Nanomedicine and Sonopermeation in the Treatment of Cancer
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- Institutt for fysikk 
Treatment of cancer is an enormous challenge that involves multiple biological barriers and drugs with limited specificity, which makes treatment both ineffective and debilitating to the patient. One of the approaches that have gotten attention during the last three decades is encapsulation of drugs into nanoparticles, to create nanomedicines. Nanoparticles can protect drugs from degradation and protein binding, alter the biodistribution to protect healthy tissue from the drug, and to some degree accumulate in tumors due to the enhanced permeability and retention effect. However, due to the size of nanomedicines, the transport barriers in tumors are even greater challenges for nanomedicines than for molecular drugs. The blood brain barrier effectively stops entry into tumors in the brain, and the dense extracellular matrix, interstitial pressure and solid stress in tumors elsewhere hinders transport of the nanoparticles. Ultrasound in combination with microbubbles can be used for what we have described as sonopermeation, which can improve the effect of drugs and nanomedicines both in the brain and in solid tumors. The mechanisms behind the improved effect are not fully understood. In this thesis the development of a drug delivery product consisting of nanoparticles and nanoparticle-stabilized microbubbles to be used for sonopermeation is described. The nanoparticles are made by miniemulsion synthesis of poly(alkyl cyanoacrylate). In the first part of the thesis these nanoparticles are characterized for cellular uptake, intracellular degradation and drug release, surface properties and toxicity, which are all important properties of a drug delivery system. We found that poly(ethyl-buthyl cyanoacrylate) nanoparticles covered with two relatively short PEGs had the most favorable properties and were used in subsequent studies. The second part of this thesis revolves tumor models and the effect of sonopermeation with the nanoparticle-microbubble system. We evaluated five tumor models for nanoparticle-related properties and found that blood vessel quantity and quality were both important factors. We found that the effect of sonopermeation differed between two of them amongst other due to the solid stress in the tumor. We also used the nanoparticle-microbubble system to open the blood brain barrier in an orthotopic glioma model in mice, and found that we could permeate the blood brain barrier, but that this was not sufficient to achieve improved drug delivery probably due to the presence of efflux pumps. This thesis shows that the development of nanomedicine is challenging. This is both due to technicalities of producing nanoparticles with a defined set of properties, and due to the biological barriers that differ between patients and diseases. The thesis is concluded by an opinon-paper where we suggest that a more disease-driven approach to nanomedicine is needed, but that nanomedicine will play an important role in future treatment regimens amongst other by using the nanomedicine toolbox in combination with external forces such as ultrasound.
Has partsPaper 1: Sulheim, Einar*; Baghirov, Habib*; von Haartman, Eva; Bøe, Andreas; Åslund, Andreas; Mørch, Ýrr Asbjørg; Davies, Catharina de Lange. Cellular uptake and intracellular degradation of poly(alkyl cyanoacrylate) nanoparticles. Journal of Nanobiotechnology 2016 ;Volum 14.(1) s.
Paper 2: Åslund, Andreas; Sulheim, Einar; Snipstad, Sofie; von Haartman, Eva; Baghirov, Habib; Starr, Nichola; Løvmo, Mia Kvåle; Lelu, Sylvie; Scurr, David; Davies, Ruth Catharina de Lange; Schmid, Ruth; Mørch, Yrr Asbjørg. Quantification and qualitative effects of different PEGylations on poly(butyl cyanoacrylate) nanoparticles. Molecular Pharmaceutics 2017 ;Volum 14.(8) s. 2560-2569
Paper 3: Sulheim, Einar; Iversen, Tore Geir; To, Vu; Klinkenberg, Geir; Sletta, Håvard; Schmid, Ruth; Hatletveit, Anne Rein; Wågbø, Ane Marit; Sundan, Anders; Skotland, Tore; Sandvig, Kirsten; Mørch, Ýrr Asbjørg. Cytotoxicity of poly(Alkyl cyanoacrylate) nanoparticles. International Journal of Molecular Sciences 2017 ;Volum 18.(11) s. -
Paper 4: Sulheim, Einar; Kim, Jana; van Wamel, Annemieke; Kim, Eugene; Snipstad, Sofie; Vidic, Igor; Grimstad, Ingeborg; Widerøe, Marius; Torp, Sverre Helge; Lundgren, Steinar; Waxman, David J.; Davies, Catharina de Lange. Multi-modal characterization of vasculature and nanoparticle accumulation in five tumor xenograft models. Journal of Controlled Release 2018 ;Volum 279. s. 292-305
Paper 5: Snipstad, Sofie; Sulheim, Einar; Davies, Catharina de Lange; Moonen, Chrit; Storm, Gert; Kiessling, Fabian; Schmid, Ruth; Lammers, Twan. Sonopermeation to improve drug delivery to tumors: from fundamental understanding to clinical translation. Expert Opinion on Drug Delivery 2018 ;Volum 15.(12) s. 1249-1261 Not included du to copyright restrictions, available at https://doi.org/10.1080/17425247.2018.1547279
Paper 6: Sulheim E, Mørch Y, Snipstad S, Borgos SE, Miletic H, Bjerkvig R, Davies CdL, Åslund AKO. Therapeutic Effect of Cabazitaxel and Blood-Brain Barrier opening in a Patient-Derived Glioblastoma Model. Nanotheranostics 2019; 3(1):103-112.
Paper 7: Sulheim, E., Hanson, I., Snipstad, S., Boucher, Y., Davies, C. de L. Sonopermeation Improves Nanomedicine Drug Delivery to Tumors with Low Stress-induced Deformation. Manuscript under preparation.
Paper 8: Meel, R. v d.*, Sulheim, E.*, Kiessling, F., Mulder, W. J. M., Lammers, T. SMART cancer nanomedicine: Concepts to create clinical impact. Manuscript under preparation