Modelling and breaking down the biophysical barriers to drug delivery in pancreatic cancer

The pancreatic ductal adenocarcinoma (PDAC) stroma and its inherent biophysical barriers to drug delivery are central to therapeutic resistance. This makes PDAC the most prevalent pancreatic cancer with poor prognosis. The chemotherapeutic drug gemcitabine is used against various solid tumours, including pancreatic cancer, but with only a modest effect on patient survival. The growing PDAC tumour mass with high densities of cells and extracellular matrix (ECM) proteins, i.e., collagen, results in high interstitial pressure, leading to vasculature collapse and a dense, hypoxic, mechanically stiff stroma with reduced interstitial flow, critical to drug delivery to cells. Despite this, most drug studies are performed on cellular models that neglect these biophysical barriers to drug delivery. Microfluidic technology offers a promising platform to emulate tumour biophysical characteristics with appropriate flow conditions and transport dynamics. We present a microfluidic PDAC culture model, encompassing the disease's biophysical barriers to therapeutics, to evaluate the use of the angiotensin II receptor blocker losartan, which has been found to have matrix-depleting properties, on improving gemcitabine efficacy. PDAC cells were seeded into our 5-channel microfluidic device for a 21-day culture to mimic the rigid, collagenous PDAC stroma with reduced interstitial flow, which is critical to drug delivery to the cancer cells, and for assessment with gemcitabine and losartan treatment. With losartan, our culture matrix was more porous with less collagen, resulting in increased hydraulic conductivity of the culture interstitial space and improved gemcitabine effect. We demonstrate the importance of modelling tumour biophysical barriers to successfully assess new drugs and delivery methods

Free-Standing Hierarchically Porous Silica Nanoparticle Superstructures: Bridging the Nano- to Microscale for Tailorable Delivery of Small and Large Therapeutics

Nanoscale colloidal self-assembly is an exciting approach to yield superstructures with properties distinct from those of individual nanoparticles. However, the bottom-up self-assembly of 3D nanoparticle superstructures typically requires extensive chemical functionalization, harsh conditions, and a long preparation time, which are undesirable for biomedical applications. Here, we report the directional freezing of porous silica nanoparticles (PSiNPs) as a simple and versatile technique to create anisotropic 3D superstructures with hierarchical porosity afforded by microporous PSiNPs and newly generated meso- and macropores between the PSiNPs. By varying the PSiNP building block size, the interparticle pore sizes can be readily tuned. The newly created hierarchical pores greatly augment the loading of a small molecule-anticancer drug, doxorubicin (Dox), and a large macromolecule, lysozyme (Lyz). Importantly, Dox loading into both the micro- and meso/macropores of the nanoparticle assemblies not only gave a pore size-dependent drug release but also significantly extended the drug release to 25 days compared to a much shorter 7 or 11 day drug release from Dox loaded into either the micro- or meso/macropores only. Moreover, a unique temporal drug release profile, with a higher and faster release of Lyz from the larger interparticle macropores than Dox from the smaller PSiNP micropores, was observed. Finally, the formulation of the Dox-loaded superstructures within a composite hydrogel induces prolonged growth inhibition in a 3D spheroid model of pancreatic ductal adenocarcinoma. This study presents a facile modular approach for the rapid assembly of drug-loaded superstructures in fully aqueous environments and demonstrates their potential as highly tailorable and sustained delivery systems for diverse therapeutics

Radioactivity levels in scales generated from crude oil production in Ghana

Trabajo presentado a la II International Conference on Radioecological Concentration Processes (50 years later), celebrada en Sevilla (España) del 6 al 9 de noviembre de 2016.Knowledge of accurate radio isotopic signatures is very necessary in assessing any potential radiological hazards and risks to members of the public and workers from exposure to NORM contaminated scales. In this work scales from crude oil production activities from Ghana have been assessed using alpha spectrometry after radiochemical separation, and non-destructive gamma spectrometry. Characterization and determination of activity concentrations of 234U, 238U, 210Po, 230Th, 232Th, 226Ra, 210Pb, 228Ra, 228Th, 224Ra and 40K have been established. The average activity concentrations of 43.9 ± 8.1 kBq.kg-1, 30.3 ± 5.1 kBq.kg-1, 11.2 ± 2.8 kBq.kg-1 and 11.2 ± 2.6 kBq.kg-1 obtained for 226Ra, 228Ra, 228Th, and 224Ra respectively in scale samples in this study exceeded the IAEA Basic Safety Standards (BSS) exemption levels giving an indication that the scale samples could present significant future radiological risk for workers, the public and environment.Peer reviewe

Radiochemical characterization of produced water from two production offshore oilfields in Ghana

Produced water from two Ghanaian offshore production oilfields has been characterized using alpha spectrometry after radiochemical separation, non-destructive gamma spectrometry and ICP-MS and other complimentary analytical tools. The measured concentrations of main NORM components were in the range of 6.2-22.3 Bq.L, 6.4-35.5 Bq.L, and 0.7-7.0 Bq.L for Ra, Ra and Ra respectively. A good correlation between several physico-chemical parameters and radium isotopes was observed in each production oilfield. The radium concentrations obtained in this study for produced water from the two oilfields of Ghana are of radiological importance and hence there may be the need to put in place measures for future contamination concerns due to their bioavailability in the media and bioaccumulation characteristics. The results will assist in critical decision making for future set up of appropriate national guidelines for the management of NORM waste from the emerging oil and gas industry in Ghana.This work was funded by the International Atomic Energy Agency in the form of an 18 months Sandwich Fellowship and the Radiation Protection Institute of the Ghana Atomic Energy Commission (fellowship grant Number GHA/14019).Peer Reviewe

MODELLING THE BIOPHYSICS OF PANCREATIC DUCTAL ADENOCARCINOMA ON-CHIP FOR EFFECTIVE THERAPEUTIC ASSESSMENT

This paper presents a microfluidic device for modelling the biophysics of pancreatic ductal adenocarcinoma (PDAC). The biophysics of PDAC hampers the delivery and uptake of chemotherapeutic drugs to the PDAC cancer cells. Understanding and modelling the biophysical nature of PDAC, its fibrotic stroma, and mechanical stiffness is key to effectively targeting PDAC cells with therapeutics

On-chip modelling of the biophysics of pancreatic ductal adenocarcinoma for assessment with new therapeutics

This paper presents a microfluidic device for the culturing of a pancreatic ductal adenocarcinoma (PDAC) model, towards mimicking the biophysics of PDAC as observed in vivo. As a solid tumour, the biophysical rigidity of PDAC's microenvironment hampers the uptake of therapeutic agents, and understanding the biophysical nature of PDAC is key to effective therapeutic strategies

Modelling and breaking down the biophysical barriers to drug delivery in pancreatic cancer

The pancreatic ductal adenocarcinoma (PDAC) stroma and its inherent biophysical barriers to drug delivery are central to therapeutic resistance. This makes PDAC the most prevalent pancreatic cancer with poor prognosis. The chemotherapeutic drug gemcitabine is used against various solid tumours, including pancreatic cancer, but with only a modest effect on patient survival. The growing PDAC tumour mass with high densities of cells and extracellular matrix (ECM) proteins, i.e., collagen, results in high interstitial pressure, leading to vasculature collapse and a dense, hypoxic, mechanically stiff stroma with reduced interstitial flow, critical to drug delivery to cells. Despite this, most drug studies are performed on cellular models that neglect these biophysical barriers to drug delivery. Microfluidic technology offers a promising platform to emulate tumour biophysical characteristics with appropriate flow conditions and transport dynamics. We present a microfluidic PDAC culture model, encompassing the disease's biophysical barriers to therapeutics, to evaluate the use of the angiotensin II receptor blocker losartan, which has been found to have matrix-depleting properties, on improving gemcitabine efficacy. PDAC cells were seeded into our 5-channel microfluidic device for a 21-day culture to mimic the rigid, collagenous PDAC stroma with reduced interstitial flow, which is critical to drug delivery to the cancer cells, and for assessment with gemcitabine and losartan treatment. With losartan, our culture matrix was more porous with less collagen, resulting in increased hydraulic conductivity of the culture interstitial space and improved gemcitabine effect. We demonstrate the importance of modelling tumour biophysical barriers to successfully assess new drugs and delivery methods.</p

Natural radioactivity concentrations in beach sands from some tourist resorts., Research Journal of Environment and Earth Sciences

Abstract: Beaches along the coastlines in Ghana are important holiday destinations for tourists from many countries around the world. The radiological quality of sand from these beaches is very important to assess exposure of the public who use the beaches for recreational purposes and other activities. This study investigates the levels and hazards associated with the U-Th series and 40 K in beach sands from some renowned tourist resorts in the Greater Accra region of Ghana. Samples of beach sand from eleven beaches were analyzed using direct gamma-ray spectrometry. The total absorbed dose rate and the annual effective doses were calculated. The radiation hazards and risks associated with the use of the beach sand as construction material were also determined. The results show specific activities in the range 11.0-31.8 Bq/kg for 238 U, 0.5-1. U activity ratios calculated for the beaches is in the range of 0.032-0.053 with an average of 0.045±0.007 and that of the other radionuclides are close to unity, indicating only natural radionuclides were detected in the samples investigated. The results are within the values found in literature and show that the natural radionuclides in samples of the beach sand do not pose any significant risk to tourists and other holiday makers. Sand from the beaches is also safe for use as construction material, indicating the relevance in terms of the radiological quality of the beaches from both human and environmental health view points

Modeling the mechanical stiffness of pancreatic ductal adenocarcinoma

Despite improvements in the understanding of disease biology, pancreatic ductal adenocarcinoma (PDAC) remains the most malignant cancer of the pancreas. PDAC constitutes ∼95% of all pancreatic cancers, and it is highly resistant to therapeutics. The increased tissue rigidity, which stems from the rich fibrotic stroma in the tumor microenvironment, is central to disease development, physiology, and resistance to drug perfusion. Pancreatic stellate cells (PSCs) are responsible for overproduction of extracellular matrix in the fibrotic stroma, and this is exacerbated by the overexpression of transforming growth factor-β (TGF-β). However, there are few in vitro PDAC models, which include both PSCs and TGF-β or mimic in vivo-like tumor stiffness. In this study, we present a three-dimensional in vitro PDAC model, which includes PSCs and TGF-β, and recapitulates PDAC tissue mechanical stiffness. Using oscillatory shear rheology, we show the mechanical stiffness of the model is within range of the PDAC tissue stiffness by day 21 of culture and highlight that the matrix environment is essential to adequately capture PDAC disease. PDAC is a complex, aggressive disease with poor prognosis, and biophysically relevant in vitro PDAC models, which take into account tissue mechanics, will provide improved tumor models for effective therapeutic assessment

Free-Standing Hierarchically Porous Silica Nanoparticle Superstructures: Bridging the Nano- to Microscale for Tailorable Delivery of Small and Large Therapeutics

Nanoscale colloidal self-assembly is an exciting approach to yield superstructures with properties distinct from those of individual nanoparticles. However, the bottom-up self-assembly of 3D nanoparticle superstructures typically requires extensive chemical functionalization, harsh conditions, and a long preparation time, which are undesirable for biomedical applications. Here, we report the directional freezing of porous silica nanoparticles (PSiNPs) as a simple and versatile technique to create anisotropic 3D superstructures with hierarchical porosity afforded by microporous PSiNPs and newly generated meso- and macropores between the PSiNPs. By varying the PSiNP building block size, the interparticle pore sizes can be readily tuned. The newly created hierarchical pores greatly augment the loading of a small molecule-anticancer drug, doxorubicin (Dox), and a large macromolecule, lysozyme (Lyz). Importantly, Dox loading into both the micro- and meso/macropores of the nanoparticle assemblies not only gave a pore size-dependent drug release but also significantly extended the drug release to 25 days compared to a much shorter 7 or 11 day drug release from Dox loaded into either the micro- or meso/macropores only. Moreover, a unique temporal drug release profile, with a higher and faster release of Lyz from the larger interparticle macropores than Dox from the smaller PSiNP micropores, was observed. Finally, the formulation of the Dox-loaded superstructures within a composite hydrogel induces prolonged growth inhibition in a 3D spheroid model of pancreatic ductal adenocarcinoma. This study presents a facile modular approach for the rapid assembly of drug-loaded superstructures in fully aqueous environments and demonstrates their potential as highly tailorable and sustained delivery systems for diverse therapeutics