Marck Norret

Unraveling the relationship between structure and stabilization of triarylpyridines as G-quadruplex binding ligands

A series of novel 2,4,6-triarylpyridines have been synthesized and their interactions with intramolecular G-quadruplexes have been measured by Förster Resonance Energy Transfer (FRET) melting and Fluorescent Intercalator Displacement (FID) assays. A few of these compounds exhibit stabilization of G4-DNA that is comparable to other benchmark G4-DNA ligands with fair to excellent G4-DNA vs. duplex selectivity and significant cytotoxicity towards HeLa cells. The nature of the 4-aryl substituents along with side chain length governs the G4-DNA stabilization ability of the compounds. In addition, we demonstrate that there is a strong correlation between the ability of the compounds to stabilize the same G4-DNA sequence in K(+) and Na(+) conditions and a strong correlation between the ability of the compounds to stabilize different G4-DNA sequences in K(+) or Na(+) buffer.

Dose-Dependent Therapeutic Distinction between Active and Passive Targeting Revealed Using Transferrin-Coated PGMA Nanoparticles.

The paradigm of using nanoparticle-based formulations for drug delivery relies on their enhanced passive accumulation in the tumor interstitium. Nanoparticles with active targeting capabilities attempt to further enhance specific delivery of drugs to the tumors via interaction with overexpressed cellular receptors. Consequently, it is widely accepted that drug delivery using actively targeted nanoparticles maximizes the therapeutic benefit and minimizes the off-target effects. However, the process of nanoparticle mediated active targeting initially relies on their passive accumulation in tumors. In this article, it is demonstrated that these two tumor-targeted drug delivery mechanisms are interrelated and dosage dependent. It is reported that at lower doses, actively targeted nanoparticles have distinctly higher efficacy in tumor inhibition than their passively targeted counterparts. However, the enhanced permeability and retention effect of the tumor tissue becomes the dominant factor influencing the efficacy of both passively and actively targeted nanoparticles when they are administered at higher doses. Importantly, it is demonstrated that dosage is a pivotal parameter that needs to be taken into account in the assessment of nanoparticle mediated targeted drug delivery.

A Domino Diels–Alder Approach toward the Tetracyclic Nicandrenone Framework

The tetracarbocyclic framework of the nicandrenone natural products is formed in one step from a linear precursor via a domino intramolecular Diels-Alder/intramolecular furan Diels-Alder/aromatization sequence. The approach represents a new 0 → ABCD strategy for the preparation of aromatic steroids.

Controlling the confinement of fullerene C60 molecules using a saddle shape Ni(II) macrocycle

A saddle-shaped Ni-macrocycle bearing flexible benzyl arms, Ni(TBTAA), 1, has been prepared and structurally authenticated in the solid state as a toluene adduct, with the toluene residing in the extended cavity of the macrocycle, close to two of benzylic substituents. The Ni-macrocycle forms a crystalline inclusion complex with fullerene C60, {C60∩(1)2}·(toluene)5, 2, which has each fullerene encapsulated by two macrocycles involving π⋯π interactions to the phenyl lined face of the macrocycles, as well as CH⋯π from the benzyl groups and toluene molecules closing up the fullerene surface. The CH⋯π for the benzyl groups effectively increases the steric demands of the macrocycle over the surface of the fullerene, circumventing any fullerene⋯fullerene interactions. The nature of the interactions in the fullerene complex has been probed using Hirshfeld surface analysis.

An Unexpected Transient Breakdown of the Blood Brain Barrier Triggers Passage of Large Intravenously Administered Nanoparticles.

The highly restrictive blood-brain barrier (BBB) plays a critically important role in maintaining brain homeostasis and is pivotal for proper neuronal function. The BBB is currently considered the main limiting factor restricting the passage of large (up to 200 nm) intravenously administered nanoparticles to the brain. Breakdown of the barrier occurs as a consequence of cerebrovascular diseases and traumatic brain injury. In this article, we report that remote injuries in the CNS are also associated with BBB dysfunction. In particular, we show that a focal partial transection of the optic nerve triggers a previously unknown transient opening of the mammalian BBB that occurs in the visual centres. Importantly, we demonstrate that this transient BBB breakdown results in a dramatic change in the biodistribution of intravenously administered large polymeric nanoparticles which were previously deemed as BBB-impermeable.

Diastereospecific dihydroxylation and highly efficient asymmetric dihydroxylation kinetic resolution of cis/trans-2,6-dimethylbenzylidenecyclohexane

Achiral dihydroxylation and catalytic asymmetric dihydroxylation (AD) lead to reaction of only the cis(and not the trans) isomer of 2,6-dimethylbenzylidenecyclohexane, dihydroxylation is diastereoisomer specific and an efficient kinetic resolution is achieved using AD.

Maternal-placental-fetal biodistribution of multimodal polymeric nanoparticles in a pregnant rat model in mid and late gestation

Multimodal polymeric nanoparticles have many exciting diagnostic and therapeutic applications, yet their uptake and passage by the placenta, and applications in the treatment of pregnancy complications have not been thoroughly investigated. In this work, the maternal-fetal-placental biodistribution of anionic and cationic multimodal poly(glycidyl methacrylate) (PGMA) nanoparticles in pregnant rats at mid (ED10) and late (ED20) gestation was examined. Fluorescently-labelled and superparamagnetic PGMA nanoparticles functionalized with/without poly(ethyleneimine) (PEI) were administered to pregnant rats at a clinically-relevant dose and biodistribution and tissue uptake assessed. Quantitative measurement of fluorescence intensity or magnetic resonance relaxometry in tissue homogenates lacked the sensitivity to quantify tissue uptake. Confocal microscopy, however, identified uptake by maternal organs and the decidua (ectoplacental cone) and trophoblast giant cells of conceptuses at ED10. At ED20, preferential accumulation of cationic vs. anionic nanoparticles was observed in the placenta, with PGMA-PEI nanoparticles localised mainly within the chorionic plate. These findings highlight the significant impact of surface charge and gestational age in the biodistribution of nanoparticles in pregnancy, and demonstrate the importance of using highly sensitive measurement techniques to evaluate nanomaterial biodistribution and maternal-fetal exposure.

The Protein Corona of PEGylated PGMA-Based Nanoparticles is Preferentially Enriched with Specific Serum Proteins of Varied Biological Function

The composition of the protein corona formed on poly(ethylene glycol)-functionalized (PEGylated) poly(glycidyl methacrylate) (PGMA) nanoparticles (NPs) was qualitatively and quantitatively compared to the protein corona on non-PEGylated PGMA NPs. Despite the reputation of PEGylated NPs for stealth functionality, we demonstrate the preferential enrichment of specific serum proteins of varied biological function in the protein corona on PEGylated NPs when compared to non-PEGylated NPs. Additionally, we suggest that the base material of polymeric NPs plays a role in the preferential enrichment of select serum proteins to the hard corona.

Immunomodulatory effects of functionalised chalcones on pro-inflammatory cytokine release from lung epithelial cells

Chalcones, prepared in high yield in polyethylene glycol, Mw = 300 (PEG300), were screened for inhibition of the thrombin-mediated release of pro-inflammatory interleukin-6 (IL-6) and interleukin-8 (IL-8) from the A549 lung epithelial cell line. Several show significant down-regulation of these pro-inflammatory mediators in a dose-dependant manner with one exhibiting pro-inflammatory properties. Computational studies on selected chalcones revealed a detailed understanding of the structure, electron density and biological activity relationship.

Templating Linear Alignment of Fullerene C60 Molecules Involving a Curved Macrocycle

A nickel macrocycle bearing 15-crown-5 ether pendant moieties forms a 1:1 complex with fullerene C60, with the macrocycle templating the formation of linear arrays of the fullerenes, and the inter-fullerene contacts being associated with parallel six-membered rings, with the fullerene…fullerene centroid distances remarkably short at 9.757 A. Three crystalline solids involving this macrocycle were isolated and studied by X-ray structure analysis and the complex reveals a self-inclusion mode of packing in its guest-free form, while acting as a host in its inclusion compounds with C60 and C60/toluene.