Development of a novel, multifunctional, membrane-interactive pyridinium salt with potent anticancer activity

The synthesis and biological evaluation of a novel pyridinium salt is reported. Initial membrane interaction with isolated phospholipid monolayers was obtained with the pyridinium salt, and two neutral analogues for comparison, and the anticancer effects of the best compound established using a cytotoxicity screening assay against glioma cells using both an established cell line and three short-term cell cultures – one of which has been largely resistant to all chemotherapeutic drugs tested to date. The results indicate that the pyridinium salt exhibits potent anticancer activity (EC50s = 9.8-312.5 μM) on all cell types, including the resistant one, for a continuous treatment of 72 hours. Microscopic examination of the treated cells using a trypan blue exclusion assay showed membrane lysis had occurred. Therefore, this letter highlights the potential for a new class of pyridinium salt to be developed as a much needed alternative treatment for glioma chemotherapy

Biocompatible superparamagnetic core-shell nanoparticles for potential use in hyperthermia-enabled drug release and as an enhanced contrast agent

Superparamagnetic iron oxide nanoparticles (SPIONs) and core-shell type nanoparticles, consisting of SPIONs coated with mesoporous silica and/or lipid, were synthesized and tested for their potential theranostic applications in drug delivery, magnetic hyperthermia and as a contrast agent. Transmission Electron Microscopy (TEM) confirmed the size of bare and coated SPIONs was in the range of 5-20 nm and 100-200 nm respectively. The superparamagnetic nature of all the prepared nanomaterials as indicated by Vibrating Sample Magnetometry (VSM) and their heating properties under an AC field confirm their potential for hyperthermia applications. Scanning Column Magnetometry (SCM) data showed that extrusion of bare-SPION (b-SPION) dispersions through a 100 nm polycarbonate membrane significantly improved the dispersion stability of the sample. No sedimentation was apparent after 18 hours compared to a pre-extrusion estimate of 43% settled at the bottom of the tube over the same time. Lipid coating also enhanced dispersion stability. Transversal relaxation time (T2) measurements for the nanoparticles, using a bench-top relaxometer, displayed a significantly lower value of 46 ms, with a narrow relaxation time distribution, for lipid silica coated SPIONs (Lip-SiSPIONs) as compared to that of 1316 ms for the b-SPIONs. Entrapment efficiency of the anticancer drug, Doxorubicin (DOX) for Lip-SPIONs was observed to be 35% which increased to 58% for Lip-SiSPIONs. Moreover, in-vitro cytotoxicity studies against human breast adenocarcinoma, MCF-7 cells showed that % cell viability increased from 57% for bSPIONs to 82% for Lip-SPIONs and to 87% for Lip-SiSPIONs. This suggests that silica and lipid coatings improve the biocompatibility of bSPIONs significantly and enhance the suitability of these particles as drug carriers. Hence, the magnetic nanomaterials prepared in this work have potential theranostic properties as a drug carrier for hyperthermia cancer therapy and also offer enhancement of contrast agent efficacy and a route to a significant increase in dispersion stability

Carbon nanotubes for stabilization of nanostructured lipid particles

Carbon nanotubes (CNTs) are increasingly studied for innovative biotechnological applications particularly where they are combined with essential biological materials like lipids. Lipids have been used earlier for enhancing the dispersibility of CNTs in aqueous solutions. Here we report a novel application of CNTs for stabilization of internally self-assembled nanostructured lipid particles of 2–5 μm size. Single-walled (pristine) as well as –OH and –COOH functionalized multi-walled CNTs were employed to produce nanostructured emulsions which stayed stable for months and could be re-dispersed after complete dehydration. Concentrations of CNTs employed for stabilization were very low; moreover CNTs were well-decorated with lipid molecules. These features contribute towards reducing their toxicity and improving biocompatibility for biomedical and pharmaceutical applications. Our approach paves the way for future development of combination therapies employing both CNTs and nanostructured lipid self-assembly together as carriers of different drugs

Aromatic Stacking Facilitated Self-Assembly of Ultrashort Ionic Complementary Peptide Sequence: β-Sheet Nanofibers with Remarkable Gelation and Interfacial Properties

Understanding peptide self-assembly mechanisms and stability of the formed assemblies is crucial for development of functional nanomaterials. Herein, we have adopted rational design approach to demonstrate how minimal structural modification to a non-assembling ultra-short ionic self-complementary tetrapeptide FEFK (Phe4) remarkably enhanced stability of self-assembly into β-sheet nanofibres and induced hydrogelation. This was achieved by replacing flexible phenylalanine residue (F) by the rigid phenylglycine (Phg) resulting in constrained analogue PhgEPhgK (Phg4), which positioned aromatic rings in an orientation favourable for aromatic stacking. Phg4 self-assembly into stable β-sheet ladders was facilitated by π-staking of aromatic sidechains alongside hydrogen bonding between backbone amides along the nanofibre axis. The contribution of these non-covalent interactions in stabilising self-assembly was predicted by in silico modelling using molecular dynamics simulations and semi-empirical quantum mechanics calculations. In aqueous medium, Phg4 β-sheet nanofibres entangled at a critical gelation concentration > 20 mg/mL forming a network of nanofibrous hydrogel. Phg4 also demonstrated unique surface activity in presence of immiscible oils and was superior to commercial emulsifiers in stabilising oil-in-water emulsions. This was attributed to interfacial adsorption of amphiphilic nanofibrilles forming nanofibrillised microspheres. To our knowledge, Phg4 is the shortest ionic self-complementary peptide rationally designed to self-assemble into stable β-sheet nanofibres capable of gelation and emulsification. Our results suggest that Ultra-short Ionic-complementary Constrained Peptides or UICPs have significant potential for the development of cost-effective, sustainable and multifunctional soft bionanomaterials

Lipid-hydrogel films for sustained drug release

We report a hybrid system, fabricated from nanostructured lipid particles and polysaccharide based hydrogel, for sustained release applications. Lipid particles were prepared by kinetically stabilizing self-assembled lipid nanostructures whereas the hydrogel was obtained by dissolving kappa-carrageenan (KC) in water. The drug was incorporated in native as well as lipid particles loaded hydrogels, which upon dehydration formed thin films. The kinetics of drug release from these films was monitored by UV–vis spectroscopy while the films were characterized by Fourier transform infra-red (FTIR) spectroscopy and small angle X-ray scattering techniques. Pre-encapsulation of a drug into lipid particles is demonstrably advantageous in certain ways; for instance, direct interactions between KC and drug molecules are prohibited due to the mediation of hydrophobic forces generated by lipid tails. Rapid diffusion of small drug molecules from porous hydrogel network is interrupted by their encapsulation into rather large sized lipid particles. The drug release from the lipid-hydrogel matrix was sustained by an order of magnitude timescale with respect to the release from native hydrogel films. These studies form a strong platform for the development of combined carrier systems for controlled therapeutic applications

Functional foldamers that target bacterial membranes: the effect of charge, amphiphilicity and conformation

By varying the molecular charge, shape and amphiphilicity of a series of conformationally distinct diarylureas it is possible to control the levels of phospholipid membrane lysis using membranes composed of bacterial lipid extracts. From the data obtained, it appears as though the lysis activity observed is not due to charge, conformation or amphiphilicity in isolation, but that surface aggregation, H-bonding and other factors may also play a part. The work provides evidence that this class of foldamer possesses potential for optimisation into new antibacterial agents

Wettability studies of topologically distinct titanium surfaces

Biomedical implants made of titanium-based materials are expected to have certain essential features including high bone-to-implant contact and optimum osteointegration, which are often influenced by the surface topography and physicochemical properties of titanium surfaces. The surface structure in the nanoscale regime is presumed to alter/facilitate the protein binding, cell adhesion and proliferation, thereby reducing post-operative complications with increased lifespan of biomedical implants. The novelty of our TiO2 nanostructures lies mainly in the high level control over their morphology and roughness by mere compositional change and optimisation of the experimental parameters. The present work focuses on the wetting behaviour of various nanostructured titanium surfaces towards water. Kinetics of contact area of water droplet on macroscopically flat, nanoporous and nanotubular titanium surface topologies was monitored under similar evaporation conditions. The contact area of the water droplet on hydrophobic titanium planar surface (foil) was found to decrease during evaporation, whereas the contact area of the droplet on hydrophobic nanorough titanium surfaces practically remained unaffected until the complete evaporation. This demonstrates that the surface morphology and roughness at the nanoscale level substantially affect the titanium dioxide surface–water droplet interaction, opposing to previous observations for microscale structured surfaces. The difference in surface topographic nanofeatures of nanostructured titanium surfaces could be correlated not only with the time-dependency of the contact area, but also with time-dependency of the contact angle and electrochemical properties of these surfaces

Superparamagnetic iron oxide nanoparticles for magnetic hyperthermia applications

Over the years, magnetic hyperthermia has attracted a lot of attention and has proved itself as an effective alternative treatment to the traditional anticancer therapies including surgery, chemotherapy and radiotherapy. The more established oncological strategies that are available today to cure malignant tumours lack specificity, pose a risk of recurrence of the disease and suffer from concerns like severe side effects. Magnetic hyperthermia, on the other hand, is thought to reduce the problems associated with the conventional therapies and can be used to provide targeted drug delivery. The treatment is based on the mechanism that magnetic nanoparticles, when exposed to a varying magnetic field, generate heat due to magnetic hysteresis loss, thus generating great interest in superparamagnetic iron oxide nanoparticles (SPIONs). SPIONs loaded with anticancer drug(s) can be targeted specifically to the cancer cells by applying an external magnetic field, which can then release the drug to the tumour cell by inducing local hyperthermia. Thus, hyperthermia treatment has the ability to destroy specifically the cancer cells while sparing the normal cells. This chapter highlights the methods of synthesis and fabrication of SPIONs for their potential in hyperthermia cancer therapy

Hermally responsive lipid coated superparamagnetic nanoparticles for frequency triggered drug delivery

Herein we report a fabrication method of core-shell type silica coated superparamagnetic iron oxide nanoparticles (SPIONs) with thermally responsive lipids for controlled and targeted drug delivery using Alternative Current (AC) magnetic field for potential applications in cancer therapy. Core-shell SPIONs, loaded with anticancer drug, Doxorubicin (DOX) were coated with lipids such as dipalmitoylphosphatidylcholine (DPPC) and cholesterol so as to cap the mesopores. The particle size of the bare and coated SPIONs was measured using the dynamic light scattering technique, scanning and transmission electron microscopy (SEM and TEM). The change in surface morphology of bare and coated SPIONs was evidenced from SEM. The in vitro drug loading and release studies were carried in phosphate buffered saline (PBS) under the AC magnetic field as well as under thermal incubation condition at 37°C. The concentration of DOX in solution was determined by measuring the absorbance at 484 nm by UV-Visible spectrophotometer. The preliminary results indicate that the drug release behaviour under the AC magnetic field is relatively controlled compared to that of normal thermal incubation condition at 37°C

Lipid nanostructures in butter oil: Structural and physicochemical characterization

Butter oil is derived from butter and constitutes of triglycerides along with small amounts of other lipids and fat-soluble components. Food grade lipids can be easily sourced from butter oil which finds a great potential in various ancient, modern as well as emerging applications. Due to almost “all fat” content, butter oil is not soluble in water, but it can be emulsified or combined with other components to enhance its applicability. In order to develop and optimize various applications, it is vital to identify self-assembled nanostructures formed within the butter oil. This report involves nanostructural studies by small (SAXS) and wide (WAXS) angle X-ray scattering and microstructural analysis of butter and butter oil using microscopic techniques. Both butter and butter oil display various polymorphs, detected by WAXS, but in general, the self-assembled nanostructure was identified to be a lamellar phase with the lattice parameter of about 41.8 Å. Physicochemical properties of butter oil, namely solubility, density, thermal behavior, functional groups and molecular structure elucidation also contribute to this report