京都大学 / 新制・課程博士 / 博士(医学) / 甲第23769号 / 医博第4815号 / 新制||医||1056(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中本 裕士, 教授 大森 孝一, 教授 上杉 志成 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Yes / We report the effect of low-energy thermal neutron irradiation on the antiproliferative activities of a highly hydrophobic organometallic arene ruthenium dithiolatoecarborane complex [Ru(p-cymene) (1,2- dicarba-closo-dodecarborane-1,2-dithiolato)] (1), and of its formulation in Pluronic® triblock copolymer P123 coreeshell micelles (RuMs). Complex 1 was highly active, with and without neutron irradiation, towards human ovarian cancer cells (A2780; IC50 0.14 mM and 0.17 mM, respectively) and cisplatinresistant human ovarian cancer cells (A2780cisR; IC50 0.05 and 0.13 mM, respectively). Complex 1 was particularly sensitive to neutron irradiation in A2780cisR cells (2.6 more potent after irradiation compared to non-irradiation). Although less potent, the encapsulated complex 1 as RuMs nanoparticles resulted in higher cellular accumulation (2.5 ), and was sensitive to neutron irradiation in A2780 cells (1.4 more potent upon irradiation compared to non-irradiation). / We thank the Leverhulme Trust (Early Career Fellowship No. ECF-2013-414 to NPEB), the University of Warwick (Grant No. RD14102 to NPEB), the University of Birmingham/EPSRC Follow-on- Fund (Grant No UOBFOF026 to BP), the ERC (Grant No. 247450 to PJS), EPSRC (EP/F034210/1 to PJS).

Yes / Boron neutron capture therapy (BNCT) has a long history of unfulfilled promises for the treatment of aggressive cancers. In the last two decades, chemists, physicists, and clinical scientists have been coordinating their efforts to overcome practical and scientific challenges needed to unlock its full therapeutic potential. From a chemistry point of view, the two current small-molecule drugs used in the clinic were developed in the 1950s, however, they both lack some of the essential requirements for making BNCT a successful therapeutic modality. Novel strategies are currently used to design new drugs, more selective towards cancer cells and tumours, as well as able to deliver high boron contents to the target. In this context, macromolecules, including polymers, are promising tools to make BNCT an effective, accepted, and front-line therapy against cancer. In this review, we will provide a brief overview of BNCT, and its potential and challenges, and we will discuss the most promising strategies that have been developed so far.

<p>Developing radiation delivery systems for optimisation of absorbed dose to the target without normal tissue toxicity requires advanced calculations for transport of radiation. In this thesis absorbed dose and fluence in different radiotherapy applications were calculated by using Monte Carlo (MC) simulations.</p><p>In paper I-III external neutron activation of gadolinium (Gd) for intravascular brachytherapy (GdNCB) and tumour therapy (GdNCT) was investigated. MC codes MCNP and GEANT4 were compared. MCNP was chosen for neutron capture reaction calculations. Gd neutron capture reaction includes both very short range (Auger electrons) and long range (IC electrons and gamma) products. In GdNCB the high-energetic gamma gives an almost flat absorbed dose delivery pattern, up to 4 mm around the stent. Dose distribution at the edges and inside the stent may prevent stent edge and in-stent restenosis. For GdNCT the absorbed dose from prompt gamma will dominate over the dose from IC and Auger electrons in an in vivo situation. The absorbed dose from IC electrons will enhance the total absorbed dose in the tumours and contribute to the cell killing.</p><p>In paper IV a model for calculation of inter-cluster cross-fire radiation dose from β-emitting radionuclides in a breast cancer model was developed. GEANT4 was used for obtaining absorbed dose. The dose internally in cells binding the isotope (self-dose) increased with decreasing β-energy except for the radionuclides with substantial amounts of conversion electrons and Auger electrons. An effective therapy approach may be a combination of radionuclides where the high self-dose from nuclides with low β-energy should be combined with the inter-cell cluster cross-fire dose from high energy β-particles.</p><p>In paper V MC simulations using correlated sampling together with importance sampling were used to calculate spectra perturbations in detector volumes caused by the detector silicon chip and its encapsulation. Penelope and EGSnrc were used and yielded similar results. The low energy part of the electron spectrum increased but to a less extent if the silicon detector was encapsulated in low z-materials.</p>

La lutte contre le cancer est l'un des défis majeurs du XXème siècle. Pour que les tumeurs puissent se développer dans l'organisme, elles ont besoin d'un apport en nutriment par le biais de vaisseaux sanguins pour se faire, elles vont avoir recours au processus angiogénique. Lors de ce processus, les cellules endothéliales qui tapissent la paroi des vaisseaux sanguins vont se multiplier et créer de nouveaux vaisseaux sanguins qui vont permettre la vascularisation des tumeurs. L'angiogenèse constitue donc aujourd'hui un axe de recherche pour la lutte contre la progression tumorale et donc contre le cancer. Lors de ce développement tumoral, une enzyme, l'aminopeptidase neutre APN est surexprimée sur les parois des cellules endothéliales. Différentes études ont été menées et montrent que l'inhibition de cette enzyme bloque la progression tumorale. Mon travail au sein de l'équipe du Pr Céline Tarnus consistait en la conception et la synthèse d'inhibiteurs de l'APN. Une relation structure activité de nos composés vis-à-vis de l'APN a tout d'abord été effectuée. Le développement de synthèse du composé le plus actif ont été faite, puis la synthèse d'inhibiteurs d'APN ayant pour objectif l'utilisation de la BNCT a été abordée. / The fight against the cancer is one of the most important struggles of this century. For the development of the tumors inside the body, they need to receive nutriments by the blood vessels and they use the angiogenic process. During this process, the endothelial cells being shown on the wall of the blood vessel will multiply and design new blood vessel, which will allow the tumor's vascularisation. Today, the angiogenesis is an axis of research for the fight against the cancer. During the tumoral development, the aminopeptidase N (APN) is overexpressed on the wall of endothelial cells. Various studies have shown that the inhibition of this enzyme stops the tumoral progression. My work in the Pr. Céline Tarnus Team consists in the conception and the synthesis of APN's inhibitors. In a first time, a structure activity relationship has been realized. Syntheses of a subnamolar compound have been developed, and then the synthesis of APN's inhibitors with the use of BNCT has been got onto.

Developing radiation delivery systems for optimisation of absorbed dose to the target without normal tissue toxicity requires advanced calculations for transport of radiation. In this thesis absorbed dose and fluence in different radiotherapy applications were calculated by using Monte Carlo (MC) simulations. In paper I-III external neutron activation of gadolinium (Gd) for intravascular brachytherapy (GdNCB) and tumour therapy (GdNCT) was investigated. MC codes MCNP and GEANT4 were compared. MCNP was chosen for neutron capture reaction calculations. Gd neutron capture reaction includes both very short range (Auger electrons) and long range (IC electrons and gamma) products. In GdNCB the high-energetic gamma gives an almost flat absorbed dose delivery pattern, up to 4 mm around the stent. Dose distribution at the edges and inside the stent may prevent stent edge and in-stent restenosis. For GdNCT the absorbed dose from prompt gamma will dominate over the dose from IC and Auger electrons in an in vivo situation. The absorbed dose from IC electrons will enhance the total absorbed dose in the tumours and contribute to the cell killing. In paper IV a model for calculation of inter-cluster cross-fire radiation dose from β-emitting radionuclides in a breast cancer model was developed. GEANT4 was used for obtaining absorbed dose. The dose internally in cells binding the isotope (self-dose) increased with decreasing β-energy except for the radionuclides with substantial amounts of conversion electrons and Auger electrons. An effective therapy approach may be a combination of radionuclides where the high self-dose from nuclides with low β-energy should be combined with the inter-cell cluster cross-fire dose from high energy β-particles. In paper V MC simulations using correlated sampling together with importance sampling were used to calculate spectra perturbations in detector volumes caused by the detector silicon chip and its encapsulation. Penelope and EGSnrc were used and yielded similar results. The low energy part of the electron spectrum increased but to a less extent if the silicon detector was encapsulated in low z-materials.

This thesis deals with the description of $\gamma-$ray deexcitation of neutron resonances produced in thermal neutron capture below neutron separation energy. A subject of this thesis is obtaining information on absolute value of \textit{photon strength function} (PSF) achieved from primary transitions in thermal neutron capture. The aim is to map and bring new information on absolute value of photon strength function (PSF) in $^{156}$Gd and $^{158}$Gd. The method which was used in this thesis can lead to refusion of several models of PSF a level density. Powered by TCPDF (www.tcpdf.org)

Bibliography: leaves 178-195.

Bibliography: leaves 178-195. / xiv, 195 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Chemistry, 2001

"January 2004" / Bibliography: leaves 163-184. / v, 184 leaves : ill. (some col.), photos ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, School of Chemistry and Physics, Discipline of Chemistry, 2004