Download Multifunctional nanoparticles and ultrasound to improve

Multifunctional nanoparticles and ultrasound to improve cancer therapy
Contact: Catharina Davies, [email protected]
Web page http://www.ntnu.edu/physics/medphys/drugdelivery
Background: Ultrasound mediated delivery of NPs in tumour tissue
Nanotechnology has started a new era in engineering
multifunctional nanoparticles (NPs) for improved cancer diagnosis and
therapy, incorporating both contrast agents for imaging and therapeutics
into so called theranostics NPs. Encapsulating the drugs into NPs improves
the pharmacokinetics and reduces the systemic exposure due to the leaky
capillaries in tumours. In most normal tissue the blood vessels are not leaky
and the NPs are constrained to the blood, thereby reducing the toxicity to
healthy tissue. Although the NP can extravasate from the blood to the
extracellular matrix, the NPs do not to travel far away from the blood
vessels. Thus, only a small population of cancer cells located close to the
blood vessels will be exposed to the cytotoxic drugs as shown in the figure.
A prerequisite for successful cancer therapy is that the therapeutic agents
reach their targets and limit the exposure to normal tissue. To ensure high
drug payload, the NPs have to be relatively large (100-200 nm) and
therefore the NPs face severe problems reaching the target cells. The
delivery depends on the vasculature, the transport across the capillary wall,
through the extracellular matrix (ECM), and if the final target is
intracellular the NPs also have to cross the cell membrane.
Although the NPs may pass the tumour capillaries rather easily, the
uptake and distribution of NPs and the released drugs are low and
heterogeneously distributed in the tumour tissue. The drug has to
penetrate the ECM which consists of a protein network of collagen
embedded in a gel of glycosaminoglycans and proteo-glycans.
Nanoparticles (blue) do not travel
far from the blood vessels (red).The
encapsulated drug is taken up by
cells (green) close to blood vessels
The delivery of nanoparticles depends
on 1) The blood vessel network 2)
Transport across the capillary wall
3) Penetration through the ECM.
In order to improve the distribution of NPs the delivery should be combined with a treatment
facilitating the delivery. Ultrasound (US) has been reported to be able to improve drug delivery by
different mechanical mechanisms, acoustic radiation force and cavitation. High frequency and highly
focused US can induce acoustic radiation force pushing the NP across the capillary wall and through
the ECM. Cavitation is the oscillation of gas filled microbubbles in the acoustic field. Such
oscillations can be stable and generate mechanical shear stress on the capillary wall thereby increasing
the vascular permeability or the microbubbles can collapse in a violent process generating jet streams
that also increase the vascular permeability, improve the transport through the ECM and increase the
cellular uptake of NP. The overall aim this project is to characterize NP and microbubbles to be used
in therapy and study how ultrasound can be used to improve the delivery of distribution of NP in
tumour cells and tissue.
Novel multifunctional nanoparticles and microbubbles
The project uses various NPs. One of the NPs are polymeric and they have the ability to
stabilize gas bubbles, i.e. the NPs form a shell around the gas bubbles forming an efficient particle for
ultrasound-mediated delivery of NP.
We provide 7 projects for the fall 2016:
1. Sonoporation of cancer cells
Supervisors Catharina Davies [email protected], Sofie Snipstad [email protected]
Aim: To study if US can improve the uptake of our NP-MB in cells. The uptake will be measured
by flow cytometry and confocal laser scanning microscopy.
2. Combining CT images and images for small animal optical imager
Supervisor Catharina Davies [email protected], Einar Sulheim [email protected]
Eugene Kim [email protected]
Various imaging modalities are used to study the distribution of NPs in tumour tissue. Computer
tomography (CT) providing anatomical information and imaging fluorescent NP in mice providing the
distribution of NP in tissue, are two imaging techniques we want to combine.
Aim: To design a frame that the mice can be attached to and that can be rotated in the animal optical
imager. The production will be done by the mechanical workshop. Write a computer program making
it possible to combine the images from various directions in the whole animal imager and merge such
images onto CT images.
3. Acoustic radiation force applied to nanoparticles in gels
Supervisor Catharina Davies [email protected], Petros Yemane [email protected]
The NPs have to penetrate the extracellular matrix to reach all cancer cells. We are using gels of
glucosaminoglycans and collagen fibers to mimic the extracellular matrix.
Aim: Study how acoustic radiation force can be used to push NPs in gels. One approach is to image
the displacement of fluorescently labelled NP using confocal laser scanning microscopy.
4. Mechanical properties of nanoparticles
Supervisor Catharina Davies [email protected], Astrid Bjørkøy [email protected]
The behavior and displacement of NPs in the acoustic field can be described by mathematical
models. One important input parameter in such models is their elasticity/stiffness.
Aim: Measure the elasticity of various NPs using atomic force microscopy.
5. Using the chicken chorioallantoic membrane (CAM) model to study tumor angiogenisis
Supervisors Catharina Davies [email protected], Andreas Åslund
[email protected], Einar Sulheim [email protected]
We are in the process of establishing a chicken embryo model to study tumor development,
angiogenisis (vascularization) and and tumor treatment. The model has the advantage of having a
circulatory system already 3 days after fertilization of the egg and can be grown in a petri dish in
an incubator. The circulatory system can be used to inject drugs and tumors can be implanted into
the CAM.
Aim: To study the angiogenisis of tumors in the CAM model. This will be done by implanting
tumor cells of different types of tumors. Injection of fluorescent dyes will be used to visualize the
vascularization and the function (leaky vs non-leaky) of the blood vessels by confocal microscopy.
The project is part of a bigger study performed in vivo.
Fig. 1: The figure depicts injection of the dye Evans blue into a CAM.
6. Ultrasound-induced transport of nanoparticles across an artificial blood-brain barrier in
vitro
Supervisor Catharina Davies [email protected], Habib Baghirov
[email protected], Andreas Åslund Andreas.å[email protected]
A layer of endothelial cells with tight junctions between the cells constitute an in vitro model for the
blood brain barrier (BBB), and the effect of various ultrasound treatments on the flux of nanoparticles
and smaller molecules across the BBB will be studied
Aim: Determine ultrasound exposure parameters for inducing a flux of nanoparticles and smaller
molecules across the BBB, and study whether the transport is paracellular or transcellular.
An immortalized endothelial cell line RB4 will be grown in transwells and incubated with
nanoparticle or smaller molecules and microbubbles. This BBB will be exposed to ultrasound and
the amount of nanoparticles on the opposite side of the endothelial cell layer measured.
7. Nanoparticle degradation and drug release
Supervisors: Catharina de Lange Davies [email protected] , Einar Sulheim [email protected] , Yrr Mørch
[email protected]
Nanoparticles can potentially be used to deliver existing drugs more efficiently to tumors. In this project the cytostatic
drug Cabazitaxel will be encapsulated into polymeric (PACA) nanoparticles with different stability.
Aim: to understand and quantify the release of the drug from the NPs. The morphology of the NPs upon degradation will
be visualized with STEM at the Nanolab and the release of the drug can be quantified using either mass spectrometry or
UV-spectroscopy. The laboratory work will take place at NTNU Nanolab and at SINTEF Materials and chemistry. The
project is well suited for students from bionanotechnology and nanomaterials. For more information contact Einar
Sulheim.