Maryam Parhizkar

Fast dissolving paracetamol/caffeine nanofibers prepared by electrospinning

A series of polyvinylpyrrolidone fibers loaded with paracetamol (PCM) and caffeine (CAF) was fabricated by electrospinning and explored as potential oral fast-dissolving films. The fibers take the form of uniform cylinders with smooth surfaces, and contain the drugs in the amorphous form. Drug-polymer intermolecular interactions were evidenced by infrared spectroscopy and molecular modeling. The properties of the fiber mats were found to be highly appropriate for the preparation of oral fast dissolving films: their thickness is around 120-130 μm, and the pH after dissolution in deionized water lies in the range of 6.7-7.2. Except at the highest drug loading, the folding endurance of the fibers was found to be >20 times. A flavoring agent can easily be incorporated into the formulation. The fiber mats are all seen to disintegrate completely within 0.5s when added to simulated saliva solution. They release their drug cargo within around 150s in a dissolution test, and to undergo much more rapid dissolution than is seen for the pure drugs. The data reported herein clearly demonstrate that electrospun PCM/CAF fibers comprise excellent candidates for oral fast-dissolving films, which could be particularly useful for children and patients with swallowing difficulties.

Electrohydrodynamic encapsulation of cisplatin in poly (lactic-co-glycolic acid) nanoparticles for controlled drug delivery

Targeted delivery of potent, toxic chemotherapy drugs, such as cisplatin, is a significant area of research in cancer treatment. In this study, cisplatin was successfully encapsulated with high efficiency (>70%) in poly (lactic-co-glycolic acid) polymeric nanoparticles by using electrohydrodynamic atomization (EHDA) where applied voltage and solution flow rate as well as the concentration of cisplatin and polymer were varied to control the size of the particles. Thus, nanoparticles were produced with three different drug:polymer ratios (2.5, 5 and 10wt% cisplatin). It was shown that smaller nanoparticles were produced with 10wt% cisplatin. Furthermore, these demonstrated the best sustained release (smallest burst release). By fitting the experimental data with various kinetic models it was concluded that the release is dependent upon the particle morphology and the drug concentration. Thus, these particles have significant potential for cisplatin delivery with controlled dosage and release period that are crucial chemotherapy parameters.

Drug Delivery Strategies for Platinum-Based Chemotherapy

Few chemotherapeutics have had such an impact on cancer management as cis-diamminedichloridoplatinum(II) (CDDP), also known as cisplatin. The first member of the platinum-based drug family, CDDPs potent toxicity in disrupting DNA replication has led to its widespread use in multidrug therapies, with particular benefit in patients with testicular cancers. However, CDDP also produces significant side effects that limit the maximum systemic dose. Various strategies have been developed to address this challenge including encapsulation within micro- or nanocarriers and the use of external stimuli such as ultrasound to promote uptake and release. The aim of this review is to look at these strategies and recent scientific and clinical developments.

Electrohydrodynamic fabrication of core-shell PLGA nanoparticles with controlled release of cisplatin for enhanced cancer treatment

Increasing the clinical efficacy of toxic chemotherapy drugs such as cisplatin (CDDP), via targeted drug delivery, is a key area of research in cancer treatment. In this study, CDDP-loaded poly(lactic-co-glycolic acid) (PLGA) polymeric nanoparticles (NPs) were successfully prepared using electrohydrodynamic atomization (EHDA). The configuration was varied to control the distribution of CDDP within the particles, and high encapsulation efficiency (>70%) of the drug was achieved. NPs were produced with either a core–shell (CS) or a matrix (uniform) structure. It was shown that CS NPs had the most sustained release of the 2 formulations, demonstrating a slower linear release post initial “burst” and longer duration. The role of particle architecture on the rate of drug release in vitro was confirmed by fitting the experimental data with various kinetic models. This indicated that the release process was a simple diffusion mechanism. The CS NPs were effectively internalized into the endolysosomal compartments of cancer cells and demonstrated an increased cytotoxic efficacy (concentration of a drug that gives half maximal response [EC50] reaching 6.2 µM) compared to free drug (EC50 =9 µM) and uniform CDDP-distributed NPs (EC50 =7.6 µM) in vitro. Thus, these experiments indicate that engineering the structure of PLGA NPs can be exploited to control both the dosage and the release characteristics for improved clinical chemotherapy treatment.

Investigating the particle to fibre transition threshold during electrohydrodynamic atomization of a polymer solution.

Electrohydrodynamic atomization (EHDA) is a key research area for producing micro and nano-sized structures. This process can be categorized into two main operating regimes: electrospraying for particle generation and electrospinning for fibre production. Producing particles/fibres of the desired size or morphology depends on two main factors; properties of the polymeric solution used and the processing conditions including flow rate, applied voltage and collection distance. In this work the particle-fibre transition region was analyzed by changing the polymer concentration of PLGA poly (lactic-co-glycolic acid) in acetone between 2 and 25wt%. Subsequently the processing conditions were adjusted to study the optimum transition parameters. Additionally the EHDA configuration was also modified by adding a metallic plate to observe the deposition area. The diameter and the distance of the plate from the capillary tip were adjusted to investigate variations in particle and fibre morphologies as well. It was found that complete transition from particles to fibres occurs at 20wt% indicating concentration to be the dominant criterion. Low flow rates yielded fibres without beads. However the applied voltage and distance between the tip of the nozzle jetting the polymer solution and collector (working distance) did not yield definitive results. Reducing the collector distance and increasing applied voltages produces smooth as well as beaded fibres. Addition of a metal plate reduces particle size by ~1μm; the fibre size increases especially with increasing plate diameter while bead density and size reduces when the disc is fixed closer to the capillary tip. Additionally, the deposition area is reduced by 70% and 57% with the addition of metal plates of 30mm and 60mm, respectively. The results indicate that a metal plate can be utilized further to tune the particle/fibre size and morphology and this also significantly increases the yield of EHDA process which is currently a limitation in adopting it as a mass production technique.

Novel preparation of controlled porosity particle/fibre loaded scaffolds using a hybrid micro-fluidic and electrohydrodynamic technique.

The purpose of this research was to produce multi-dimensional scaffolds containing biocompatible particles and fibres. To achieve this, two techniques were combined and used: T-Junction microfluidics and electrohydrodynamic (EHD) processing. The former was used to form layers of monodispersed bovine serum albumin (BSA) bubbles, which upon drying formed porous scaffolds. By altering the T-Junction processing parameters, bubbles with different diameters were produced and hence the scaffold porosity could be controlled. EHD processing was used to spray or spin poly(lactic-co-glycolic) (PLGA), polymethysilsesquioxane (PMSQ) and collagen particles/fibres onto the scaffolds during their production and after drying. As a result, multifunctional BSA scaffolds with controlled porosity containing PLGA, PMSQ and collagen particles/fibres were obtained. Product morphology was studied by optical and scanning electron microscopy. These products have potential applications in many advanced biomedical, pharmaceutical and cosmetic fields e.g. bone regeneration, drug delivery, cosmetic cream lathers, facial scrubbing creams etc.

The effect of surfactant type and concentration on the size and stability of microbubbles produced in a capillary embedded T-junction device

This work presents an investigation of the effect of various surfactants on microbubble formation, size and stability in a capillary embedded T-Junction microfluidic device. Four different surfactants were chosen. An anionic surfactant, sodium dodecyl sulfate (SDS), two non-ionic surfactants, polyoxyethylene sorbitan monopalmitate (Tween 40) and polyoxyethylene glycol 40 stearate (PEG 40), and a cationic surfactant, cetyltrimethyl ammonium bromide (CTAB). Each surfactant was added to 50 wt% aqueous glycerol solution at high concentration (above the critical micelle concentration) varying from 2 to 5 and 10 wt%. Static surface tension and contact angle were measured, as well as the viscosity of the solutions. While the value of surface tension did not significantly change with increasing surfactant concentration, other properties of the solutions (i.e. viscosity and contact angle) were affected. Microbubbles with sizes varying from 50 to 360 μm all with polydispersity index values of <2% were produced with this technique. The nonionic surfactants were found to produce smaller bubbles. This is likely to have been due to their higher adsorption on to the hydrophobic channel surface and hence increase in the thickness of the liquid film at the contact line between the three phases for approximately similar capillary numbers and viscosities. Bubble stability for all cases was evaluated by monitoring the change in average diameter with time. Microbubbles coated with PEG 40 were found to be the most stable, lasting for 150 days with a uniform size reduction of ∼1.5% as compared with SDS microbubbles lasting only for 30 min after collection.

Combining microfluidic devices with coarse capillaries to reduce the size of monodisperse microbubbles

In this work we report a significant advance for the preparation of monodispersed microbubbles, which are increasingly used and have become a key constituent in many advanced technologies. A new device comprising of two T-junctions containing coarse capillaries and operating in series was assembled. Microbubble generation was facilitated by using bovine serum albumin solution and nitrogen as the liquid and the gas phase, respectively. The effect of operating parameters such as gas pressure and liquid flow rate on the size of the microbubbles generated were investigated for the two T-junction systems and the results were compared with a single T-junction process. The experimental results showed that microbubbles produced via the double T-junction setup were smaller at any given gas pressure for both liquid flow rates of 100 and 200 μm studied in this work. A predictive model is developed from the experimental data, and the number of T-junctions was incorporated into this scaling model. It was demonstrated that the diameter of the monodisperse microbubbles generated can be tailored using multiple T-junctions while the operating parameters such as gas pressure and liquid flow rates were kept constant. The stability of the microbubbles produced was also examined and indicated that microbubbles produced through the double T-junction were more stable.

Latest developments in innovative manufacturing to combine nanotechnology with healthcare

Nanotechnology has become increasingly important in advancing the frontiers of many key areas of healthcare, for example, drug delivery and tissue engineering. To fully harness the many benefits of nanotechnology in healthcare, innovative manufacturing is necessary to mass produce nanoparticles and nanofibers, the two major types of nanofeatures currently sought after and of immense utilitarian value in healthcare. For example, nanoparticles are a key drug delivery enabler, the structural and mechanical mimicry are important attributes of nanofiber which are increasingly used as biomimetic agents.

Ultrasound enhanced delivery of cisplatin loaded nanoparticles

Cisplatin forms the basis for many chemotherapy regimens, however the maximum permissible dose is limited by its systemic toxicity. Nanoencapsulation of drugs has been shown to reduce off-target side effects and can potentially improve treatment burden on patients. However, uptake of nanoformulations at tumor sites is minimal without some form of active delivery. We have developed a submicron, polymeric nanoparticle based on biocompatible and degradable poly(lactic-co-glycolic acid) (PLGA) capable of encapsulating cisplatin and which can be bound to the surface of a phospholipid coated microbubble. The acoustic behavior and stability of the resulting nanoparticle loaded microbubbles will be compared with those of unloaded microbubbles. Results will also be presented on the extravasation of particles in a tissue mimicking phantom using a novel long working distance confocal microscope that enables particle distributions to be measured in situ and in real time.