DNA nanotechnology and particularly DNA origami, in which long, single-stranded DNA molecules are folded into predetermined shapes, can be used to form complex self-assembled nanostructures. Although DNA itself has limited chemical, optical or electronic functionality, DNA nanostructures can serve as templates for building materials with new functional properties. Relatively large nanocomponents such as nanoparticles and biomolecules can also be integrated into DNA nanostructures and imaged. Here, we show that chemical reactions with single molecules can be performed and imaged at a local position on a DNA origami scaffold by atomic force microscopy. The high yields and chemoselectivities of successive cleavage and bond-forming reactions observed in these experiments demonstrate the feasibility of post-assembly chemical modification of DNA nanostructures and their potential use as locally addressable solid supports.

Cancer cells generally generate higher amounts of reactive oxygen species than normal cells. On the basis of this difference, prodrugs have been developed (e.g., hydroxyferrocifen), which remain inactive in normal cells, but become activated in cancer cells. In this work we describe novel aminoferrocene-based prodrugs, which, in contrast to hydroxyferrocifen, after activation form not only quinone methides (QMs), but also catalysts (iron or ferrocenium ions). The released products act in a concerted fashion. In particular, QMs alkylate glutathione, thereby inhibiting the antioxidative system of the cell, whereas the iron species induce catalytic generation of hydroxyl radicals. Since the catalysts are formed as products of the activation reaction, it proceeds autocatalytically. The most potent prodrug described here is toxic toward cancer cells (human promyelocytic leukemia (HL-60), IC(50) = 9 μM, and human glioblastoma-astrocytoma (U373), IC(50) = 25 μM), but not toxic (up to 100 μM) toward representative nonmalignant cells (fibroblasts).

DNA sequences can hybridize with each other in a predictable and a programmable manner to form linear and branched double-stranded (ds) helical structures. This ability makes DNA an excellent building block for preparation of nanostructures of defined shapes and sizes. For example, surface patterns and complex 2D and even 3D objects have been obtained by self-assembly of DNA strands.[1] To make dsDNA conductive, it has been coated with metals, metal oxides, or metal sulfides. For example, a number of methods for the complete coverage of DNA with Au 0 , Pd 0 , Pt 0 , Ag 0 , Cu 0 , and CdS have been reported. [2,3] However, less is known about the controlled modification of pre-selected sections of DNA. The first example of the selective coating of DNA with metal was reported by Braun and co-workers.[4] In particular, they protected a portion of l DNA with a RecA protein/ ssDNA complex. This step was followed by metallization of the unprotected DNA by sequential reduction of Ag + and Au 3+ . Finally, the RecA protein was degraded, exposing the protected region of l DNA for further manipulations. This method provided two stretches of conducting DNA wires that are interrupted by a circa 1 mm-long stretch of nonconductive DNA. However, as RecA-induced homologous recombination is efficient only with long DNA sections, this approach is limited to construction of rather large molecular objects (>1 mm).Chemical synthesis of dsDNA containing metal ions between coordinating base pairs has been reported. [5] By the variation of the number of such base pairs, the length of the metal-containing stretches within the DNA can be varied.[5] It still remains to be experimentally confirmed that the metal ion/DNA complexes obtained are conductive and, therefore, applicable as conducting wires.Herein we describe a method for selective metallization of ds regions of DNA with copper(0) (Figure 1). ssDNA overhangs present in the duplexes could potentially be used as addressable anchors for preparation of functional devices based on metallized dsDNA. We prepared a simple device of this type containing two metallized dsDNA connected by a non-metallized rigid linker.

As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non–BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.

Cancer cells produce elevated levels of reactive oxygen species, which has been used to design cancer specific prodrugs. Their activation relies on at least a bimolecular process, in which a prodrug reacts with ROS. However, at low micromolar concentrations of the prodrugs and ROS, the activation is usually inefficient. Herein, we propose and validate a potentially general approach for solving this intrinsic problem of ROS-dependent prodrugs. In particular, known prodrug 4-(N-ferrocenyl-N-benzylaminocarbonyloxymethyl)phenylboronic acid pinacol ester was converted into its lysosome-specific analogue. Since lysosomes contain a higher concentration of active ROS than the cytoplasm, activation of the prodrug was facilitated with respect to the parent compound. Moreover, it was found to exhibit high anticancer activity in a variety of cancer cell lines (IC =3.5-7.2 μm) and in vivo (40 mg kg , NK/Ly murine model) but remained weakly toxic towards non-malignant cells (IC =15-30 μm).