Delivery of nanoparticles in tumour tissue

Delivery of nanoparticles in tumour tissue

– Ultrasound and delivery of drugs and nanoparticles

Two researchers in the lab. One studying a sample in a microscope and the other checking the image on a computer screen. Photo

Research activity

Research

Ultrasound and delivery of drugs and nanoparticles

Ultrasound can be used to improve the delivery of drugs and nanoparticles to tumours and across the blood-brain barrier 

Nanotechnology has started a new era in engineering multifunctional nanoparticles for improved cancer diagnosis and therapy, incorporating both contrast agents for imaging and therapeutics into so called theranostic nanoparticles. Encapsulating the drugs into nanoparticles improves the pharmacokinetics and reduces the systemic exposure due to the leaky capillaries in tumours. However, the distribution of nanoparticles in tumour tissue is low and heterogeneous.

Ultrasound has the potential of improving delivery of nanoparticles, and is found to be especially efficient in the presence of microbubbles. Under the exposure of ultrasound, the microbubbles being injected in the blood vessels will oscillate thereby inducing mechanical forces on the blood vessel wall. This will increase the transport of nanoparticles and drugs across the capillary wall and into the extracellular matrix.

The same technique can also be used to open the blood-brain barrier in a non-invasive, localized and reversible manner to deliver various drugs to the brain making it possible to treat disorders in the central nervous system.

We are studying how ultrasound can improve the delivery of nanoparticles to cancer cells.

The figure shows enhanced uptake of drug-loaded nanoparticles in a tumor exposed to focused ultrasound.  Tumors are growing in mice and after ultrasound treatment, tumor sections are made for microscopy. Red is blood vessels and green is the nanoparticles.  The scale bars are 50 micrometers. 

Ultrasound Improves the Delivery and Therapeutic Effect of Nanoparticle-Stabilized Microbubbles in Breast Cancer Xenografts.

The effect of ultrasound depends on several parameters such as ultrasound frequency, acoustic pressure, duration of the ultrasound pulse, and properties of the microbubbles such as size, concentration and shell characteristics. Also, the properties of the nanoparticles such as size and charge, and tumour characteristics such as vascular density, vascular permeability, interstitial fluid pressure, extracellular matrix, and cell density will determine the efficiency of ultrasound-mediated delivery. Using advanced imaging techniques, we are aiming at understanding the mechanisms for the improved delivery of drugs and nanoparticles to optimise the delivery of nanoparticles thereby improving cancer therapy.

Our research is part of the Center for Research-based Innovation:

CIUS - Center for innovative Ultrasound Solutions.

We are also collaborating with SINTEF AS on nanoparticles for drug delivery applications.


Acoustic Cluster Therapy (ACT) for targeted drug delivery

Ultrasound-mediated delivery of drugs might be even more efficient using a novel concept called acoustic cluster therapy (ACT).  ACT makes use of similar mechanisms as regular microbubbles, but addresses important shortcomings of the latter.

Regular microbubbles have a diameter in the range 2-6 μm. Thus, the magnitude of the biomechanical work they can induce is relatively limited. In addition, being free flowing they display limited contact with the endothelial wall, reducing the level and range of the biomechanical effects. Furthermore, microbubbles are typically cleared from vascular compartments within 2–3 min. The ACT formulation is a mix of negatively charged microbubbles and positively charged microdroplets, with the ensuing formation of microbubble/microdroplet clusters from the electrostatic attraction between the two components.

The ACT Cluster Dispersion for Injection may be co-administered with a regular medicament (e.g. chemotherapeutic) to induce locally enhanced uptake of the systemically injected drug. The clusters are small enough to be free flowing in the microvasculature after i.v. injection. When insonated with diagnostic ultrasound, the microbubbles transfers energy to the microdroplets that vaporizes forming bigger microbubbles. The 20-30 µm microbubbles are transiently deposit in the local microvasculature, stopping the blood flow for 5-10 minutes. Post activation, low intensity ultrasound is used to induce oscillations of the large bubbles ensuing biomechanical effects to allow for enhanced extravasation and distribution of drug molecules to the targeted tissue.

The concept is visualized in the figure. This project is done in collaboration with the company Phoenix solutions.

 

 

We have found that ACT enhances the tumour uptake of macromolecules  and improves the therapeutic response in mice. In 2019 a clinical trial started. 

 

Ultrasound and delivery of nanoparticles to the brain

We have shown that microbubbles combined with focused ultrasound can temporarily open the blood-brain barrier. This enables treatment of diseases in the central nervous system. 
The blood-brain barrier (BBB) protects the brain tissue from harmful toxic agents. However, it also prevents therapeutic agents from entering the brain tissue.

The blood-brain barrier (BBB) protects the brain tissue from harmful toxic agents. However, it also prevents therapeutic agents from entering the brain tissue. The BBB is formed by tight junctions between adjacent endothelial cells lining the vessels, which impede paracellular transport and force most molecular traffic through a transcellular route. If molecules successfully enter endothelial cells, they will probably be forced back to the blood by special pumps on the cell surface. 

We have found that focused ultrasound in combination with two different bubble concepts successfully deliver nanoparticles and macromolecules to brain tissue. The opening of the BBB is temporary and safe. 


Clinical studies at St.Olavs Hospital to improve chemotherapy

The promising therapeutic results in mice using focused ultrasound and microbubbles to improve the delivery of drugs and nanoparticles, have initiated clinical trials aiming at improving chemotherapy for cancer patients. 

In collaboration with St.Olavs Hospital, The Cancer Clinic and The Clinic for Medical Imaging, Department of radiology and nuclear medicine, two clinical studies have been initiated. 

Colorectal cancer patients and breast cancer patients with liver metastases are given standard chemotherapy and one liver metastasis is treated with focused ultrasound and another metastasis is used as internal control. The microbubble SonoVue which is used in contrast enhanced ultrasound imaging, is injected immediately before the ultrasound treatment. 

Ultrasound-enhanced Delivery of Chemotherapy to Patients With Liver Metastasis From Breast- and Colorectal Cancer

In the next clinical study patients with in-operable pancreatic tumors are treated with standard chemotherapy plus the clinically approved microbubble SonoVue and focused ultrasound. A novel dual frequency ultrasound transducer (High frequency for imaging and lower frequency for treatment) is used. 

Ultrasound-enhanced Uptake of Chemotherapy in Patients With Inoperable Pancreatic Ductal Adenocarcinoma (PDAC)