The ability to activate drugs only at desired locations avoiding systemic immunosuppression and other dose limiting toxicities is highly desirable. Here we present a new approach, named local drug activation, that uses bioorthogonal chemistry to concentrate and activate systemic small molecules at a location of choice. This method is independent of endogenous cellular or environmental markers and only depends on the presence of a preimplanted biomaterial near a desired site (e.g., tumor). We demonstrate the clear therapeutic benefit with minimal side effects of this approach in mice over systemic therapy using a doxorubicin pro-drug against xenograft tumors of a type of soft tissue sarcoma (HT1080).

In vitro exogenous activation of siRNA nanodrug using bio-orthogonal de-click chemistry.

Conventional piezoelectric materials change shape in response to an applied external electric field, frequently deforming at grain boundaries in addition to intrinsic unit cell changes. We detail a computational investigation, using density functional theory (DFT) calculations of single-molecule piezoelectrics. Rather than deforming along covalent bond lengths or angles, these molecular springs, derivatives of [6]helicene and phenanthrene, change conformation in response to the applied field, up to 15% of the molecular length. A substituted [6]helicene has a predicted piezoelectric coefficient of 48.8 pm/V, and one of the phenanthrenes yields a piezoelectric coefficient of up to 54.3 pm/V, which is significantly higher than polymers such as polyvinylidine difluoride (PVDF) and comparable to conventional inorganic materials such as zinc oxide (ZnO). We discuss structural properties that are found to yield large piezoresponse and hypothetical target molecules with up to 64% length change and a predicted piezoelectric coefficient of 272 pm/V. Based on these findings, we believe a new class of highly responsive piezoelectric materials may be created from the "bottom up", yielding immense electromechanical response.

Paramagnetic resonance enhancement (PRE) is an NMR technique that allows studying three-dimensional structures of RNA-protein complexes in solution. RNA strands are typically spin labeled using nitroxide reagents, which provide minimal perturbation to the native structure. The current work describes an alternative approach, which is based on a Co2+-based probe that can be covalently attached to RNA in the vicinity of the protein’s binding site using ‘click’ chemistry. Similar to nitroxide spin labels, the transition metal based probe is capable of attenuating NMR signal intensities from protein residues localized <40 Å away. The extent of attenuation is related to the probe’s distance, thus allowing for construction of the protein’s contact surface map. This new paradigm has been applied to study binding of HIV-1 nucleocapsid protein 7, NCp7, to a model RNA pentanucleotide.