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Overview | Gene delivery controlled by redox potential gradients | Layer-by-layer DNA films for gene delivery | Stimulus-controlled drug delivery from nanoporous inorganic nanoparticles Research Macromolecular and nano- and microparticle systems used for systemic delivery of traditional small molecule drugs and modern biotech macromolecular drugs evolved immensely in the last decade. This resulted in number of successful clinical applications and even more interest in this class of delivery systems. The use of the macromolecular and particulate delivery systems, however, creates a new set of challenges that are related to their relatively large size. Irrespective of the size, a drug must safely reach its target cell and the appropriate location within the target cell to achieve the desired therapeutic effect. Small molecule drugs are transported freely and enter cells by diffusion and reaching the desired subcellular location is often fairly straightforward. Unlike small molecule drugs, transport of macromolecules and particles is severely restricted due to their large size. Efficient delivery of therapeutic molecules to designated cells and subcellular locations therefore greatly relies upon successful passage across biological membranes. While it is often possible to design delivery systems with improved efficiency of their transport across a single selected barrier, it has become apparent that different biophysical and biological properties are required to successfully overcome each of the barriers faced during the delivery. One of the most promising approaches to overcome the difficulties with multiple barriers is to design stimulus-responsive delivery vectors capable of changing their properties and behavior. Variety of external and endogenous stimuli can be utilized to improve overall efficiency of delivery systems. While the external stimuli are by nature physical (ultrasound, heat, magnetic field, light), the endogenous ones offer a wider variety ranging from simple chemical stimuli to complex biochemical stimuli. Irrespective of its nature, a given stimulus can improve the delivery efficiency by one of three distinct mechanisms. First, a stimulus can be used to facilitate spatial and temporal control of the release of therapeutic agents from the delivery system. Examples of successfully used stimuli to release nucleic acids from polyplexes include pH gradient and redox potential gradient. Second, a stimulus can be used to alter properties of the delivery systems and thus allow overcoming selected barriers. This approach is relatively less investigated than the first one and can be based on both external and endogenous stimuli (heat, ultrasound, pH gradient, redox potential gradient). An example of such an approach is to use hyperthermia to improve transfection activity. Third, a stimulus can be used to favorably alter physiological properties of target tissues to increase the efficiency of polyplexes. This approach creates potential risks as well as benefits and is limited to external stimuli such as acoustic cavitation. Our research applies interdisciplinary approach to the design of "smart" nanosized delivery systems (also called nanotherapeutics) that are capable of changing their properties and behavior in response to a variety of endogenous and external stimuli. Here are some projects that are currently pursued in the lab.
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