Targeted, noninvasive neuromodulation of the brain of an otherwise awake subject could revolutionize both basic and clinical neuroscience. Toward this goal, we have developed nanoparticles that allow noninvasive uncaging of a neuromodulatory drug, in this case the small molecule anesthetic propofol, upon the application of focused ultrasound. These nanoparticles are composed of biodegradable and biocompatible constituents and are activated using sonication parameters that are readily achievable by current clinical transcranial focused ultrasound systems. These particles are potent enough that their activation can silence seizures in an acute rat seizure model. Notably, there is no evidence of brain parenchymal damage or blood-brain barrier opening with their use. Further development of these particles promises noninvasive, focal, and image-guided clinical neuromodulation along a variety of pharmacological axes.

Introduction: Gene delivery technologies are being developed for an increasing number of biomedical applications, with delivery vehicles including viruses and non-viral materials. Among biomaterials used for non-viral gene delivery, poly(beta-amino ester)s (PBAEs), a class of synthetic, biodegradable polymers, have risen as a leading gene delivery vehicle that has been used for multiple applications in vitro and in vivo.Areas covered: This review summarizes the key properties of PBAEs and their development, including a discussion of the advantages and disadvantages of PBAEs for gene delivery applications. The use of PBAEs to improve the properties of other drug delivery vehicles is also summarized. Expert opinion:PBAEs are designed to have multiple characteristics that are ideal for gene delivery, including their reversible positive charge, which promotes binding to nucleic acids as well as imparting high buffering capacity, and their rapid degradability under mild conditions. Simultaneously, some of their properties also lead to nanoparticle instability and low transfection efficiency in physiological environments. The ease with which PBAEs can be chemically modified

Growing evidence shows that cancer cells use mRNA-binding proteins and miRNAs to posttranscriptionally regulate signaling pathways to adapt to harsh tumor microenvironments. In ovarian cancer, cytoplasmic accumulation of mRNA-binding protein HuR (ELAVL1) is associated with poor prognosis. In this study, we observed high HuR expression in ovarian cancer cells compared with ovarian primary cells, providing a rationale for targeting HuR. RNAi-mediated silencing of HuR in ovarian cancer cells significantly decreased cell proliferation and anchorage-independent growth, and impaired migration and invasion. In addition, HuR-depleted human ovarian xenografts were smaller than control tumors. A biodistribution study showed effective tumortargeting by a novel Cy3-labeled folic acid (FA)-derivatized DNA dendrimer nanocarrier (3DNA). We combined siRNAs against HuR with FA-3DNA and found that systemic administration of the resultant FA-3DNA-siHuR conjugates to ovarian tumorbearing mice suppressed tumor growth and ascites development, significantly prolonging lifespan. NanoString gene expression analysis identified multiple HuR-regulated genes that function in many essential cellular and molecular pathways, an attractive feature of candidate therapeutic targets. Taken together, these results are the first to demonstrate the versatility of the 3DNA nanocarrier for in vivo-targeted delivery of a cancer therapeutic and support further preclinical investigation of this system adapted to siHuR-targeted therapy for ovarian cancer.