07:23pm Wednesday 13 December 2017

Better quality nanomedicine

A cancer cell has absorbed fluorescent nanoparticles (in red). A large portion of the nanoparticles end up inside the small vesicles that break down the large molecules (lysosomes, in green). A magnified version is shown at the bottom right. The blue portion is the cell nucleus. (Photo: Tore-Geir Iversen) One of the main tracks to developing better cancer medicines combines biotechnology and nanotechnology. Norwegian research groups have come up with a handful of highly promising projects. Medication encased in nanoparticles is transported into and through the body to the cancer cells, where the agent (medication) is released directly on the diseased tissue, causing less damage to other parts of the body.

“This description is very simplified, but it sums up how it works for the most part,” says Dr Tore Skotland at the Norwegian Radium Hospital/Oslo University Hospital. “The popular understanding is that the nanoparticles “target” the cancer tumour, but that is not correct. Rather, the nanoparticles help to deliver a higher concentration of the medication to the affected area. This reduces exposure in the rest of the body to the active agent and reduces the risk of side effects.”

This is an important improvement because, for patients undergoing chemotherapy, it is the side effects that make them sick. Chemotherapy leaves patients physically diminished after the cancer has been defeated.

Must be biodegradable

The project Dr Skotland is working on is headed by Professor Kirsten Sandvig at the Institute for Cancer Research at Oslo University Hospital. They are investigating biodegradable nanoparticles made of proteins, lipids and saccharides that can transport drug cocktails to tumours.

According to Dr Skotland, the method works by injecting nanoparticle-filled fluid into the bloodstream. The surface structure of the nanoparticles and the structure of blood vessels in the tumour will cause the nanoparticles to pile up just exactly at the tumour site. This concentration results in a relatively higher number of nanoparticles dissolving in and around the tumour than elsewhere in the body.

“It’s a passive approach, but it works,” Dr Sandvig states.

The design of biodegradable particles – that is, particles that dissolve or “disappear” from the body – is a must for Dr Sandvig and her colleagues. “Unfortunately, biodegradability has not been given focus in all the projects carried out in this area so far,” she says.

The project management group at the Norwegian Radium Hospital/Oslo University Hospital: Senior Researcher Tore Skotland (back, left), Senior Researcher Tore- Geir Iversen and Professor Kirsten Sandvig (Photo: Atle Abelsen)

Increasing competency

This is why this project is targeted towards increasing competency within this field at the Norwegian Radium Hospital/Oslo University Hospital in particular, as well as in other Norwegian scientific circles at large.

“Many groups have succeeded in producing functional nanoparticles and charged ahead and carried out studies in subject areas where they have a limited overview. We want to develop methods and standards that will improve the quality of this research,” Dr Sandvig adds. 

Dr Sandvig and Dr Skotland point to the multidisciplinary background of the project group as an important support. Efforts draw on resources from SINTEF, NTNU, UiT The Arctic University of Norway and PCI Biotech. The project was launched in September 2013 and has been allocated NOK 30.5 million in funding from the Research Council over a five-year period.

Interdisciplinary approach

“The lack of interdisciplinarity has compromised the quality of several earlier studies. This is a very important research field for Norway and there is a great need to develop better diagnostics and therapies for cancer patients,” says Dr Sandvig, who points out that several medicines based on nanoparticles are already on the market.

Two of the most promising products, which are also available in Norway, are the liposome-based Doxil (Caelyx) from Johnson & Johnson and the protein-based Abraxane from Celgene. They are used to treat breast cancer among other things. In addition to their enhanced effect, they have also been documented to cause fewer side effects in the form of heart complications and hair loss.

In addition to breast cancer, this research is targeting treatments for colorectal cancer.

Professor Catharina de Lange Davies from NTNU. (Photo: Claude R. Olsen) Another group of researchers at NTNU is working on packing chemotherapy medication inside nanoparticles which then adhere to the surface of micro gas bubbles in the blood stream. Ultrasound is used to burst the gas bubbles when they are near the tumour so that the nanoparticles and medicine work directly on the tumour. The method is suitable for many sites in the body, but is particularly interesting for treatment of brain cancer.

Professor Catharina de Lange Davies at NTNU explains that brain tissue is protected from toxic substances by a physical barrier – the blood-brain barrier – formed by the tight connection of cells of the artery wall. In addition, there is an effective pump on the surface of the cells which sends substances out again if they penetrate the cells.

These two mechanisms make it difficult to treat diseases in the brain because they block medications. The injection of gas-filled microbubbles into the veins accompanied by targeted ultrasound on specific areas of the brain makes it possible to create small, temporary openings or pores in the blood-brain barrier, allowing medications to pass into the brain tissue.

“We have developed a nanoparticle microbubble. The nanoparticles can contain medications and stabilise gas bubbles by forming a shell along their surface. Targeted ultrasound on the brain allows a high concentration of nanoparticles containing medication inside the brain tissue,” Dr Davies states.

The project was launched in 2013 and will run until the end of 2017. The budget is just over NOK 20 million. NTNUs partners are SINTEF; St. Olavs Hospital, Trondheim University Hospital; the University of Bergen and the Medical University of Graz in Austria.

Strengthening the immune system

CEO Esben A. Nilssen. (Photo: IC Targets ) The Oslo-based company IC Targets (formerly Epitarget) has developed a method that uses a fat-based (lipid) nanoparticle to transport medication to a tumour, where it accumulates. The particles dissolve and release the agent at the tumour site.

“Our project aims to improve existing cancer medications by stimulating the patient’s immune system,” states CEO Esben A. Nilssen. The liposome helps to create an overall increase in, and activation of, white blood cells, which means that the body makes better use of monoclonal antibodies, which is a type of cancer medicine. And there are few known, serious side effects. “In addition, treatment does not require any complicated, technical procedures,” Mr Nilssen says.

IC Targets only has two employees at present, but there are at least six other specialists involved in moving the process forward. A strong research environment of close to 30 persons in Lyon (France) and Oslo, Trondheim and Tromsø (Norway) provides a solid scientific foundation on which to develop this type of concept.

“This is not something that emerges in a vacuum. We are at the forefront of research on biochemistry and nanoparticles in Norway.”

The project is planned to continue through 2016, after which will come the standard clinical testing and the approval process associated with pharmaceutical development. An optimistic, realistic estimate for the market launch of a medicine based on this technology is by 2023.

 

Written by:
Atle Abelsen

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