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NANO2021-Nanoteknologi og nye materiale

NanoSonoChemotherapy for Diffuse Intrinsic Pontine Glioma (NSC4DIPG)

Awarded: NOK 3.6 mill.

NSC4DIPG is a transnational European project with partners from Germany, The Netherlands and Norway. The consortium is composed of experts in clinical patient treatment, preclinical drug development, nanomedicine, ultrasound diagnostics and treatment, and sonoporation. Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive brain tumours that typically affect 300-400 children in Europe at an age of 6-10, and for which no curative treatments are currently available. DIPG are diffusely located within the brainstem, which controls vital functions, making surgery impossible and radiotherapy very difficult. Moreover, both classical and targeted chemotherapeutic drugs fail in DIPG, because they cannot pass the blood-brain barrier (BBB) and therefore do not reach the pathological site. More than 95% of children suffering from DIPG die within two years after initial diagnosis. The NSC4DIPG project is now formally closed at SINTEF, however a final in vivo study with nanoformulations developed in the project will be run by project partners. The main goal of NSC4DIPG was to establish sonochemotherapy as a novel treatment method for DIPG. By combining nanocarriers of different sizes, loaded with optimal drug combinations against DIPG, with local opening of the BBB using focused ultrasound and microbubbles, the project aimed at achieving significant concentrations of drug in the diseased tissue in the brain. Focus was on optimizing both the drug-loaded nanocarriers and the ultrasound treatment to achieve a high therapeutic effect. All new products were carefully characterized, and efficacy and toxicity were tested in cell-based assays. In vivo experiments in mice with patient-derived, implanted tumours were used to test the efficacy of the best nanomedicines from the in vitro studies and the optimized ultrasound conditions. A special focus was on assuring that the novel treatment method is safe for use in patients. At the end of the project, hopefully 1-2 novel nanomedicine products would be ready for further preclinical assessment and clinical studies. Regulatory, ethical and market topics were taken into consideration in all steps of the product development. The consortium has had two Face-to-Face meetings at the Prinses Máxima Centre in the Netherlands, where many DIPG patients are treated. From spring 2020 on, due to the pandemic, regular virtual meetings were hold. SINTEF performed in total three comprehensive in vitro screening studies of various drugs that are expected to be efficient in killing DIPG cancer cells. First, each drug was tested alone, followed by studying various combinations. Several types of relevant DIPG cancer cells were cultivated in SINTEFs laboratories, as model cell-based systems for in vitro studies of various drugs and nanocarriers. Results were discussed regularly in consortium meetings and the results from the first drug screening study were presented to representatives of the Norwegian Cancer Society at one of SINTEFs regular stakeholder meetings. Based on these results clear drug synergies were identified and one frontrunner drug combination was selected for encapsulation in various types of nanocarriers for further in vitro and in vivo studies. SINTEF also developed polymeric nanocarriers labelled with two different dyes. These nanocarriers serve as model systems in in vitro and in vivo assays to study the interaction of nanocarriers with cells and their distribution in tissue and the brain. These labelled nanocarriers have been sent to other partners for testing. In the meantime, it was observed that the polymer used in these nanocarriers is not well-suited for encapsulation of the initially selected drugs. SINTEF therefore developed novel nanocarriers based on another polymer. Initial tests showed that the initially selected drugs could be encapsulated in these novel nanocarriers. Unfortunately, the results from the final drug screening experiment were available too late in the project for further encapsulation experiments of the most relevant drug combination in our polymeric nanocarriers during this project. Researchers at the Prinses Máxima Centre have performed several initial in vivo studies, with and without ultrasound treatment, with novel drugs of interest for DIPG, to see if ultrasound results in increased drug concentrations in the brain. SINTEF contributed to these studies with quantification of the drugs in various organs. First results indicate that ultrasound may have a positive effect. Towards the end of the project, SINTEF performed in vitro cell-based cytotoxicity studies of nanocarriers from other partners, as well as all ingredients used in their preparation and showed that they do not induce cytotoxicity in the selected cell lines. These nanocarriers will now at one partner site be tested in animal studies, together with ultrasound and microbubbles, to demonstrate the potential of nanosonochemotherapy as future treatment for DIPG.

DIPG er en aggressiv hjernekreft hos barn uten effektiv behandlingsmulighet og med meget høy dødelighet. NSC4DIPG prosjektet har bidratt med ny kunnskap rundt effekt av mange ulike medikamenter og medikamentkombinasjoner og har utviklet nye medikamentfylte nanobærere egnet for nanosonokjemoterapi, som vil følges opp av prosjektpartnerne i etterkant av prosjektet. Resultatene fra prosjektet kan få stor betydning for kreftpasienter i framtiden og dermed bidra til bærekraftsmål 3, god helse og livskvalitet. Prosjektet har gjennom tverrfaglig internasjonalt samarbeid etablert viktig ny kunnskap rundt effekten av medikament og medikamentkombinasjoner på DIPG cellelinjer, hvilke nanobærere som egner seg best for innkapsling av disse medikamentene, samt om ultralydbetingelser for sonoporering. SINTEF har gjennom prosjektet fått utvidet sin kompetanse innen medikamentscreening, preklinisk karakterisering, innkapsling av medikamenter og sonoporering, samt etablert samarbeid med en tysk bedrift.

NSC4DIPG er et transnasjonalt Europeisk prosjekt med partnere fra Tyskland, Nederland og Norge. Konsortiet består av eksperter innen klinisk pasientbehandling, preklinisk medikament utvikling, nanomedisin, ultralyddiagnostikk og -behandling og sonoporering. Diffuse intrinsic pontine glioma (DIPG) er en meget aggressiv hjernetumor som hvert år rammer 300-400 barn i alderen fra 6 til 10 år i Europa. Det finnes ingen behandling i øyeblikket som kurerer denne sykdommen. Mer enn 95% av barn med DIPG dør innen 2 år etter diagnosen. DIPG er diffust lokalisert i hjernestammen som kontrollerer livsviktige funksjoner. Derfor er operasjon ikke mulig og strålebehandling veldig vanskelig. Kreftmedisiner har ingen virkning, fordi de ikke klarer å passere blod-hjerne barrieren og derfor ikke når det syke vevet. Hovedmålet med NSC4DIPG er å etablere nanosonokjemoterapi som ny behandlingsmetode for DIPG. Ved å kombinere nanobærere av ulike størrelser, fylt med optimale medikamentkombinasjoner mot DIPG, med midlertidig og lokal åpning av blod-hjerne barrieren ved hjelp av fokusert ultralyd og mikrobobler, vil man oppnå en oppkonsentrering av medikamenter i det syke vevet i hjernen. Både nanomedisinene og ultralydbehandlingen vil bli optimalisert for en best mulig effekt. Alle nye produkter vil bli nøye karakterisert og effekt og toksisitet testet i celle-baserte analyser. In vivo forsøk i mus med implantert kreft fra pasienter vil bli brukt for å teste effekten av de beste nanomedisinene og de optimale ultralydbetingelser. Spesiell fokus vil bli på å teste at den nye behandlingsmetoden er trygg for pasienten. Etter endt prosjekt håper man å ha utviklet 1-2 nye nanomedisinprodukter klare for videreutvikling og kliniske studier. Regulatoriske, etiske og markedsmessige spørsmål blir inkludert på alle trinn av produktutviklingen.

Funding scheme:

NANO2021-Nanoteknologi og nye materiale