RESUMEN
In the frame of Higuchi's type functionality, this paper presents the anisotropy influences on the drug delivery mechanisms through the joint invariant functions to the simultaneous actions of the two SL(2R) isomorphic groups. Then, a new equation for drug delivery mechanism, independent of the type of polymer matrix and/or drug, is proposed.
Asunto(s)
Sistemas de Liberación de Medicamentos , Anisotropía , Materiales Biocompatibles , Biología Computacional , Simulación por Computador , Difusión , Sistemas de Liberación de Medicamentos/estadística & datos numéricos , Humanos , Conceptos Matemáticos , Modelos Biológicos , PolímerosRESUMEN
In this paper, we propose a new approach for the dynamics of drug delivery systems, assimilated to complex systems, an approach based on concepts like fractality, non-differentiability, and multiscale evolution. The main advantage of using these concepts is the possibility of eliminating the approximations used in the standard approach by replacing complexity with fractality, that imposes, in mathematical terms, the mandatory use of the non-differential character of defined physical quantities. The theoretical model presented, validated for other physical systems, demonstrates its functionality also for drug delivery systems, highlighting, in addition, new insights into the complexity of this system. The spatio-temporal scales of system evolution are characterized through the fractality degree, as a measure of the complexity of the phenomena occurring at each scale. Numerical analysis of the experiment showed that the overall drug release kinetics can be obtained by composing "smaller release kinetics" occurring at scales appropriate for each phase of the drug release mechanism, phases whose expansion depends on the system density. Moreover, the uncertainties in establishing the exact limits of the phases were removed by applying the principle of scale superposition, resulting in a global fractality degree corresponding to the entire release kinetics. Even if the theoretical model is perfectible by identifying constants specific to each delivery system, this paper is intended to be the beginning of an alternative approach to drug delivery mechanisms.
Asunto(s)
Liberación de Fármacos , Dinámicas no Lineales , Polímeros , Sistemas de Liberación de MedicamentosRESUMEN
The study proposes modeling calcein release kinetics (considered as a hydrophilic drug model) from an interpenetrating network matrix of hydrogels, based on the combination of two polymers, of which chitosan is the most commonly used polymer. The release process is analyzed for different increasing time intervals, based on the evolution of the release kinetics. For each time interval, a dominant release mechanism was identified and quantitative analyses were performed, to probe the existence of four distinct stages during its evolution with each stage governed by a different kinetics model. An interesting and original aspect, which is analyzed through a novel approach, is that of drug release at longer time scales, which is often overlooked. It revealed that the system behaves as a complex one and its evolution can be described through a nonlinear theoretical model, which offers us new insights into its order-disorder evolution.
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Quitosano/química , Fluoresceínas/química , Hidrogeles/química , Cinética , Modelos MolecularesRESUMEN
We present a traveling-wave analysis of a reduced mathematical model describing the growth of a solid tumor in the presence of an immune system response in the framework of Scale Relativity theory. Attention is focused upon the attack of tumor cells by tumor-infiltrating cytotoxic lymphocytes (TICLs), in a small multicellular tumor, without necrosis and at some stage prior to (tumor-induced) angiogenesis. For a particular choice of parameters, the underlying system of partial differential equations is able to simulate the well-documented phenomenon of cancer dormancy and propagation of a perturbation in the tumor cell concentration by cnoidal modes, by depicting spatially heterogeneous tumor cell distributions that are characterized by a relatively small total number of tumor cells. This behavior is consistent with several immunomorphological investigations. Moreover, the alteration of certain parameters of the model is enough to induce soliton like modes and soliton packets into the system, which in turn result in tumor invasion in the form of a standard traveling wave. In the same framework of Scale Relativity theory, a very important feature of malignant tumors also results, that even in avascular stages they might propagate and invade healthy tissues, by means of a diffusion on a Newtonian fluid.
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Neoplasias/inmunología , Neoplasias/patología , Secuencia de Bases , Cartilla de ADN , Humanos , Modelos TeóricosRESUMEN
The formation and dynamics of a laser-produced aluminum plasma have been experimentally and theoretically investigated. The visible-emitting regions of the plasma form two structures with different lifetimes and expansion velocities. The first part of the transient ionic signal simultaneously recorded by a Langmuir probe presents an oscillatory structure. A hydrodynamic model in a nondifferentiable space-time has been established. The numerical simulation of the plasma expansion showed the plasma plume separation into two patterns. Moreover, the self-structuring of the interface appears through a negative differential conductance and the current oscillations are explained as being induced by thermal fluctuations that appear in the plasma cooling processes.
RESUMEN
Our group is developing a novel technology, enzyme-mediated cancer imaging and therapy (EMCIT), that aims to entrap radioiodinated compounds within solid tumors for noninvasive tumor detection and therapy. In this approach, a water-soluble, radioiodinated prodrug is hydrolyzed in vivo to a highly water-insoluble compound by an enzyme overexpressed extracellularly by tumor cells. We have synthesized and characterized the water-soluble prodrug, 2-(2'-phosphoryloxyphenyl)-6-[(125)I]iodo-4-(3H)-quinazolinone [(125)I]5, which is readily hydrolyzed by alkaline phosphatase, an enzyme expressed by many tumor cell lines, to a water-insoluble drug, 2-(2'-hydroxyphenyl)-6-[(125)I]iodo-4-(3H)-quinazolinone [(125)I]1. In the course of our study, we discovered that ammonium 2-(2'-phosphoryloxyphenyl)-6-tributylstannyl-4-(3H)-quinazolinone, an intermediate in the radioiodination of the prodrug, exists as two isomers (3 and 4) whose radioiodination leads, respectively, to [(125)I]6 and [(125)I]5. These prodrugs have different in vitro and in vivo biologic activities. Compound 6 is not hydrolyzed by alkaline phosphatase (ALP), whereas 5 is highly soluble (mg/mL) in aqueous solution and is rapidly dephosphorylated in the presence of ALP to 1, a water-insoluble molecule (ng/mL). Mouse biodistribution studies indicate that [(125)I]6 has high uptake in kidney and liver and [(125)I]5 has very low uptake in all normal organs. Compounds 3 and 6 are converted, respectively, to 4 and 5 after incubation in DMSO. The stability of 5 in human serum is high. The minimum ALP concentration needed to hydrolyze 5 is much greater than the ALP level in the blood of patients with cancer, and the latter should not affect the pharmacokinetics of the compound. Incubation of 5 with viable human and mouse tumor-cell lines--but not with normal human cells and mouse tissues--leads to its hydrolysis and the formation of large crystals of 1. We expect that 5 will also be hydrolyzed in vivo by tumor cells that express phosphatase activity extracellularly and anticipate the specific precipitation of radioiodinated 1 within tumor cell clusters. This should lead to high tumor-to-normal-tissue ratios and enable imaging (SPECT/PET) and radionuclide therapy of solid tumors.
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Neoplasias/metabolismo , Organofosfatos/química , Organofosfatos/farmacocinética , Profármacos/química , Profármacos/farmacocinética , Quinazolinonas/química , Quinazolinonas/farmacocinética , Fosfatasa Alcalina/metabolismo , Animales , Línea Celular Tumoral , Células Cultivadas , Humanos , Hidrólisis , Radioisótopos de Yodo/química , Riñón/metabolismo , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Neoplasias/diagnóstico por imagen , Neoplasias/radioterapia , Organofosfatos/síntesis química , Profármacos/síntesis química , Quinazolinonas/síntesis química , Cintigrafía , Solubilidad , Distribución TisularRESUMEN
As part of the development of enzyme-mediated cancer imaging and therapy, a novel technology to entrap water-insoluble radioactive molecules within solid tumors, we show that a water-soluble, radioactive quinazolinone prodrug, ammonium 2-(2'-phosphoryloxyphenyl)-6-[125I]iodo-4-(3H)-quinazolinone (125IQ(2-P)), is hydrolyzed by alkaline phosphatase to a water-insoluble, radiolabeled drug, 2-(2'-hydroxyphenyl)-6-[125I]iodo-4-(3H)-quinazolinone (125IQ(2-OH)). Biodistribution data suggest the existence of two isoforms of the prodrug (IQ(2-P(I)) and IQ(2-P)), and this has been confirmed by their synthesis and characterization. Structural differences of the two isoforms have been examined using in silico molecular modeling techniques and docking methods to describe the interaction/binding between the isoforms and human placental alkaline phosphatase (PLAP), a tumor cell, membrane-associated, hydrolytic enzyme whose structure is known by X-ray crystallographic determination. Docking data show that IQ(2-P), but not IQ(2-P(I)), fits the active binding site of PLAP favorably and interacts with the catalytic amino acid Ser(92), which plays an important role in the hydrolytic process. The binding free energies (DeltaG(binding)) of the isoforms to PLAP predict that IQ(2-P) will be the better substrate for PLAP. The in vitro incubation of the isoforms with PLAP leads to the rapid hydrolysis of IQ(2-P) only and confirms the in silico expectations. Fluorescence microscopy shows that in vitro incubation of IQ(2-P) with mouse and human tumor cells causes the extracellular, alkaline phosphatase-mediated hydrolysis of the molecule and precipitation of fluorescent crystals of IQ(2-OH). No hydrolysis is seen in the presence of normal mouse and human cells. Furthermore, the intratumoral injection of 125IQ(2-P) into alkaline phosphatase-expressing solid human tumors grown s.c. in nude rats results in efficient hydrolysis of the compound and retention of approximately 70% of the injected radioactivity, whereas similar injection into normal tissues (e.g., muscle) does not produce any measurable hydrolysis (approximately 1%) or retention of radioactivity at the injected site. These studies support the enzyme-mediated cancer imaging and therapy technology and show the potential of such quinazolinone derivatives in the in vivo radiodetection (123I/124I) and therapy (131I) of solid tumors.
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Fosfatasa Alcalina/química , Fosfatasa Alcalina/metabolismo , Neoplasias/enzimología , Profármacos/síntesis química , Profármacos/farmacocinética , Quinazolinonas/síntesis química , Quinazolinonas/farmacocinética , Animales , Autorradiografía/métodos , Línea Celular Tumoral , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Hidrólisis , Radioisótopos de Yodo , Marcaje Isotópico/métodos , Ratones , Ratones Endogámicos C3H , Microscopía Confocal/métodos , Microscopía Fluorescente/métodos , Modelos Moleculares , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Profármacos/química , Profármacos/farmacología , Quinazolinonas/química , Quinazolinonas/farmacología , Ratas , TermodinámicaRESUMEN
PURPOSE: To assess the therapeutic potential of methotrexate (MTX) and 5-[1251]liodo-2'-deoxyuridine (125IdUrd) administered sequentially in rats bearing advanced (ten-day-old) intrathecal (i.t.) TE671 human rhabdomyosarcoma tumours. MATERIALS AND METHODS: Nude rats were injected with TE671 cells through an i.t. placed catheter. Ten days later, the animals were injected i.t. over a 12-day period with (i) saline daily, (ii) MTX every other day, (iii) 125IdUrd every other day, or (iv) MTX and 125IdUrd on alternating days. Onset of paralysis was determined as a function of time, and the medians for onset (M), percentage of cells killed (% kill), and log cell kill were calculated. RESULTS: The data show that (i) injection of MTX leads to a moderate delay in the onset of paralysis (M(MTX) = 29 d versus Msaline = 20 d), (ii) administration of 125IdUrd is more effective (M(IdUrd) = 36 d), and (iii) sequential administration of MTX- 125IdUrd further increases the therapeutic efficacy of 125IdUrd (M(MTX)-IdUrd = 47 d). CONCLUSIONS: Intrathecal injection of MTX-(125)IdUrd is efficacious in the therapy of advanced intrathecal tumours.
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Idoxuridina/administración & dosificación , Meningitis/prevención & control , Metotrexato/administración & dosificación , Parálisis/prevención & control , Neoplasias de la Columna Vertebral/tratamiento farmacológico , Neoplasias de la Columna Vertebral/radioterapia , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Terapia Combinada , Sinergismo Farmacológico , Inyecciones Espinales , Neoplasias Meníngeas/complicaciones , Neoplasias Meníngeas/tratamiento farmacológico , Neoplasias Meníngeas/radioterapia , Meningitis/etiología , Cuidados Paliativos/métodos , Parálisis/etiología , Tolerancia a Radiación/efectos de los fármacos , Radiofármacos/administración & dosificación , Ratas , Rabdomiosarcoma/complicaciones , Rabdomiosarcoma/tratamiento farmacológico , Rabdomiosarcoma/radioterapia , Índice de Severidad de la Enfermedad , Neoplasias de la Columna Vertebral/complicaciones , Resultado del TratamientoRESUMEN
The measurements of micro-hardness was achieved with a view to studying the influence of chemical composition and fabrication with a view to obtain metal-ceramic dental restorations. The materials used were specimens of metal alloys (Remanium Cs) and specimens of metal alloys-ceramics (Remanium-Biodent ceramic) prepared through polish, lustre and acid attack; the PMT3 machine for microhardness measurements; a 50 grams weight and a length of loading 15 sec. The results of determinations are prove the technological process for cover metal structure of Remanium Cs with ceramics influence significantly the microhardness of metal ingot and Remanium further polish (with and without oxidation).
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Pruebas de Dureza/métodos , Aleaciones de Cerámica y Metal , Algoritmos , Humanos , Aleaciones de Cerámica y Metal/química , Prostodoncia , Estadísticas no Paramétricas , Tecnología OdontológicaRESUMEN
The occlusal forces have an effect on the dental structure in the longitudinal axis of the tooth, on the one hand, but, on the other hand, in the horizontal plane, they are conducted through interdental contact points. In this paper we try to simulate the stress and the deformations determined by different forces in different directions, over the dental interfaces. We have used the method of finite elements and Fastflo domain for the mathematical calculations of probability. Our conclusions are that the changes in the deformation field appear only for those materials that comply with the rate of elasticity changes in the condition where delta = E1/E2 < 20.