Position Matters: Pyridine Regioisomers Influence Secondary Structure and Micelle Morphology in Polymer-Homopolypeptide Micelles.

Polymer-homopolypeptide block copolymers are a class of bioinspired materials that combine the processability and stability of synthetic polymers with the biocompatibility and unique secondary structures of peptides, such as α-helices and β-sheets. These properties make them ideal candidates for a wide variety of applications, for example, in the pharmaceutical field, where they are frequently explored as building blocks for polymeric micelle drug delivery systems. While homopolypeptide side chains can be furnished with an array of different moieties to impart the copolymers with desirable properties, such as stimulus responsivity, pyridine derivatives represent an underutilized functional group for this purpose.

Microstructure-Thermal Property Relationships of Poly (Ethylene Glycol--Caprolactone) Copolymers and Their Micelles.

The crystallinity of polymers strongly affects their properties. For block copolymers, whereby two crystallisable blocks are covalently tethered to one another, the molecular weight of the individual blocks and their relative weight fraction are important structural parameters that control their crystallisation. In the case of block copolymer micelles, these parameters can influence the crystallinity of the core, which has implications for drug encapsulation and release.

Using GPCRs as Molecular Beacons to Target Ovarian Cancer with Nanomedicines.

The five-year survival rate for women with ovarian cancer is very poor despite radical cytoreductive surgery and chemotherapy. Although most patients initially respond to platinum-based chemotherapy, the majority experience recurrence and ultimately develop chemoresistance, resulting in fatal outcomes. The current administration of cytotoxic compounds is hampered by dose-limiting severe adverse effects.

Interrogating the relationship between the microstructure of amphiphilic poly(ethylene glycol-b-caprolactone) copolymers and their colloidal assemblies using non-interfering techniques.

Understanding the microstructural parameters of amphiphilic copolymers that control the formation and structure of aggregated colloids (e.g., micelles) is essential for the rational design of hierarchically structured systems for applications in nanomedicine, personal care and food formulations.

Pentafulvene-Maleimide Cycloaddition for Bioorthogonal Ligation.

The applications of bioconjugation chemistry are rapidly expanding, and the addition of new strategies to the bioconjugation and ligation toolbox will further advance progress in this field. Herein, we present a detailed study of the Diels-Alder cycloaddition (DAC) reaction between pentafulvenes and maleimides in aqueous solutions and investigate the reaction as an emerging bioconjugation strategy. The DAC reactions were found to proceed efficiently, quantitatively yielding cycloadducts with reaction rates ranging up to ∼0.

Neutral Re(I) Complex Platform for Live Intracellular Imaging.

Luminescent metal complexes are a valuable platform for the generation of cell imaging agents. However, many metal complexes are cationic, a factor that can dominate the intracellular accumulation to specific organelles. Neutral Re(I) complexes offer a more attractive platform for the development of bioconjugated imaging agents, where charge cannot influence their intracellular distribution.

Strategies for the Development of pH-Responsive Synthetic Polypeptides and Polymer-Peptide Hybrids: Recent Advancements.

Synthetic polypeptides and polymer-peptide hybrid materials have been successfully implemented in an array of biomedical applications owing to their biocompatibility, biodegradability and ability to mimic natural proteins. In addition, these materials have the capacity to form complex supramolecular structures, facilitate specific biological interactions, and incorporate a diverse selection of functional groups that can be used as the basis for further synthetic modification. Like conventional synthetic polymers, polypeptide-based materials can be designed to respond to external stimuli (e.

Drug-Eluting Biodegradable Implants for the Sustained Release of phosphonates.

Despite being one of the first-line treatments for osteoporosis, the phosphonate drug class exhibits an extremely low oral bioavailability (<1%) due to poor absorption from the gastrointestinal tract. To overcome this, and to explore the potential for sustained drug release, bioerodible poly(lactic acid) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA) implants loaded with the phosphonate alendronate sodium (ALN) were prepared via hot-melt extrusion. The rate of drug release in vitro was modulated by tailoring the ratio of lactide to glycolide in the polymer and by altering the ALN-loading of the implants.

Investigating Intracellular Localisation and Cytotoxicity Trends for Neutral and Cationic Iridium Tetrazolato Complexes in Live Cells.

A family of five neutral cyclometalated iridium(III) tetrazolato complexes and their methylated cationic analogues have been synthesised and characterised. The complexes are distinguished by variations of the substituents or degree of π conjugation on either the phenylpyridine or tetrazolato ligands. The photophysical properties of these species have been evaluated in organic and aqueous media, revealing predominantly a solvatochromic emission originating from mixed metal-to-ligand and ligand-to-ligand charge transfer excited states of triplet multiplicity.

An integrated approach for discovery of highly potent and selective Mnk inhibitors: Screening, synthesis and SAR analysis.

Deregulation of protein synthesis is a common event in cancer. As MAPK-interacting kinases (Mnks) play critical roles in regulation of protein synthesis, they have emerged as novel anti-cancer targets. Mnks phosphorylate eukaryotic initiation factor 4E (eIF4E) and promote eIF4E-mediated oncogenic activity.

Identification of a Highly Conserved Allosteric Binding Site on Mnk1 and Mnk2.

Elevated levels of phosphorylated eukaryotic initiation factor 4E (eIF4E) have been implicated in many tumor types, and mitogen activated protein kinase-interacting kinases (Mnks) are the only known kinases that phosphorylate eIF4E at Ser209. The phosphorylation of eIF4E is essential for oncogenic transformation but is of no significance to normal growth and development. Pharmacological inhibition of Mnks therefore provides a nontoxic and effective strategy for cancer therapy.

Pharmacologic co-inhibition of Mnks and mTORC1 synergistically suppresses proliferation and perturbs cell cycle progression in blast crisis-chronic myeloid leukemia cells.

The Ras/Raf/MAPK and PI3K/Akt/mTORC1 cascades are two most aberrantly regulated pathways in cancers. As MAPK-interacting kinases (Mnks) are part of the convergent node of these two pathways, and play a pivotal role in cellular transformation, targeting Mnks has emerged as a potential therapeutic strategy. Herein, a dual-specific Mnk1/2 inhibitor MNKI-57 and a potent Mnk2-specific inhibitor MNKI-4 were selected for a panel screen against 28 human cancer cell lines.