Comparing the permeability of human and porcine small intestinal mucus for particle transport studies.

The gastrointestinal mucus layer represents the last barrier between ingested food or orally administered pharmaceuticals and the mucosal epithelium. This complex gel structure plays an important role in the process of small intestinal absorption. It provides protection against hazardous particles such as bacteria but allows the passage of nutrients and drug molecules towards the intestinal epithelium. In scientific research, mucus from animal sources is usually used to simulate difficult-to-obtain human small intestinal mucus for investigating the intramucus transport of drug delivery systems or food nanoparticles. However, there is a lack of evidence the human mucus can be reliably substituted by animal counterparts for human-relevant transport models. In this report, a procedure for collecting human mucus has been described. More importantly, the permeability characteristics of human and porcine small intestinal mucus secretions to sub-micron sized particles have been compared under simulated intestinal conditions. Negatively charged, 500 nm latex beads were used in multiple-particle tracking experiments to examine the heterogeneity and penetrability of mucus from different sources. Diffusion of the probe particles in adult human ileal mucus and adult pig jejunal and ileal mucus revealed no significant differences in microstructural organisation or microviscosity between the three mucus types (P > 0.05). In contrast to this interspecies similarity, the intraspecies comparison of particle diffusivity in the mucus obtained from adult pigs vs. 2-week old piglets showed better penetrability of the piglet mucus. The mean Stokes-Einstein viscosity of the piglet jejunal mucus was approx. two times lower than the viscosity of the pig jejunal mucus (P < 0.05). All mucus structures were also visualised by scanning electron microscopy. This work validates the use of porcine small intestinal mucus collected from fully-grown pigs for studying colloidal transport of sub-micron sized particles in mucus under conditions mimicking the adult human small intestinal environment.

Anthocyanins decrease the internalization of TiO2 nanoparticles into 3D Caco-2 spheroids.

The influence of food components on nanoparticle (NP) internalization indicates a need to investigate the behaviors of NPs in a complex system. This study measured the changes of TiO2 NP colloidal stability and quenching of anthocyanin fluorescence to indicate NP-anthocyanin interactions, and cytotoxicity, oxidative stress, expression of ABC transporters and intracellular Ti concentrations in 3D Caco-2 spheroids co-exposed to NPs and anthocyanins to indicate the influence of anthocyanins on NP bio-effects. The anthocyanins were observed to have minimal impacts on colloidal properties of TiO2 NPs. Meanwhile, NP-anthocyanin co-exposure did not induce cytotoxicity or oxidative stress. The fluorescence quenching study indicated the binding of anthocyanins onto TiO2 NPs, and the binding affinity was inversely correlated with NP internalization into 3D Caco-2 spheroids. This may be partially related with the up-regulation of ABC transporters. Our results may provide novel insights into understanding the interactions of NPs and anthocyanins with human intestinal cells.

Poloxamer-407 thickened lipid colloidal system of agomelatine for brain targeting: Characterization, brain pharmacokinetic study and behavioral study on Wistar rats.

The current study was designed to enhance the brain bioavailability and to extract maximum therapeutic benefit from a novel antidepressant drug, agomelatine. For this purpose, a thermoresponsive in situ gel was prepared by dissolving 20% w/v of Poloxamer-407 in agomelatine containing nanoemulsion. To impart mucoadhesive property, 0.5% w/v concentration of chitosan was ensured in the final formulation, named as Ago-NE-gel+0.5%chitosan. The gelling point and mucoadhesive strength of Ago-NE-gel+0.5%chitosan were found to be 28 ± 1 °C, and 6246.27 dynes/cm2 respectively. The size of free micelles of Poloxamer-407 was recorded graphically at 18.43 ± 0.95 nm whereas the size of sterically stabilized Ago-NE was observed at 142.58 ± 4.21 nm. The viscosity and pH of Ago-NE-gel+0.5%chitosan were found to be 2439 ± 23 cP (at 35 ± 1 °C temperature) and 5.8 ± 0.2 respectively. The developed formulation was found safe on nasal mucosa during the toxicity study. CLSM based brain distribution study suggested that Ago-NE-gel+0.5%chitosan is more competent to deliver the drug into the brain as compared to agomelatine-suspension. After intranasal administration of Ago-NE-gel+0.5%chitosan in Wistar rats, the AUC0-8h in brain and plasma were found to be 1418.591 ± 71.87 and 473.901 ± 32.42 ng.h/ml respectively. The hypothesis conceived at the beginning of this research work was delivered as 2.82 folds enhanced bioavailability of agomelatine in the brain. The behavioral studies confirmed that the antidepressant activity of agomelatine can be improved by loading the drug into a mucoadhesive-nanoemulsion-gel system followed by its intranasal administration.

Recombinant Protein Polymers for Colloidal Stabilization and Improvement of Cellular Uptake of Diamond Nanosensors.

Fluorescent nanodiamonds are gaining increasing attention as fluorescent labels in biology in view of the fact that they are essentially nontoxic, do not bleach, and can be used as nanoscale sensors for various physical and chemical properties. To fully realize the nanosensing potential of nanodiamonds in biological applications, two problems need to be addressed: their limited colloidal stability, especially in the presence of salts, and their limited ability to be taken up by cells. We show that the physical adsorption of a suitably designed recombinant polypeptide can address both the colloidal stability problem and the problem of the limited uptake of nanodiamonds by cells in a very straightforward way, while preserving both their spectroscopic properties and their excellent biocompatibility.

Adverse effects of crystalloid and colloid fluids.

Guidelines for infusion fluid therapy rarely take into account that adverse effects occur in a dose-dependent fashion. Adverse effects of crystalloid fluids are related to their preferential distribution to the interstitium of the subcutis, the gut, and the lungs. The gastrointestinal recovery time is prolonged by 2 days when more than 2 litres is administered. Infusion of 6-7 litres during open abdominal surgery results in poor wound healing, pulmonary oedema, and pneumonia. There is also a risk of fatal postoperative pulmonary oedema that might develop several days after the surgery. Even larger amounts cause organ dysfunction by breaking up the interstitial matrix and allowing the formation of lacunae of fluid in the skin and central organs, such as the heart. Adverse effects of colloid fluids include anaphylactic reactions, which occur in 1 out of 500 infusions. The possibility that hydroxyethyl starch causes kidney injury in patients other than those with sepsis is still unclear. For both crystalloid and colloid fluids, coagulation becomes impaired when the induced haemodilution has reached 40%. Coagulopathy is aggravated by co-existing hypothermia. Although oedema can occur from both crystalloid and colloid fluids, these differ in pathophysiology. To balance fluid-induced adverse effects, this review suggests that a colloid fluid is indicated when the infused crystalloid volume exceeds 3-4 litres, plasma volume support is still needed, and the transfusion of blood products is not yet indicated.

Chitosan Tethered Colloidal Gold Nanospheres for Drug Delivery Applications.

Gold Nanospheres (AuNS) have been widely explored as an emerging system for various biomedical applications including drug delivery, bioimaging and photomedicine. However, method of synthesizing nanoparticles and its toxicity including bioaccumulation has been a problem of concern. In the present study, we explored the appropriateness of 12.0 ±1.99 nm chitosan reduced AuNS in vivo models with respect to its bioavailability and toxicity against various concentrations (2.5-7.5 mg/kg). Administration of AuNS did not show any signs of morbidity. Inductively coupled plasma optical emission spectrometry (ICP-OES) analysis of blood (0.156 ± 0.154), urine (0.084 ± 0.08) and tissues indicates gradual dissipation and obligatory clearance within 24 h time interval. Nevertheless, pres- ence of AuNS in blood after 24 h confirms the bioavailability of AuNS demonstrating the evidence for no immune clearance and efficient tissue uptake. Further, brain shows the lowest quantity of injected AuNS. From this result, we determine this chitosan monolayer protected AuNS could cross the blood brain barrier and enter to the neural tissues. Interestingly there was no evidence of toxicity in any of the organs. In conclusion, our data suggest that AuNS injected though tail vain were easily taken up by tissues and does not produce sub-acute physiological damage even at high concentrations tested, supporting chitosan reduced AuNS as biocompatible, nontoxic nanoconjugates for targeted drug delivery and other biomedical applications.

Modeled Analysis of Entrance of Colloid Suspensions into the Middle Ear Cavity.

Otic suspensions have a positive effect on the duration of otorrhea in children with a tympanostomy tube. It is still questionable how eardrops reach the middle ear. We hypothesized that otic suspensions do not pass the tympanostomy tube if the middle ear is dry but pass by diffusion when wet. The median concentration of Evans blue (colorant) in the middle ear was <15.6 mg/mL (lower limit of quantification) when diffusion was impossible but 45.3 µg/mL when diffusion was possible (P = .01). When the outward flow was increased to 0.1 mL/h, the concentration of Evans blue in the middle ear increased significantly (P = .03). With further-increasing outward flows, the concentration of Evans blue decreased linearly (ß = -144, P < .001, R (2) = 0.44). We conclude that diffusion is the mechanism by which otic suspensions enter the middle ear in children with tympanostomy tubes and otorrhea.

Foro de debate: seguridad de las alternativas a la transfusión alogénica en el paciente quirúrgico y/o crítico / Forum for debate: Safety of allogeneic blood transfusion alternatives in the surgical/critically ill patient

Estos últimos años han aparecido alertas de seguridad, no siempre bien sustentadas, que cuestionan el uso de algunas alternativas farmacológicas a la transfusión de sangre alogénica y/o lo restringen en indicaciones establecidas. Asistimos también a la preconización de otras alternativas, incluyendo productos hemáticos y fármacos antifibrinolíticos, sin que haya una base científica sólida que lo justifique. Por iniciativa del Grupo de Estudios Multidisciplinares sobre Autotransfusión y del Anemia Working Group España se reunió a un panel multidisciplinar de 23 expertos del área de cuidados de la salud en un foro de debate para: 1) analizar las diferentes alertas de seguridad en torno a ciertas alternativas a la transfusión; 2) estudiar los antecedentes que las han propiciado, la evidencia que las sustentan y las consecuencias que conllevan para la práctica clínica, y 3) emitir una valoración argumentada de la seguridad de cada alternativa a la transfusión cuestionada, según el uso clínico de la misma. Los integrantes del foro mantuvieron contactos por vía telemática y una reunión presencial en la que presentaron y discutieron las conclusiones sobre cada uno de los elementos examinados. Se elaboró un primer documento que fue sometido a 4 rondas de revisión y actualización hasta alcanzar un consenso, unánime en la mayoría de los casos. Presentamos la versión final del documento, aprobada por todos los miembros del panel, esperando sea de utilidad para nuestros colegas

In recent years, several safety alerts have questioned or restricted the use of some pharmacological alternatives to allogeneic blood transfusion in established indications. In contrast, there seems to be a promotion of other alternatives, based on blood products and/or antifibrinolytic drugs, which lack a solid scientific basis. The Multidisciplinary Autotransfusion Study Group and the Anemia Working Group España convened a multidisciplinary panel of 23 experts belonging to different healthcare areas in a forum for debate to: 1) analyze the different safety alerts referred to certain transfusion alternatives; 2) study the background leading to such alternatives, the evidence supporting them, and their consequences for everyday clinical practice, and 3) issue a weighted statement on the safety of each questioned transfusion alternative, according to its clinical use. The members of the forum maintained telematics contact for the exchange of information and the distribution of tasks, and a joint meeting was held where the conclusions on each of the items examined were presented and discussed. A first version of the document was drafted, and subjected to 4 rounds of review and updating until consensus was reached (unanimously in most cases). We present the final version of the document, approved by all panel members, and hope it will be useful for our colleagues

Natural colloidal P and its contribution to plant P uptake.

Phosphorus (P) bioavailability depends on its concentration and speciation in solution. Andisols and Oxisols have very low soil solution concentration of free orthophosphate, as they contain high concentrations of strongly P-sorbing minerals (Al/Fe oxyhydroxides, allophanes). Free orthophosphate is the form of P taken up by plants, but it is not the only P species present in the soil solution. Natural colloidal P (P associated with Al, Fe, and organic matter of sizes ranging from 1 to 1000 nm) constitutes an important fraction of soil solution P in these soils; however, its availability has not been considered. We measured the uptake of P by wheat (Triticum aestivum) from radiolabeled nonfiltered (colloid-containing) and 3-kDa filtered (nearly colloid-free) soil-water extracts from Andisols and Oxisols. In the Andisol extracts, P uptake was up to 5-fold higher from the nonfiltered solutions than the corresponding 3-kDa filtered solutions. In the Oxisol extract, no difference in P uptake between both solutions was observed. Also the diffusional flux of P as measured with the DGT technique was larger in the nonfiltered than in the 3-kDa filtered solutions. Our results suggest that colloidal P from Andisols is not chemically inert and contributes to plant uptake of P.

Patient-specific dosimetry for intracavitary 32P-chromic phosphate colloid therapy of cystic brain tumours.

PURPOSE: (32)P-chromic phosphate colloid treatments of astrocytoma and craniopharyngioma cystic brain tumours in paediatric patients are conventionally based on a sphere model under the assumption of uniform uptake. The aims of this study were to determine the distribution of the absorbed dose delivered by (32)P on a patient-specific basis and to evaluate the accuracy with which this can be predicted from a pretherapy administration of (99m)Tc-Sn colloid. METHODS: Three patients were treated with (32)P-chromic phosphate colloid following (99m)Tc-Sn colloid administrations. Convolution dosimetry was performed using pretherapy and posttherapy sequential SPECT imaging, and verified with EGSnrc Monte Carlo radiation transport simulations. Mean absorbed doses to the cyst wall and dose-volume histograms were also calculated and compared with those obtained by the sphere model approach. RESULTS: Highly nonuniform uptake distributions of both the (99m)Tc and (32)P colloids were observed and characterized by dose-volume histograms to the cyst wall. Mean absorbed doses delivered to the cyst wall, obtained with the convolution method, were on average 21 % (SD 18 %) and 50 % (SD 30 %) lower than those predicted by the (99m)Tc distribution and the uniform assumption of the sphere model, respectively. CONCLUSION: Absorbed doses delivered to the cyst wall by (32)P are more accurately predicted from image-based patient-specific convolution dosimetry than from simple sphere models. These results indicate the necessity to perform personalized treatment planning and verification for intracavitary irradiation of cystic brain tumours treated with radiocolloids. Patient-specific dosimetry can be used to guide the frequency and levels of repeated administrations and would facilitate data collection and comparison to support the multicentre trials necessary to progress this therapy.

Does increased tumor burden of sentinel nodes in breast cancer affect detection procedure?

Numerous studies have shown that sentinel lymph node biopsy (SLN) has a high level of detection sensitivity. Successful detection procedure depends on the amount of radioactivity and accumulation of blue dye in the SN. Our aim was to relate the differences observed in intraoperative SN presentation to tumor burden, characteristics of the primary tumor and patient attributes. Our retrospective analysis included 369 patients undergoing SLN in the Department of Gynecology of the University Hospital of Zurich within five years. Data was collected from the patients (age, BMI), the primary tumor (size, grading, hormone receptors, HER2 status) and the SNs removed (counts per second [cps], blue dye, size of nodular metastasis, extracapsular involvement, number of SNs excised). Because patients typically had more than one SN, a linear mixed-effects model was used to account for the clustering within one patient. SNs presented with significantly lower radioactivity in elderly (-1.8%/year, p < 0.001) and obese patients (-3.9%/kg/m2, p = 0.006) as well as in G3 primary tumors (p = 0.002). Radiocolloid accumulation decreased with increasing metastasis size (-6.1%/mm, p = 0.006). In conclusion the detection procedure of SNs is mainly affected by the patient's age and BMI and by nodular metastasis' size. Phagocytotic activity in the lymph node may increase radiotracer accumulation, showing the highest tracer signals in micrometastatic SNs. In large SN metastasis the lymph flow appears obstructed, reducing the axillary drainage and therefore making detection procedure difficult.

Development and evaluation of colloidal modified nanolipid carrier: application to topical delivery of tacrolimus, Part II--in vivo assessment, drug targeting, efficacy, and safety in treatment for atopic dermatitis.

In atopic dermatitis (AD), topical anti-inflammatory therapy with skin barrier restoration to prevent repeated inflammatory episodes leads to long-term therapeutic success. Tacrolimus, although effective against AD, is a challenging molecule due to low solubility, low-penetration, poor-bioavailability, and toxicity. Part I of this paper, reported novel modified nanolipid carrier system for topical delivery of tacrolimus (T-MNLC), offering great opportunity to load low-solubility drug with improved entrapment efficiency, enhanced stability and improved skin deposition. Present investigation focused on restoration of skin barrier, site-specific delivery, therapeutic effectiveness, and safety of novel T-MNLC. T-MNLC greatly enhanced occlusive properties, skin hydration potential and reduced transepidermal water loss. This might help to reduce the number of flares and better control the disease. Cutaneous uptake and drug deposition in albino rats by HPLC and confocal laser scanning microscopy revealed prominently elevated drug levels in all skin strata with T-MNLC as compared to reference. T-MNLC demonstrated efficient suppression of inflammatory responses in BALB/c mice model of AD. Safety assessment by acute and repeated-dose dermal toxicity demonstrated mild keratosis and collagenous mass infiltration at the treatment area with repeated application of reference. Interestingly, T-MNLC showed no evident toxicity exhibiting safe drug delivery. Thus, novel T-MNLC would be a safe, effective, and esthetically appealing alternative to conventional vehicles for treatment for AD.

Development and characterization of colloidal soft nano-carriers for transdermal delivery and bioavailability enhancement of an angiotensin II receptor blocker.

The purpose of this study was to develop and characterize a successful colloidal soft nano-carrier viz. microemulsion system, for the transdermal delivery of an angiotensin II receptor blocker: olmesartan medoxomil. Different microemulsion formulations were prepared. The microemulsions were characterized visually, with the polarizing microscope, and by photon correlation spectroscopy. In addition, the pH and conductivity (σ) of the formulations were measured. The type and structure of microemulsions formed were determined using conductivity measurements analysis, Freezing Differential Scanning Calorimetry (FDSC) and Diffusion-Ordered Spectroscopy (DOSY). Alterations in the molecular conformations of porcine skin were determined using Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) biophysical assessment. Olmesartan medoxomil delivery from the investigated formulations was assessed across porcine skin ex-vivo using Franz diffusion cells; the drug was analyzed by liquid chromatography mass spectroscopy (LC/MS/MS). A comparative pharmacokinetic study was done on healthy human subjects between the selected microemulsion and the commercial oral tablets. The physico-chemical and spectroscopic methods revealed the presence of water-in-oil and bicontinuous structures. Biophysical assessment demonstrated various stratum corneum (SC) changes. Olmesartan medoxomil was delivered successfully across the skin with flux achieving 3.65µgcm(-2)h(-1). Higher bioavailability compared to commercial oral tablets with a more sustainment behavior was achieved.

A comparison of the effects of preanesthetic administration of crystalloid versus colloid on intrathecal spread of isobaric spinal anesthetics and cerebrospinal fluid movement.

BACKGROUND: Movement of the cerebrospinal fluid (CSF) is one of the most important factors in determining the intrathecal spread of isobaric spinal anesthetics. Preanesthetic administration of either crystalloid or colloid immediately before spinal anesthesia (preload) may result in different CSF pulsatile movement because of their different physical properties. We examined whether preload of crystalloid versus colloid may have different effects on the intrathecal spread of isobaric spinal anesthetics as a result of their different CSF dynamics regarding its pulsatile movement. METHODS: In a clinical study of isobaric spinal anesthesia, patients were allocated into 1 of 2 groups according to preload with either crystalloid (n = 30) or colloid (n = 30) before spinal anesthesia with 0.5 isobaric tetracaine. The pulsatile movements of CSF at the L2-3 intervertebral space and midportion of the aqueduct of Sylvius were also examined by magnetic resonance images in healthy volunteers (n = 23) at 0, 30, and 60 minutes after administering either crystalloid or colloid. RESULTS: In the clinical study, the time to reach the peak sensory block level was delayed significantly in the crystalloid preload group (27.2 ± 17.8 minutes; P < 0.01) compared with the colloid preload group (13.9 ± 7.0 minutes). The median sensory block levels of the crystalloid preload group at 15 minutes (T10, P < 0.05) and 20 minutes (T9.5, P < 0.05) were significantly lower than those (T8, T7, respectively) of the colloid preload group. In the magnetic resonance imaging study, cranially directed CSF pulsatile movement decreased significantly at the L2-3 intervertebral intrathecal space at 30 minutes after crystalloid administration, but not after colloid administration. The CSF production rate significantly increased at 30 minutes (637 µL/min, P < 0.05) after crystalloid preload compared with the baseline measurement (448 µL/min), and then slightly decreased (609 µL/min) at 60 minutes. In the colloid preload group, the CSF production rate was not statistically significant compared with the baseline measurement (464, 512, and 542 µL/min at baseline, 30, and 60 minutes, respectively). CONCLUSIONS: Compared with a colloid preload, which may be comparable to the no-preload condition, crystalloid preload prolonged the time to reach the peak sensory block level in isobaric spinal anesthesia, which might have been caused by a significant decrease in CSF pulsatile movement. This attenuated CSF pulsatile movement in the crystalloid preload group might have resulted from significant increases of CSF production.

Effect of chitosan chain architecture on gene delivery: comparison of self-branched and linear chitosans.

Chitosan possesses many characteristics of an ideal gene delivery system. However, the transfection efficiency of conventional chitosans is generally found to be low. In this study, we investigated the self-branching of chitosans as a strategy to improve its gene transfer properties without compromising its safety profile. Self-branched (SB) and self-branched trisaccharide-substituted (SBTCO) chitosans with molecular weights of 11-71 kDa were synthesized, characterized, and compared with their linear counterparts with respect to transfection efficiency, cellular uptake, formulation stability, and cytotoxicity. Our studies show that in contrast with unmodified linear chitosans that were unable to transfect HeLa cells, self-branched chitosans mediated high transfection efficiencies. The most efficient chitosan, SBTCO30, yielded gene expression levels two and five times higher than those of Lipofectamine and Exgen, respectively, and was nontoxic to cells. Nanoparticles formed with SBTCO chitosans exhibited a higher colloidal stability of formulation, efficient internalization without excessive cell surface binding, and low cytotoxicity.

Revisión del estado actual y posibilidades de las aproximaciones más importantes al transporte específico de agentes quimioterápicos a las células tumorales / Review of the “state of the art” and possibilities of the most significant approaches to the specific delivery of chemotherapy agents to tumor cells

Los principales problemas de la quimioterapia proceden esencialmente de la relativa falta deespecificidad derivada de la extensa biodistribución de los agentes antitumorales y de los efectossecundarios generados por la acción inespecífica de éstos en tejidos y órganos sanos. La necesidad deencontrar tratamientos eficaces contra el cáncer ha hecho que se incrementen las líneas deinvestigación en esta materia. Una de las aproximaciones más prometedoras en este sentido es eldesarrollo de sistemas coloidales biodegradables para el transporte de fármacos antitumorales.Gracias a éstos, se logra acumular específicamente la cantidad de fármaco administrada en el lugar deacción, logrando así un aumento significativo de la eficacia clínica, junto con una minimización delas reacciones adversas asociadas. En este trabajo, pretendemos analizar el estado actual en el diseñode coloides como transportadores de fármacos antitumorales, junto con la aplicación de las novedosasestrategias de transporte pasivo y activo de fármacos(AU)

The main problems related to chemotherapy mainly come from a relative lack of selectivity, that isassociated to the extensive biodistribution of antitumor molecules, and to the severe side effectsgenerated by the unspecific drug action on healthy tissues and organs. The need of finding outefficient treatments against cancer has led to an enhancement in the number of research lines in thefield. In this way, one of the most promising approaches is the development of biodegradable colloidsfor the delivery of antitumor drugs. Thanks to them, it is possible to specifically concentrate the druginto the site of action. Therefore, a significant improvement of the chemotherapy effect is obtainedalong with a minimization of the related adverse side effects. In this review, we analyze the current“state of the art” in the development of colloidal systems for the efficient delivery of anticancerdrugs. The possibilities of novel drug delivery strategies based on passive and active targetingmechanisms are also discussed(AU)

Nanopartículas sensibles a estímulos para el transporte eficaz de fármacos a órganos y tejidos diana / Stimuli-sensitive nanoparticles for an efficient drug delivery to targeted organs and tissues

Las nanopartículas utilizadas en el transporte de fármacos pueden, en principio, alcanzar la masa tumoral de forma “pasiva” (estrategias de transporte pasivo). Sin embargo, para asegurar un efecto farmacológico óptimo debe controlarse el destino biológico del coloide transportador de fármacos. De esta manera, cualquier sistema de este tipo debe ser capaz de responder a estímulos fisiológicos o físicos, para así aumentar la acumulación del principio activo en el lugar de acción. Para ello, es necesario un adecuado control de los factores biomecánicos que regulan la liberación de fármaco y el mantenimiento de unas concentraciones plasmáticas dentro del margen terapéutico de la molécula activa. Ante esto, se han desarrollado materiales sensibles a estímulos que aseguran una biodistribución modificada del fármaco vehiculizado y, así, una farmacoterapia más eficiente. Entre las estrategias de transporte activo basadas en coloides sensibles a estímulos destacan el transporte activo de fármacos controlado por entornos (pHs) ácidos, hipertermia, gradientes magnéticos, luz, sistemas enzimáticos y ultrasonidos. Se espera que su introducción en clínica permita mejorar significativamente la actividad farmacológica de los principios activos. Si bien se han logrado resultados preclínicos muy prometedores, el futuro de esta estrategia depende de un mayor conocimiento sobre la estabilidad, fisicoquímica, toxicidad y destino biológico de estos coloides(AU)

Nanoparticulate drug delivery systems can in principle passively target tumors. However, in order to assure an optimal drug activity, it is needed the control of the biological fate of the colloid. Thus, drug carriers should be capable of responding to physiological or physical stimuli, as well as able to enhance the delivery of active agents to targeted tissues. This involves the need for an effective drug transport into the site of action, an adequate control of the biochemical factors regulating drug release, and the maintenance of drug levels under the minimum toxic concentration. Special approaches based on stimuli-sensitive materials are expected to assure the modification of the biodistribution of loaded drugs and, thus, resulting in a more efficient pharmacotherapy. The main objective of this work is to analyze the most important approaches in the formulation of stimuli-sensitive materials for active drug targeting to the specific site of action. Stimuli-sensitive drug carriers can alter their physical properties (swelling/deswelling, disruption/aggregation, etc.) under exposure to a stimulus. This property is widely used to trigger drug release at the targeted site, but can also be utilized to accumulate the drug at the non-healthy tissue or cell before allowing its release (e.g., magnetically responsive carriers). In both cases, the systemic distribution of the drug is minimized (and, subsequently, the undesired side effects), meanwhile its therapeutic activity is enhanced. Very promising active targeting strategies involving the use of stimuli-sensitive carriers include acid-triggered drug release, hyperthermia-induced drug delivery, magnetic drug targeting, light-triggered drug release, enzyme-triggered drug release, and ultrasound mediated delivery(AU)

The introduction of the wide variety of stimuli-sensitive strategies in clinic is expected to significantly enhance the pharmacotherapy. Even though the very promising preclinical results, the future of the strategy will depend on a better understanding of the stability, physicochemistry, toxicity, and biological fate of such kind of colloids(AU)

Diseño de coloides para el transporte específico de fármacos a células diana mediante procesos de reconocimiento molecular / Formulation of drug nanocarriers to target cells by molecular recognition processes

Los agentes quimioterápicos utilizados en la actualidad tienen una especificad muy escasa por las células malignas, lo que reduce su eficacia clínica y aumenta la incidencia de reacciones adversas severas. Se han investigado diferentes soluciones para este problema, p. ej., la introducción de modificaciones químicas en la estructura molecular del antitumoral y el desarrollo de coloides para el transporte de principios activos. Así se pretende aumentar la localización/acumulación del fármaco en la masa tumoral y, de esta forma, la eficacia anticancerosa, junto con una minimización de la incidencia y severidad de los efectos adversos. Esta última estrategia sólo logra aumentar la eficacia de la quimioterapia en el tratamiento de tumores asociados al sistema fagocítico mononuclear. Recientemente, el transporte activo de fármacos basado en procesos de reconocimiento molecular (transporte mediado por ligandos) ha recibido especial interés en el tratamiento del cáncer. En este trabajo investigamos las estrategias más importantes de transporte de fármacos basadas en procesos de reconocimiento molecular, analizando sus posibilidades reales en clínica(AU)

Conventional chemotherapy relies on the premise that rapidly proliferating cancer cells should be easily killed by a chemotherapy agent. However, these molecules have almost negligible specificity, resulting in very low activity, and severe side effects. In order to beat this challenge, several approaches, e.g., chemical modifications and development of colloids for drug delivery, have been proposed to improve drug localization at the tumor region and, hence, to increase anti-tumor efficacy, while reducing systemic side effects. The latter strategy has merely led to improved chemotherapy in tumors located in the mononuclear phagocyte system (MPS). Recently, the formulation of colloids foractive drug targeting through molecular recognition processes (ligand-mediated drug delivery) has gained important attention for the delivery of anticancer drugs to tumors. In this work we investigate the most significant strategies for drug targeting to specific tissues based on molecular recognition processes. Additionally, we carefully analyze the real possibilities of such nanostrategy in drug delivery(AU)

Colloidal DNA carriers for direct localization in cell compartments by pH sensoring.

Multifunctional colloidal microparticles allow the integration of various active agents as well as reporter molecules into one system without interfering combining delivery and sensing functions. In this study, calcium carbonate particles were functionalized with fluorescein isothiocyanate-labeled poly(allylamine hydrochloride) (FITC-PAH) allowing particle localization in cell compartments of different pH. Plasmid DNA (pEGFP-C1 and pDsRed1-N1) as a reporter agent for drug release in the cytoplasm and rhodamine-B-isothiocyanate-labeled protamine (RITC-PRM) were integrated into biocompatible and biodegradable PRM/DXS multilayers. The uptake and processing of the particles by HEK293T/17 cells were investigated via flow cytometry and confocal laser scanning microscopy. The presented data show a clear correlation between the fluorescence intensity of the FITC-labeled core, that is, the particle localization after cellular uptake, and the expression of fluorescent proteins by the cells without further cell staining. In conclusion, this particle design allows the simultaneous study of particle location and processing to monitor the transport and release of active agents and should thus be an invaluable tool for the study and design of nano- and microcarrier systems.

Skin efficacy and biophysical assessment of glycerol-containing hydrocolloid patches.

Hydrocolloid patches are developed with 10, 20 and 30% (w/w) glycerol as the main active ingredient. By making use of two experimental forearm models, skin efficacy and its dependency on the glycerol concentration applied were compared with a blank reference patch, a commercialized protective patch and a cosmetic barrier cream. Skin hydration and transepidermal water loss measurements were combined with skin erythema assessments. After a single application to healthy skin, a clear concentration-dependent effect of glycerol-containing patches was observed with - for the highest glycerol content - a 31% increase in skin hydration and an improvement in skin barrier properties of 15%. This glycerol-containing patch also accelerated barrier recovery of mechanically irritated skin after stripping with cyanoacrylate tape. After 7 days of repetitive application, a significantly hydrating effect of the 30% glycerol-containing patch was observed, which was of the same order of magnitude as observed for the cosmetic barrier cream, the latter being applied twice daily. The effects seen were maximal after 3 days of patch application.