicoles/química , Acetales/química , Animales , Supervivencia Celular , Células Cultivadas , Etilenos/química , Fibroblastos/citología , Radicales Libres/química , Células Endoteliales de la Vena Umbilical Humana/citología , Humanos , Cetonas/química , Macrófagos/citología , Ratones , Estructura Molecular , Células 3T3 NIH , Polietilenglicoles/síntesis química , PolimerizacionRESUMEN
In this paper, a straightforward method to produce poly(3-hydroxyalkanoate)-based multicompartment micelles (MCMs) is presented. Thiol-ene addition is used to graft sequentially perfluorooctyl chains and poly(ethylene glycol) oligomers onto poly(3-hydroxyoctanoate-co-hydroxyundecenoate) oligomers backbone. Well-defined copolymers are obtained as shown by ¹H NMR and size-exclusion chromatography. After nanoprecipitation in water, novel PHA-based MCMs are evidenced by cryo-transmission electron microscopy. Moreover, the cytocompatibility of MCMs is demonstrated in vitro via cell viability assay.
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Materiales Biocompatibles/química , Micelas , Polihidroxialcanoatos/química , Alquenos/química , Animales , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/toxicidad , Supervivencia Celular/efectos de los fármacos , Luz , Ratones , Células 3T3 NIH , Nanoestructuras/química , Polihidroxialcanoatos/toxicidad , Dispersión de Radiación , Compuestos de Sulfhidrilo/químicaRESUMEN
Nanomedicines have gained more and more attention in cancer therapy thanks to their ability to enhance the tumour accumulation and the intracellular uptake of drugs while reducing their inactivation and toxicity. In parallel, nanocarriers have been successfully employed as diagnostic tools increasing imaging resolution holding great promises both in preclinical research and in clinical settings. Lipid-based nanocarriers are a class of biocompatible and biodegradable vehicles that provide advanced delivery of therapeutic and imaging agents, improving pharmacokinetic profile and safety. One of most promising engineering challenges is the design of innovative and versatile multifunctional targeted nanotechnologies for cancer treatment and diagnosis. This review aims to highlight rational approaches to design multifunctional non liposomal lipid-based nanocarriers providing an update of literature in this field.
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Antineoplásicos , Portadores de Fármacos , Lípidos , Nanomedicina , Nanopartículas , Animales , Línea Celular Tumoral , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Recently, we carried out a research on new liposomal systems prepared by using in their composition a few penetration enhancers which differ for chemical structure and physicochemical properties. The penetration enhancer-containing vesicles (PEVs) were prepared by using soy lecithin and different amounts of three penetration enhancers, 2-(2-ethoxyethoxy) ethanol (Transcutol(®)), capryl-caproyl macrogol 8-glyceride (Labrasol(®)), and cineole.To study the influence of the PEVs on (trans)dermal delivery of minoxidil, in vitro diffusion experiments were performed through new born pig skin and the results were compared with that obtained applying the vesicular system without enhancer (control) after pretreatment of the skin with the various enhancers. In this study, Fourier transform infrared spectroscopy (FTIR), attenuated total reflectance FTIR (ATR-FTIR) and FTIR imaging were used to evaluate the effective penetration of minoxidil in the skin layers and to discover the influence of the enhancer on the drug topical delivery. These analytical studies allowed us to characterize the drug formulations and to evaluate the vesicle distribution into the skin. Recorded spectra confirmed that the vesicle formulations with penetration enhancers promoted drug deposition into the skin.
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Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Minoxidil/administración & dosificación , Minoxidil/química , Administración Cutánea , Animales , Química Farmacéutica/métodos , Ciclohexanoles/química , Glicoles de Etileno/química , Eucaliptol , Glicéridos , Lecitinas/química , Minoxidil/farmacocinética , Monoterpenos/química , Compuestos Orgánicos/química , Permeabilidad , Piel/metabolismo , Absorción Cutánea , Proteínas de Soja/química , Espectrofotometría Infrarroja/métodos , PorcinosRESUMEN
The purpose of this study was to develop a new delivery system capable of improving bioavailability and controlling release of hydrophilic drugs. Metformin-loaded liposomes were prepared and to improve their stability surface was coated with chitosan cross-linked with the biocompatible ß-glycerolphosphate. X-ray diffraction, differential scanning calorimetry, as well as rheological analysis were performed to investigate interactions between chitosan and ß-glycerolphosphate molecules. The entrapment of liposomes into the chitosan-ß-glycerolphosphate network was assessed by scanning electron microscopy and transmission electron microscopy. Swelling and mucoadhesive properties as well as drug release were evaluated in vitro while the drug oral bioavailability was evaluated in vivo on Wistar rats. Results clearly showed that, compared to control, the proposed microcomplexes led to a 2.5-fold increase of metformin T(max) with a 40% augmentation of the AUC/D value.
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Quitosano/química , Portadores de Fármacos , Glicerofosfatos/química , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacocinética , Metformina/administración & dosificación , Metformina/farmacocinética , Adhesividad , Administración Oral , Animales , Área Bajo la Curva , Disponibilidad Biológica , Rastreo Diferencial de Calorimetría , Química Farmacéutica , Quitosano/análogos & derivados , Preparaciones de Acción Retardada , Mucosa Gástrica/metabolismo , Hipoglucemiantes/química , Absorción Intestinal , Mucosa Intestinal/metabolismo , Liposomas , Masculino , Metformina/química , Microscopía Electrónica de Rastreo , Microscopía Electrónica de Transmisión , Ratas , Ratas Wistar , Reología , Solubilidad , Tecnología Farmacéutica/métodos , Difracción de Rayos XRESUMEN
Up to now the lipid bilayers were rarely considered as targets in cancer therapy despite pronounced differences in lipid composition between plasma membranes of benign and malignant cells. In this study we demonstrate that the lipid bilayer of the plasma membrane is druggable and suitable for facilitating selective delivery of amphiphilic gemcitabine-squalene nanomedicines to cancer cells. Data from radioactive assays, fluorescent membrane probes and molecular dynamics simulations provide evidence of selective accumulation of gemcitabine-squalene in the plasma membranes with disrupted lipid asymmetry and its subsequent preferential uptake by malignant cells. This causes pronounced cytotoxicity on cancer cells in comparison to their benign counterparts originating from the same tissue.
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Neoplasias , Profármacos , Gemcitabina , Membrana Dobles de Lípidos/metabolismo , Escualeno/metabolismo , Membrana Celular/metabolismo , Neoplasias/metabolismoRESUMEN
While considerable efforts have been made to develop new therapies, progress in the treatment of pancreatic cancer has so far fallen short of patients' expectations. This is due in part to the lack of predictive in vitro models capable of accounting for the heterogeneity of this tumor and its low immunogenicity. To address this point, we have established and characterized a 3D spheroid model of pancreatic cancer composed of tumor cells, cancer-associated fibroblasts, and blood-derived monocytes. The fate of the latter has been followed from their recruitment into the tumor spheroid to their polarization into a tumor-associated macrophage (TAM)-like population, providing evidence for the formation of an immunosuppressive microenvironment.This 3D model well reproduced the multiple roles of TAMs and their influence on drug sensitivity and cell migration. Furthermore, we observed that lipid-based nanosystems consisting of sphingomyelin and vitamin E could affect the phenotype of macrophages, causing a reduction of characteristic markers of TAMs. Overall, this optimized triple coculture model gives a valuable tool that could find useful application for a more comprehensive understanding of TAM plasticity as well as for more predictive drug screening. This could increase the relevance of preclinical studies and help identify effective treatments.