Showing papers by "C. Shad Thaxton published in 2011"

Nanoparticle therapeutics: FDA approval, clinical trials, regulatory pathways, and case study.

Abstract: The approval of drugs for human use by the US Food and Drug Administration (FDA) through the Center for Drug Evaluation and Research (CDER) is a time-consuming and expensive process, and approval rates are low (DiMasi et al., J Health Econ 22:151-185, 2003; Marchetti and Schellens, Br J Cancer 97:577-581, 2007). In general, the FDA drug approval process can be separated into preclinical, clinical, and postmarketing phases. At each step from the point of discovery through demonstration of safety and efficacy in humans, drug candidates are closely scrutinized. Advances in nanotechnology are being applied in the development of novel therapeutics that may address a number of shortcomings of conventional small molecule drugs and may facilitate the realization of personalized medicine (Ferrari, Curr Opin Chem Biol 9:343-346, 2005; Ferrari, Nat Rev Cancer 5:161-171, 2005; Ferrari and Downing, BioDrugs 19:203-210, 2005). Appealingly, nanoparticle drug candidates often represent multiplexed formulations (e.g., drug, targeting moiety, and nanoparticle scaffold material). By tailoring the chemistry and identity of variable nanoparticle constituents, it is possible to achieve targeted delivery, reduce side effects, and prepare formulations of unstable (e.g., siRNA) and/or highly toxic drugs (Ferrari, Curr Opin Chem Biol 9:343-346, 2005; Ferrari, Nat Rev Cancer 5:161-171, 2005; Ferrari and Downing, BioDrugs 19:203-210, 2005). With these benefits arise new challenges in all aspects of regulated drug development and testing.This chapter distils the drug development and approval process with an emphasis on special considerations for nanotherapeutics. The chapter concludes with a case study focused on a nanoparticle therapeutic, CALAA-01, currently in human clinical trials, that embodies many of the potential benefits of nanoparticle therapeutics (Davis, Mol Pharm 6:659-668, 2009). By choosing CALAA-01, reference is made to the infancy of the therapeutic nanoparticle field; in 2008, CALAA-01 was the first targeted siRNA nanoparticle therapeutic administered to humans. Certainly, there will be many more that will follow the lead of CALAA-01 and each will have its own unique challenges; however, much can be learned from this drug in the context of nanotherapeutics and the evolving development and approval process as it applies to them.

Biomimetic High Density Lipoprotein Nanoparticles For Nucleic Acid Delivery

Abstract: We report a gold nanoparticle-templated high density lipoprotein (HDL AuNP) platform for gene therapy that combines lipid-based nucleic acid transfection strategies with HDL biomimicry. For proof-of-concept, HDL AuNPs are shown to adsorb antisense cholesterylated DNA. The conjugates are internalized by human cells, can be tracked within cells using transmission electron microscopy, and regulate target gene expression. Overall, the ability to directly image the AuNP core within cells, the chemical tailorability of the HDL AuNP platform, and the potential for cell-specific targeting afforded by HDL biomimicry make this platform appealing for nucleic acid delivery.

Synthetic nanostructures including nucleic acids and/or other entities

Abstract: Articles, compositions, kits, and methods relating to nanostructures, including synthetic nanostructures, are provided. Certain embodiments described herein include structures having a core-shell type arrangement; for instance, a nanostructure core may be surrounded by a shell including a material, such as a lipid bilayer, and may include other components such as oligonucleotides. In some embodiments, the structures, when introduced into a subject, can be used to deliver nucleic acids and/or can regulate gene expression. Accordingly, the structures described herein may be used to diagnose, prevent, treat or manage certain diseases or bodily conditions. In some cases, the structures are both a therapeutic agent and a diagnostic agent.

Hybridization-induced "off-on" 19F-NMR signal probe release from DNA-functionalized gold nanoparticles.

Abstract: therapeutic delivery, [ 2 ] imaging, [ 3 ] and applications that combine modalities (i.e., theranostic). [ 4 ] In addition to tracking the location of nanoparticles, [ 5 ] imaging modalities also can be used to detect specifi c molecular interactions within cells by way of nanoparticle-enabled “off–on” switches. [ 6 ] Nucleicacid-functionalized gold nanoparticles (DNA or RNA AuNPs, structures where nucleic acids are covalently attached to gold nanoparticles) [ 7 ] are a promising new gene regulation platform. In addition to exhibiting excellent cell transfection capabilities (over 50 different cell lines), [ 7e ] they can be combined with imaging agents (e.g., gadolinium), allowing researchers to track their location using magnetic resonance imaging (MRI). [ 8 ] AuNPs are also effi cient distancedependent quenchers of molecular fl uorescence, [ 9 ] and have been used to develop a new class of nucleic-acid and smallmolecule probes, which release fl uorescent signaling agents

Applications: Nanobiosystems, Medicine, and Health

Abstract: Over the past decade, nanomedicine and nanobiology have undergone radical transformations from fantasy to real science. The days of discussing advances in this area in the context of “nanobots” are over, and systems and nanomaterials have emerged that provide major analytical or therapeutic advantages over conventional molecule-based structures and approaches. We have come to recognize that much of biology is executed at the nanoscale level, therefore providing a rational approach to using the structure and function of engineered nanomaterials at the nano-bio interface for interrogation of disease, diagnosis, treatment, and imaging at levels of sophistication not possible before [1]. Fabrication of a host of nanostructures has been coupled with advanced chemical manipulation in order to impart biological recognition and interaction capabilities. Often, chemical manipulation results in nanomaterials that provide performance enhancement of therapeutics, imaging agents, diagnostics, and materials for tissue engineering and for basic science applications.

Crosslinked polynucleotide structure

Abstract: The present invention provides structures formed from crosslinked polynucleotides, where a subset of the polynucleotides binds to a target under physiological conditions, where the signal group detectably changes upon binding.

Structure polynucléotidique réticulée

Abstract: La presente invention concerne des structures formees a partir de polynucleotides reticules, ou un sous-ensemble des polynucleotides se lie a une cible selon des conditions physiologiques, le groupe signal changeant de maniere detectable lors de la liaison.