高い腫瘍選択性を有する高分子化抗がん剤の開発に関する基礎的研究

博士（薬学）崇城大

Synthesis and In Vitro Assessment of pH-Sensitive Human Serum Albumin Conjugates of Pirarubicin

In a previous study, we reported on the development of a synthetic polymer conjugate of pirarubicin (THP) that was formed via an acid-labile hydrazone bond between the polymer and the THP. However, the synthetic polymer itself was non-biodegradable, which could lead to unexpected adverse effects. Human serum albumin (HSA), which has a high biocompatibility and good biodegradability, is also a potent carrier for delivering antitumor drugs. The objective of this study was to develop pH-sensitive HSA conjugates of THP (HSA-THP), and investigate the release of THP and the cytotoxicity under acidic conditions in vitro for further clinical development. HSA-THP was synthesized by conjugating maleimide hydrazone derivatives of THP with poly-thiolated HSA using 2-iminothiolane, via a thiol-maleimide coupling reaction. We synthesized two types of HSA-THP that contained different amounts of THP (HSA-THP2 and HSA-THP4). Free THP was released from both of the HSA conjugates more rapidly at an acidic pH, and the rates of release for HSA-THP2 and HSA-THP4 were similar. Moreover, both HSA-THPs exhibited a higher cytotoxicity at acidic pH than at neutral pH, which is consistent with the effective liberation of free THP under acidic conditions. These findings suggest that these types of HSA-THPs are promising candidates for further development

プロポリス成分カフェ酸エステル類がガングリオシドGD3 単分子膜に及ぼす影響

The distribution of benzyl caffeate (BC), cinnamyl caffeate (CC) and phenethyl caffeate (PC) isolated from propolis in ganglioside GD3 (GD3) monolayer as a model of a tumor membrane, and their effects of the caffeic acid esters on the GD3 monolayer were observed by atomic force microscopy (AFM). BC and PC distributed in the GD3 monolayer markedly changed the morphology of the GD3 monolayer from a flat surface to a percolated pattern, whereas CC distributed in the GD3 monolayer exhibited a broken percolation pattern. The effects of BC and PC on the GD3 membrane were similar to those of known antitumor compounds, suggesting that BC and PC may possess antitumor activity. The activity of CC seems to be weaker than that of BC and PC

ガングリオシドG[D3](GD3)単分子膜およびリン脂質/GD3混合単分子膜中へのカフェ酸の分布と作用

The distribution of caffeic acid (CA) in ganglioside GD3 (GD3) monolayer and in mixeddipalmitoylphosphatidylcholine (DPPC)/GD3 monolayer as models of tumor membrane, and the effects ofCA on the GD3 monolayer and the mixed DPPC/GD3 monolayer were observed by atomic forcemicroscopy (AFM). CA distributed in the GD3 monolayer markedly changed the morphology of the GD3monolayer from a flat and uniform surface to a percolated pattern. Furthermore, CA distributed in themixed DPPC/GD3 monolayer clearly changed the morphology of the mixed DPPC/GD3 monolayer froman unclear percolated surface to a typical percolation pattern. The effects of CA on the GD3 membraneand the mixed DPPC/GD3 membrane were similar to those of benzyl caffeate and known antitumorcompounds, suggesting that CA might possess antitumor activity

リン脂質/ガングリオシドG[D]₃混合単分子膜中へのカフェ酸エステル類の分布と作用

The distribution of benzyl caffeate (BC), cinnamyl caffeate (CC) and phenethyl caffeate (PC) isolatedfrom propolis in mixed dipalmitoylphosphatidylcholine (DPPC)/ganglioside GD3 (GD3) monolayer as amodel of a tumor membrane, and the effects of the caffeic acid esters on the mixed DPPC/GD3monolayer were observed by atomic force microscopy (AFM). BC distributed in the mixed DPPC/GD3monolayer formed a clear percolation pattern. The effect of BC on the mixed DPPC/GD3 membranewas similar to those of known antitumor compounds, suggesting that BC might possess antitumoractivity. The effect of PC on the mixed monolayer seems to be weaker than that of BC; however, onGD3 alone monolayer, the effect was similar to that of BC. It was suggested that the molecular size ofthe caffeic acid esters affected their activity on the mixed DPPC/GD3 monolayer

Biodistribution, clearance, and long‐term fate of clinically relevant nanomaterials

Realization of the immense potential of nanomaterials for biomedical applications will require a thorough understanding of how they interact with cells, tissues, and organs. There is evidence that, depending on their physicochemical properties and subsequent interactions, nanomaterials are indeed taken up by cells. However, the subsequent release and/or intracellular degradation of the materials, transfer to other cells, and/or translocation across tissue barriers are still poorly understood. The involvement of these cellular clearance mechanisms strongly influences the long-term fate of used nanomaterials, especially if one also considers repeated exposure. Several nanomaterials, such as liposomes and iron oxide, gold, or silica nanoparticles, are already approved by the American Food and Drug Administration for clinical trials; however, there is still a huge gap of knowledge concerning their fate in the body. Herein, clinically relevant nanomaterials, their possible modes of exposure, as well as the biological barriers they must overcome to be effective are reviewed. Furthermore, the biodistribution and kinetics of nanomaterials and their modes of clearance are discussed, knowledge of the long-term fates of a selection of nanomaterials is summarized, and the critical points that must be considered for future research are addressed

The education systems of Norway and New Zealand : a comparative historical analysis

Norway and New Zealand present striking disparities in the value base and purpose of their national education systems. Norway, both historically and in contemporary times has tended to emphasise the social and moral purposes of education rather than the academic and vocational. Conversely, the vocational purpose of education has tended to take precedence in New Zealand, to the detriment of social and moral values and purposes. These differences have persisted across time from initial foundations to become central to the education ideologies of the welfare state and the new right in both contexts. This thesis examines these differences through the lens of religion. Integral differences exist between the religious foundations of Norway and New Zealand that account for the differences in the education systems of both countries. Norway has a Lutheran religious foundation and influence, while New Zealand is characterised by reformed Protestantism. Lutheranism emphasised morality and community as a means to salvation, while reformed Protestantism placed significance upon vocation and prosperity. Subsequently, for Lutheran Norway, morality and community is an integral aspect of their education system. New Zealand, congruent with reformed Protestant beliefs, has accordingly emphasised the vocational purposes of education that stresses the relationship of education to work and prosperity

Phases of differentiated schooling : a theoretical and conceptual framework of the relationship between religion and schooling in New Zealand and Norway : a dissertation presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Education at Massey University, Palmerston North, New Zealand

This thesis offers a conceptual and theoretical map of the trajectory of relationship between religion and schooling that explains why and how religion has changed within state education policy. The concepts and theories of phases of differentiated schooling are built by applying the theoretical insight from the sociology of religion to the field of education using the case studies of Norway and New Zealand. Phases of differentiated schooling elucidates a general pattern of religious change in schooling, identifying global political, cultural and philosophical variables that have changed the concept of religion within nation state education policy using the methodological insight of historical sociology. The concepts and theories of phases of differentiated schooling are organised by a multi-level structure that allows for the identification and synthesis of these global variables, while also providing flexibility to account for national context and interpretation. Phases of differentiated schooling identifies three distinct theoretical and conceptual phases of relationship between religion and schooling. The first phase, undifferentiated schooling, has its origins in the Middle Ages where Christianity arose to form a monolithic sacred authority over western society. Because Christianity defined knowledge, beliefs and values, Churches held an almost uncontested authority and provision over schooling until the mid-19th century. The second phase, differentiated schooling arose from consolidations of the enlightenment, liberalism, the rise of the nation state and, the scientific revolution. These variables contributed to the progressive differentiation and secularisation of schooling. Finally, the third phase, post-differentiated schooling, reflects what sociologists have observed as the de-privatisation of religion and the desecularisation of society. Religion has changed in concept and increased in significance upon developments in multiculturalism, postmodernism, political ideology and religious education pedagogies. Consequently, from the late 20th century religion has increased in political and public significance, reconceptualising the role of religion within state education policy. This thesis provides a means to understand the variables that determine the conceptualisation of religion within nation state education policy, thereby enhancing the ability to critically evaluate the relationship between religion and schooling

Synthesis and In Vitro Assessment of pH-Sensitive Human Serum Albumin Conjugates of Pirarubicin

In a previous study, we reported on the development of a synthetic polymer conjugate of pirarubicin (THP) that was formed via an acid-labile hydrazone bond between the polymer and the THP. However, the synthetic polymer itself was non-biodegradable, which could lead to unexpected adverse effects. Human serum albumin (HSA), which has a high biocompatibility and good biodegradability, is also a potent carrier for delivering antitumor drugs. The objective of this study was to develop pH-sensitive HSA conjugates of THP (HSA-THP), and investigate the release of THP and the cytotoxicity under acidic conditions in vitro for further clinical development. HSA-THP was synthesized by conjugating maleimide hydrazone derivatives of THP with poly-thiolated HSA using 2-iminothiolane, via a thiol-maleimide coupling reaction. We synthesized two types of HSA-THP that contained different amounts of THP (HSA-THP2 and HSA-THP4). Free THP was released from both of the HSA conjugates more rapidly at an acidic pH, and the rates of release for HSA-THP2 and HSA-THP4 were similar. Moreover, both HSA-THPs exhibited a higher cytotoxicity at acidic pH than at neutral pH, which is consistent with the effective liberation of free THP under acidic conditions. These findings suggest that these types of HSA-THPs are promising candidates for further development