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1.
Nano Lett ; 18(10): 6449-6454, 2018 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-30211557

RESUMEN

mRNA therapeutics hold great potential for treating a variety of diseases through protein-replacement, immunomodulation, and gene editing. However, much like siRNA therapy the majority of progress in mRNA delivery has been confined to the liver. Previously, we demonstrated that poly(ß-amino esters), a class of degradable polymers, are capable of systemic mRNA delivery to the lungs in mice when formulated into nanoparticles with poly(ethylene glycol)-lipid conjugates. Using experimental design, a statistical approach to optimization that reduces experimental burden, we demonstrate herein that these degradable polymer-lipid nanoparticles can be optimized in terms of polymer synthesis and nanoparticle formulation to achieve a multiple order-of-magnitude increase in potency. Furthermore, using genetically engineered Cre reporter mice, we demonstrate that mRNA is functionally delivered to both the lung endothelium and pulmonary immune cells, expanding the potential utility of these nanoparticles.


Asunto(s)
Endotelio/efectos de los fármacos , Pulmón/efectos de los fármacos , Nanopartículas/administración & dosificación , ARN Interferente Pequeño/administración & dosificación , Animales , Endotelio/inmunología , Endotelio/patología , Técnicas de Transferencia de Gen , Humanos , Lípidos/administración & dosificación , Lípidos/química , Pulmón/inmunología , Pulmón/patología , Ratones , Nanopartículas/química , Polietilenglicoles/química , Polímeros/química , ARN Mensajero/química , ARN Mensajero/genética , ARN Interferente Pequeño/química , ARN Interferente Pequeño/genética
2.
Angew Chem Int Ed Engl ; 55(44): 13808-13812, 2016 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-27690187

RESUMEN

Therapeutic nucleic acids hold great promise for the treatment of disease but require vectors for safe and effective delivery. Synthetic nanoparticle vectors composed of poly(ß-amino esters) (PBAEs) and nucleic acids have previously demonstrated potential utility for local delivery applications. To expand this potential utility to include systemic delivery of mRNA, hybrid polymer-lipid nanoformulations for systemic delivery to the lungs were developed. Through coformulation of PBAEs with lipid-polyethylene glycol (PEG), mRNA formulations were developed with increased serum stability and increased in vitro potency. The formulations were capable of functional delivery of mRNA to the lungs after intravenous administration in mice. To our knowledge, this is the first report of the systemic administration of mRNA for delivery to the lungs using degradable polymer-lipid nanoparticles.


Asunto(s)
Lípidos/química , Pulmón/química , Nanopartículas/química , Polímeros/química , ARN Mensajero/química , Administración Intravenosa , Animales , Ratones , Estructura Molecular , Tamaño de la Partícula , Polímeros/administración & dosificación , ARN Mensajero/administración & dosificación , ARN Mensajero/síntesis química , Propiedades de Superficie
3.
J Drug Target ; 27(3): 229-243, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-29415575

RESUMEN

Over the last century, there has been a dramatic change in the nature of therapeutic, biologically active molecules available to treat disease. Therapies have evolved from extracted natural products towards rationally designed biomolecules, including small molecules, engineered proteins and nucleic acids. The use of potent drugs which target specific organs, cells or biochemical pathways, necessitates new tools which can enable controlled delivery and dosing of these therapeutics to their biological targets. Here, we review the miniaturisation of drug delivery systems from the macro to nano-scale, focussing on controlled dosing and controlled targeting as two key parameters in drug delivery device design. We describe how the miniaturisation of these devices enables the move from repeated, systemic dosing, to on-demand, targeted delivery of therapeutic drugs and highlight areas of focus for the future.


Asunto(s)
Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Preparaciones de Acción Retardada , Humanos , Nanoestructuras , Tamaño de la Partícula , Preparaciones Farmacéuticas/administración & dosificación
4.
Regen Med ; 10(8): 989-1003, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26628407

RESUMEN

Although the importance of translation for the development of tissue engineering, regenerative medicine and cell-based therapies is widely recognized, the process of translation is less well understood. This is particularly the case among some early career researchers who may not appreciate the intricacies of translational research or make decisions early in development which later hinders effective translation. Based on our own research and experiences as early career researchers involved in tissue engineering and regenerative medicine translation, we discuss common pitfalls associated with translational research, providing practical solutions and important considerations which will aid process and product development. Suggestions range from effective project management, consideration of key manufacturing, clinical and regulatory matters and means of exploiting research for successful commercialization.


Asunto(s)
Selección de Profesión , Tratamiento Basado en Trasplante de Células y Tejidos , Medicina Regenerativa , Ingeniería de Tejidos , Investigación Biomédica Traslacional , Humanos
5.
Biomaterials ; 61: 257-65, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26005764

RESUMEN

Cardiomyocytes from human stem cells have applications in regenerative medicine and can provide models for heart disease and toxicity screening. Soluble components of the culture system such as growth factors within serum and insoluble components such as the substrate on which cells adhere to are important variables controlling the biological activity of cells. Using a combinatorial materials approach we develop a synthetic, chemically defined cellular niche for the support of functional cardiomyocytes derived from human embryonic stem cells (hESC-CMs) in a serum-free fully defined culture system. Almost 700 polymers were synthesized and evaluated for their utility as growth substrates. From this group, 20 polymers were identified that supported cardiomyocyte adhesion and spreading. The most promising 3 polymers were scaled up for extended culture of hESC-CMs for 15 days and were characterized using patch clamp electrophysiology and myofibril analysis to find that functional and structural phenotype was maintained on these synthetic substrates without the need for coating with extracellular matrix protein. In addition, we found that hESC-CMs cultured on a co-polymer of isobornyl methacrylate and tert-butylamino-ethyl methacrylate exhibited significantly longer sarcomeres relative to gelatin control. The potential utility of increased structural integrity was demonstrated in an in vitro toxicity assay that found an increase in detection sensitivity of myofibril disruption by the anti-cancer drug doxorubicin at a concentration of 0.05 µM in cardiomyocytes cultured on the co-polymer compared to 0.5 µM on gelatin. The chemical moieties identified in this large-scale screen provide chemically defined conditions for the culture and manipulation of hESC-CMs, as well as a framework for the rational design of superior biomaterials.


Asunto(s)
Técnicas de Cultivo Celular por Lotes/métodos , Materiales Biocompatibles/síntesis química , Miocitos Cardíacos/citología , Miocitos Cardíacos/fisiología , Células Madre/citología , Células Madre/fisiología , Adhesión Celular/fisiología , Diferenciación Celular/fisiología , Línea Celular , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Técnicas Químicas Combinatorias , Medio de Cultivo Libre de Suero , Humanos , Ensayo de Materiales/métodos , Polímeros/síntesis química
6.
Adv Mater ; 27(27): 4006-12, 2015 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-26033422

RESUMEN

A scalable and cost-effective synthetic polymer substrate that supports robust expansion and subsequent multilineage differentiation of human pluripotent stem cells (hPSCs) with defined commercial media is presented. This substrate can be applied to common cultureware and used off-the-shelf after long-term storage. Expansion and differentiation of hPSCs are performed entirely on the polymeric surface, enabling the clinical potential of hPSC-derived cells to be realized.


Asunto(s)
Técnicas de Cultivo de Célula/instrumentación , Diferenciación Celular/fisiología , Células Madre Pluripotentes/fisiología , Polímeros , Adhesión Celular/fisiología , Línea Celular , Linaje de la Célula , Medios de Cultivo , Técnica del Anticuerpo Fluorescente , Ensayos Analíticos de Alto Rendimiento , Humanos , Análisis por Micromatrices
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