A microfluidic platform for combinatorial synthesis and optimization of targeted polymeric nanoparticles for cancer therapy

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2013."November 2012." Cataloged from PDF version of thesis.Includes bibliographical references.The use of nanotechnology to engineer drug delivery vehicles comprised of controlled release polymers with targeting molecules has the potential to revolutionize cancer therapy, among other diseases. Although a myriad of nanotherapeutics have been developed at the bench side, many of them stay at the research stage due to their complexity and difficulty in their optimization. A key challenge for optimization of nanoparticles (NPs) for drug delivery is the ability to systematically and combinatorially create and screen libraries of NPs with distinct physicochemical properties, from which promising formulations can be moved forward to preclinical and clinical studies. In this work, the development of a controlled method to synthesize libraries of NPs with distinct properties is described. The procedure uses a microfluidic platform that rapidly mixes reagents and provides homogeneous reaction environments, resulting in the reproducible, single-step synthesis of NPs with well-defined properties and narrow size distributions. The microfluidic system is composed of a mixing unit and a NP assembly unit. The mixing unit consists of a multi-inlet, 2-layer mixer where different precursors such as polymers of different MW and charge, ligand- and drug-conjugated polymers, free drugs, and solvents are mixed at different ratios into a homogenous solution. In the assembly unit, the precursor solution is quickly mixed with an anti-solvent (i.e. water) using 3D hydrodynamic flow focusing where NPs self-assemble after complete mixing. With the microfluidic platform, a library of 100 NPs with different sizes (15-200nm), charge (-30 to +30mV), surface chemistry (i.e. PEG coverage), surface ligand density (0-2.510⁵ ligands/[mu]m²), and drug loading (0-5 w/w%) was producedd in a high-throughput manner by simply varying the flow ratios of precursors entering the system. This library was implemented for (i) screening for formulations (in vitro and in vivo) with optimal clinical properties for cancer treatment and (ii) deepening the understanding of how NP properties affect their biological behavior. The platform developed in this work would likely lead to better understanding of the design parameters for polymeric NPs and their smoother transition to the clinic.by Pedro M. Valencia.Ph.D

Participación Social y Priorización de Proyectos de Inversión Pública en Lima Metropolitana, 2015

El objetivo general de esta investigación fue determinar la relación existente entre la participación social y la priorización de proyectos de inversión pública en Lima Metropolitana, 2015. La población estuvo conformada por 170 agentes participantes debidamente inscritos al proceso del Presupuesto Participativo 2015 de Lima Metropolitana. El método empleado fue el hipotético-deductivo, el diseño seleccionado fue de tipo no experimental. El estudio se caracterizó por ser de nivel correlacional, de corte transversal. La técnica aplicada fue la encuesta y el instrumento fue el cuestionario de preguntas: Cuestionario de la participación social, constituida por 20 preguntas en escala de Likert; y el cuestionario de proyectos de inversión pública, constituida por 20 preguntas en escala de Likert. Los instrumentos seleccionados nos permitieron recoger y analizar información acerca de la participación social en la elaboración y selección de proyectos de inversión pública. Aspectos que han sido analizados dimensionalmente en el capítulo de resultados. Concluida el estudio resulta pertinente señalar que existe evidencia para afirmar que la participación social se relaciona significativamente con la priorización de los proyectos de inversión en Lima Metropolitana, 2015, habiéndose encontrado un coeficiente de correlación Rho Spearman de 0,829, lo que significa que existe una alta relación positiva entre las variables

Microfluidic technologies for accelerating the clinical translation of nanoparticles

Using nanoparticles for therapy and imaging holds tremendous promise for the treatment of major diseases such as cancer. However, their translation into the clinic has been slow because it remains difficult to produce nanoparticles that are consistent 'batch-to-batch', and in sufficient quantities for clinical research. Moreover, platforms for rapid screening of nanoparticles are still lacking. Recent microfluidic technologies can tackle some of these issues, and offer a way to accelerate the clinical translation of nanoparticles. In this Progress Article, we highlight the advances in microfluidic systems that can synthesize libraries of nanoparticles in a well-controlled, reproducible and high-throughput manner. We also discuss the use of microfluidics for rapidly evaluating nanoparticles in vitro under microenvironments that mimic the in vivo conditions. Furthermore, we highlight some systems that can manipulate small organisms, which could be used for evaluating the in vivo toxicity of nanoparticles or for drug screening. We conclude with a critical assessment of the near- and long-term impact of microfluidics in the field of nanomedicine.Prostate Cancer Foundation (Award in Nanotherapeutics)MIT-Harvard Center for Cancer Nanotechnology Excellence (U54-CA151884)National Heart, Lung, and Blood Institute (Programs of Excellence in Nanotechnology (HHSN268201000045C))National Science Foundation (U.S.) (Graduate Research Fellowship

Mejoramiento e implementación de plan de mantenimiento preventivo para mejorar la confiabilidad y reducir los gastos de mantenimiento en el área de acabados de la empresa Iberoplast

En la presente tesis se utiliza la metodología RCM (mantenimiento basado en la confiabilidad) para mejorar la confiabilidad de las máquinas y reducir los gastos de mantenimiento en el área de acabados de la empresa Iberoplast, para ello se tiene que seguir una serie de pasos indicados. Lo primero que se realizó fue verificar los indicadores de mantenimiento actuales del área de acabados com son la disponibilidad, confiabilidad, MTTR, MTBF, además se verifico los gastos de mantenimiento para tener un panorama más amplio del estado de las maquinarias y ver en qué actividades de mantenimiento se gasta más. Luego se identificó las maquinas con índice de confiabilidad bajo y en ella nos centramos para aplicar esta metodología, analizando sus fallas mediante diagramas de Pareto, además de clasificar cada máquina por sistemas y partes. Se pudo redactar las tareas para un plan de mantenimiento preventivo basándonos en los manuales de las máquinas, las experiencias del personal técnico que labora en dicha área y la experiencia propia. Se elaboró un cronograma de actividades para aplicar dichas tareas dándose como punto de partida el mes de junio del año 2021, con esto se obtuvieron los indicadores de mantenimiento de dicho mes y finalmente se pudieron comparar los resultados obtenidos, de igual forma se realizó para comparar los gastos generador por el nuevo plan de mantenimiento a comparación del plan antiguo

Effects of ligands with different water solubilities on self-assembly and properties of targeted nanoparticles

The engineering of drug-encapsulated targeted nanoparticles (NPs) has the potential to revolutionize drug therapy. A major challenge for the smooth translation of targeted NPs to the clinic has been developing methods for the prediction and optimization of the NP surface composition, especially when targeting ligands (TL) of different chemical properties are involved in the NP self-assembly process. Here we investigated the self-assembly and properties of two different targeted NPs decorated with two widely used TLs that have different water solubilities, and developed methods to characterize and optimize NP surface composition. We synthesized two different biofunctional polymers composed of poly(lactide-co-glycolide)-b-polyethyleneglycol-RGD (PLGA-PEG-RGD, high water solubility TL) and PLGA-PEG-Folate (low water solubility TL). Targeted NPs with different ligand densities were prepared by mixing TL-conjugated polymers with non-conjugated PLGA-PEG at different ratios through nanoprecipitation. The NP surface composition was quantified and the results revealed two distinct nanoparticle assembly behaviors: for the case of PLGA-PEG-RGD, nearly all RGD molecules conjugated to the polymer were found to be on the surface of the NPs. In contrast, only ~20% of the folate from PLGA-PEG-Folate was present on the NP surface while the rest remained presumably buried in the PLGA NP core due to hydrophobic interactions of PLGA and folate. Finally, in vitro phagocytosis and cell targeting of NPs were investigated, from which a window of NP formulations exhibiting minimum uptake by macrophages and maximum uptake by targeted cells was determined. These results underscore the impact that the ligand chemical properties have on the targeting capabilities of self-assembled targeted nanoparticles and provide an engineering strategy for improving their targeting specificity.Prostate Cancer Foundation (Award in Nanotherapeutics)National Cancer Institute (U.S.) (Center of Cancer Nanotechnology Excellence at MIT-Harvard U54-CA151884)National Heart, Lung, and Blood Institute (Program of Excellence in Nanotechnology Award Contract HHSN268201000045C)National Science Foundation (U.S.). Graduate Research Fellowshi

Parallel microfluidic synthesis of size-tunable polymeric nanoparticles using 3D flow focusing towards in vivo study

Microfluidic synthesis of nanoparticles (NPs) can enhance the controllability and reproducibility in physicochemical properties of NPs compared to bulk synthesis methods. However, applications of microfluidic synthesis are typically limited to in vitro studies due to low production rates. Herein, we report the parallelization of NP synthesis by 3D hydrodynamic flow focusing (HFF) using a multilayer microfluidic system to enhance the production rate without losing the advantages of reproducibility, controllability, and robustness. Using parallel 3D HFF, polymeric poly(lactide-co-glycolide)-b-polyethyleneglycol (PLGA-PEG) NPs with sizes tunable in the range of 13-150 nm could be synthesized reproducibly with high production rate. As a proof of concept, we used this system to perform in vivo pharmacokinetic and biodistribution study of small (20 nm diameter) PLGA-PEG NPs that are otherwise difficult to synthesize. Microfluidic parallelization thus enables synthesis of NPs with tunable properties with production rates suitable for both in vitro and in vivo studies

A coarse-grained approach to model the dynamics of the actomyosin cortex

Background: The dynamics of the actomyosin machinery is at the core of many important biological processes. Several relevant cellular responses such as the rhythmic compression of the cell cortex are governed, at a mesoscopic level, by the nonlinear interaction between actin monomers, actin crosslinkers, and myosin motors. Coarse-grained models are an optimal tool to study actomyosin systems, since they can include processes that occur at long time and space scales, while maintaining the most relevant features of the molecular interactions. Results: Here, we present a coarse-grained model of a two-dimensional actomyosin cortex, adjacent to a three-dimensional cytoplasm. Our simplified model incorporates only well-characterized interactions between actin monomers, actin crosslinkers and myosin, and it is able to reproduce many of the most important aspects of actin filament and actomyosin network formation, such as dynamics of polymerization and depolymerization, treadmilling, network formation, and the autonomous oscillatory dynamics of actomyosin. Conclusions: We believe that the present model can be used to study the in vivo response of actomyosin networks to changes in key parameters of the system, such as alterations in the attachment of actin filaments to the cell corte

Persistent right aortic arch in peruvian hairless dog - a case report

Un canino de la raza Perro sin Pelo del Perú, de dos meses de edad, fue atendido con historia de regurgitación por un mes y pérdida progresiva de su condición corporal desde el destete. Al examen clínico presentó un estado de alerta y baja condición corporal. El paciente recibió tratamiento de sostén y se le realizó estudios imagenológicos, radiografía cervical, torácica y esofagografía, evidenciando una dilatación de esófago craneal al corazón. Se realizó la eutanasia a solicitud del propietario. En el examen anatomopatológico, se evidenció la persistencia del cuarto arco aórtico derecho y un ligamento arterioso que unía la arteria pulmonar a la aorta anómala formando un anillo vascular que produjo el desarrollo de cambios anatomopatológicos secundarios comunes a esta alteración en esófago y tráquea. Este caso constituye el primer reporte de un defecto congénito cardiovascular en el Perro sin Pelo del Perú.A Peruvian Hairless puppy dog, two months old, presented a history of regurgitation for a month and progressive loss of body condition since weaning. Clinical examination showed an alert status and poor body condition. The patient received supportive treatment and imagenologic studies were taken: cervical and thoracic radiography, and esophagography, indicating a dilated oesophagus cranial to the heart. Euthanasia was performed at the request of the owner. The animal was subjected to pathological examination, showing the persistence of the fourth right aortic arch and ligament arteriosum that joined the pulmonary artery to the anomalous aorta forming a vascular ring, which resulted in the development of pathological changes, secondary to this alteration in the esophagus and trachea. This case represents the first report of a congenital cardiovascular defect in the Peruvian Hairless Dog

PanDrugs: a novel method to prioritize anticancer drug treatments according to individual genomic data

BACKGROUND: Large-sequencing cancer genome projects have shown that tumors have thousands of molecular alterations and their frequency is highly heterogeneous. In such scenarios, physicians and oncologists routinely face lists of cancer genomic alterations where only a minority of them are relevant biomarkers to drive clinical decision-making. For this reason, the medical community agrees on the urgent need of methodologies to establish the relevance of tumor alterations, assisting in genomic profile interpretation, and, more importantly, to prioritize those that could be clinically actionable for cancer therapy. RESULTS: We present PanDrugs, a new computational methodology to guide the selection of personalized treatments in cancer patients using the variant lists provided by genome-wide sequencing analyses. PanDrugs offers the largest database of drug-target associations available from well-known targeted therapies to preclinical drugs. Scoring data-driven gene cancer relevance and drug feasibility PanDrugs interprets genomic alterations and provides a prioritized evidence-based list of anticancer therapies. Our tool represents the first drug prescription strategy applying a rational based on pathway context, multi-gene markers impact and information provided by functional experiments. Our approach has been systematically applied to TCGA patients and successfully validated in a cancer case study with a xenograft mouse model demonstrating its utility. CONCLUSIONS: PanDrugs is a feasible method to identify potentially druggable molecular alterations and prioritize drugs to facilitate the interpretation of genomic landscape and clinical decision-making in cancer patients. Our approach expands the search of druggable genomic alterations from the concept of cancer driver genes to the druggable pathway context extending anticancer therapeutic options beyond already known cancer genes. The methodology is public and easily integratable with custom pipelines through its programmatic API or its docker image. The PanDrugs webtool is freely accessible at http://www.pandrugs.org .The authors thank Joaquín Dopazo, Patricia León, and José Carbonell for kindly providing the modelled pathways employed in PanDrugs implementation; and Michael Tress for his helpful comments and suggestions in the earlier version of the manuscript.S