The effectiveness of anticancer drugs in treating a solid tumour is dependent on delivery of the drug to virtually all cancer cells in the tumour. The distribution of drug in tumour tissue depends on the plasma pharmacokinetics, the structure and function of the tumour vasculature and the transport properties of the drug as it moves through microvessel walls and in the extravascular tissue. The aim of this Review is to provide a broad, balanced perspective on the current understanding of drug transport to tumour cells and on the progress in developing methods to enhance drug delivery. First, the fundamental processes of solute transport in blood and tissue by convection and diffusion are reviewed, including the dependence of penetration distance from vessels into tissue on solute binding or uptake in tissue. The effects of the abnormal characteristics of tumour vasculature and extravascular tissue on these transport properties are then discussed. Finally, methods for overcoming limitations in drug transport and thereby achieving improved therapeutic results are surveyed.

Transport of drugs from blood vessels to tumour tissue.

Current metal film-based electronics, while sensitive to external stretching, typically fail via uncontrolled cracking under a relatively small strain (~30%), which restricts their practical applications. To address this, here we report a design approach inspired by the stereocilia bundles of a cochlea that uses a hierarchical assembly of interfacial nanowires to retard penetrating cracking. This structured surface outperforms its flat counterparts in stretchability (130% versus 30% tolerable strain) and maintains high sensitivity (minimum detection of 0.005% strain) in response to external stimuli such as sounds and mechanical forces. The enlarged stretchability is attributed to the two-stage cracking process induced by the synergy of micro-voids and nano-voids. In-situ observation confirms that at low strains micro-voids between nanowire clusters guide the process of crack growth, whereas at large strains new cracks are randomly initiated from nano-voids among individual nanowires. Metal film-based electronics usually fail via uncontrolled cracking at small strains. Here, the authors design a micro-/nano-structured surface with bundled flexible nanowires onto which a metal film can stretch more than a regular flat surface, retard penetrating cracks and remain sensitive.

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Micro-/nano-voids guided two-stage film cracking on bioinspired assemblies for high-performance electronics.

Microglia rapidly respond to changes in neural activity and inflammation to regulate synaptic connectivity. The extracellular signals, particularly neuron-derived molecules, that drive these microglial functions at synapses remain a key open question. Here we show that whisker lesioning, known to dampen cortical activity, induces microglia-mediated synapse elimination. This synapse elimination is dependent on signaling by CX3CR1, the receptor for microglial fractalkine (also known as CXCL1), but not complement receptor 3. Furthermore, mice deficient in CX3CL1 have profound defects in synapse elimination. Single-cell RNA sequencing revealed that Cx3cl1 is derived from cortical neurons, and ADAM10, a metalloprotease that cleaves CX3CL1 into a secreted form, is upregulated specifically in layer IV neurons and in microglia following whisker lesioning. Finally, inhibition of ADAM10 phenocopies Cx3cr1-/- and Cx3cl1-/- synapse elimination defects. Together, these results identify neuron-to-microglia signaling necessary for cortical synaptic remodeling and reveal that context-dependent immune mechanisms are utilized to remodel synapses in the mammalian brain.

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Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling.

The ~1.6 Ga Tirohan Dolomite of the Lower Vindhyan in central India contains phosphatized stromatolitic microbialites. We report from there uniquely well-preserved fossils interpreted as probable crown-group rhodophytes (red algae). The filamentous form Rafatazmia chitrakootensis n. gen, n. sp. has uniserial rows of large cells and grows through diffusely distributed septation. Each cell has a centrally suspended, conspicuous rhomboidal disk interpreted as a pyrenoid. The septa between the cells have central structures that may represent pit connections and pit plugs. Another filamentous form, Denaricion mendax n. gen., n. sp., has coin-like cells reminiscent of those in large sulfur-oxidizing bacteria but much more recalcitrant than the liquid-vacuole-filled cells of the latter. There are also resemblances with oscillatoriacean cyanobacteria, although cell volumes in the latter are much smaller. The wider affinities of Denaricion are uncertain. Ramathallus lobatus n. gen., n. sp. is a lobate sessile alga with pseudoparenchymatous thallus, “cell fountains,” and apical growth, suggesting florideophycean affinity. If these inferences are correct, Rafatazmia and Ramathallus represent crown-group multicellular rhodophytes, antedating the oldest previously accepted red alga in the fossil record by about 400 million years.

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Three-dimensional preservation of cellular and subcellular structures suggests 1.6 billion-year-old crown-group red algae.

Current state of knowledge on biological effects from contaminants on arctic wildlife and fish

ADAM10 and ADAM17 have been shown to contribute to the acquired drug resistance of HER2-positive breast cancer in response to trastuzumab. The majority of ADAM10 and ADAM17 inhibitor development has been focused on the discovery of compounds that bind the active site zinc, however, in recent years, there has been a shift from active site to secondary substrate binding site (exosite) inhibitor discovery in order to identify non-zinc-binding molecules. In the present work a glycosylated, exosite-binding substrate of ADAM10 and ADAM17 was utilized to screen 370,276 compounds from the MLPCN collection. As a result of this uHTS effort, a selective, time-dependent, non-zinc-binding inhibitor of ADAM10 with Ki = 883 nM was discovered. This compound exhibited low cell toxicity and was able to selectively inhibit shedding of known ADAM10 substrates in several cell-based models. We hypothesize that differential glycosylation of these cognate substrates is the source of selectivity of our novel inhibitor. The data indicate that this novel inhibitor can be used as an in vitro and, potentially, in vivo, probe of ADAM10 activity. Additionally, results of the present and prior studies strongly suggest that glycosylated substrate are applicable as screening agents for discovery of selective ADAM probes and therapeutics.

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Jean-Phillipe Pettiloud

Papers

Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate.