Biodegradable Nanoparticles in Cancer Diagnosis and Therapy

The goal of this project has been to build competence in synthesis and preclinical testing of biodegradable nanoparticles (NPs), and thereby develop safe and efficient NPs for diagnosis and personalized therapy of cancer. To this end we established an interdisciplinary cluster of experts in the fields of NP synthesis, cell biology, immunology, human tumour models in mice, different imaging modalities, biodistribution, pharmacokinetics, and clinical studies. Thus, biodegradable NPs were developed through iterative and collaborative processes between biological studies and optimization of the NPs. NPs displaying beneficial behaviours in in vitro studies were subjected to in vivo studies in various human tumour xenografts in mice, with focus on breast- and colorectal carcinomas. Whole body imaging was performed by different modalities depending on the NPs used and how they were labelled. The therapeutic effect of the NPs was measured and their biodistribution, metabolism and excretion investigated. New polymeric and lipid-based NPs were synthesized as carriers of both hydrophobic and hydrophilic cytostatic drugs. Polymeric NPs were used for establishing different cytotoxicity tests, and several assays has been used. Furthermore, uptake and transport of the NPs in cancer cells were studied by fluorescence microscopy techniques. Immunological responses of different PACA NPs were investigated. Possible changes in metabolism after intravenous injection of these NPs were also studied by MR spectroscopy of liver tissue. Studies of drug-loaded NPs in a breast cancer xenograft in mice showed promising results on reduction of tumour growth. In a recent publication, we reported the effect of doxorubicin encapsulation in liposomes with and without ceramide species that were included due to their pro-apoptotic properties. We demonstrated that the ceramide species enhance the liposomal doxorubicin effect in a cell-specific manner. Furthermore, our data show that toxicity obtained with NPs in vitro is not necessarily reflected by their ability to inhibit tumour growth in vivo. In another article, we demonstrated remarkable good therapeutic effect on breast tumors in mice following injections of cabazitaxel encapsulated in PACA particles. Moreover, we found less infiltration of pro-tumorigenic macrophages in the tumors of mice injected with these NPs, suggesting that these NPs killed the protumorigenic macrophages and thereby contributed to the pronounced therapeutic effect.

Prosjektet har hatt som målsetting å bygge den kompetanse som er nødvendig for utvikling og preklinisk dokumentasjon av biologisk nedbrytbare nanopartikler (NP). For å lykkes med dette etablerte vi en tverrfaglig prosjektgruppe med eksperter innen områdene syntese og design av NP, cellebiologi, immunologi, humane tumormodeller i mus, ulike typer billeddiagnostikk, biodistribusjon, farmakokinetikk og kliniske studier. Forskjellige NP er blitt optimalisert gjennom iterative prosesser basert på resultater i celleforsøk og dyremodeller. Forskningsgruppene har oppnådd betydelige nytteeffekter og bygd tverrfaglig kompetanse om hva som trengs for å bringe slike produkter fram mot markedet. Det inkluderer kunnskap basert både på aktiviteter som resulterte i publikasjoner og på de som medførte terminering. Prosjektet har skapt oppmerksomhet om fagmiljøene og skaffet oss nye samarbeidspartnere, både innen grunnforskning, og i sykehusmiljøer og industri.

The goal of this project is to build the necessary expertise in design/synthesis and preclinical testing of biodegradable nanoparticles (NPs), and thereby engineer safe and efficient NPs for use in medical imaging and personalized therapy of cancer. Novel polymeric and lipid-based NPs will be manufactured as carriers of both hydrophobic and hydrophilic drugs, thus enabling delivery of unique drug cocktails needed for personalized medicine. To this end, multiple challenges must be overcome, and we have est ablished an interdisciplinary cluster of experts in the fields of NP synthesis and design, cell biology, immunology, mouse tumour models, preclinical imaging, biodistribution, pharmacokinetics and clinical studies. Well-characterized biodegradable NPs wil l be made through iterative processes whereby the NPs become optimized based on the outcome of the biological and preclinical experiments. Endocytosis and intracellular transport of the NPs will be studied, i.e. by fluorescent microscopy. Degradation of t he NPs, cytosolic release of the drugs, and cytotoxic effects will be investigated using cellular, biochemical and immunological assays. NPs displaying beneficial behaviours in vitro will be subjected to in vivo studies of various tumour xenografts, focus ing on breast cancer, colorectal carcinoma and ostesarcomas. The therapeutic effect of the NPs will be measured, and the biodistribution, metabolism and excretion will be investigated. We will perform imaging of small animals with different modalities dep ending on the NPs used and how they are labelled. Fluorescent imaging will be used to investigate the biodistribution and accumulation of NPs injected in animals. Whole body imaging will be performed by MR imaging following injection of iron oxide NPs or particles carrying paramagnetic metals, or by using PET/CT imaging of NPs carrying suitable radioactive emitters.