title: Studies Towards a pH-Sensitive Anticancer Prodrug Model

authors: Teng, Xiao Shi

subjects: tumour-activated prodrug (TAP)

abstract: Tumour-activated prodrug (TAP) is designed to aim at increasing the prodrug selectivity to kill cancer cells. One strategy to is to design a TAP containing an amine cytotoxin, present as an amide function, which could be released more rapidly in the low pH environment of tumour tissues when amide undergoes hydrolysis.
The prodrug model (1) was the subject of the current study. At lower pH its un-ionised carboxylic acid group provides neighbouring catalysis of hydrolysis of the adjacent amide. It was synthesised via ring-opening of the imide (2) which itself was directly synthesised from endo-bicyclo[2.2.2]octa-5-ene-2,3-dicarboxylic anhydride and p-methoxyaniline.
The pH-rate profile of (1) was established over the pH range of 3-10, covering rapid hydrolysis of un-ionised acid-amide at lower pH but slower imide formation above pH 8 from the ionised acid-amide. From the kinetic data were calculated the dissociation constant for (1) (pKa: 5.1 at 30 C) and limiting lower pH rate constant for hydrolysis of (1) in its fully neutral form (klim: 0.44 min-1 at 30 C). The data in the pH range of 8-10 provided klow (0.067 min-1) representing formation of (2) from fully ionised (1).
The following equilibrium reaction was also investigated at high pH, at which (1) was in its fully ionised amide carboxylate form, by kinetic studies on (2) in hydroxide solutions.
Imide + OH- Amide carboxylate
The second order rate constant for the forward reaction, kf, was 74 L mol-1 min-1 which with klow for the reverse reaction gave K as 1100 L mol-1.

text: Studies Towards a pH-Sensitive Anticancer Prodrug Model Tumour-activated prodrug (TAP) is designed to aim at increasing the prodrug selectivity to kill cancer cells. One strategy to is to design a TAP containing an amine cytotoxin, present as an amide function, which could be released more rapidly in the low pH environment of tumour tissues when amide undergoes hydrolysis.
The prodrug model (1) was the subject of the current study. At lower pH its un-ionised carboxylic acid group provides neighbouring catalysis of hydrolysis of the adjacent amide. It was synthesised via ring-opening of the imide (2) which itself was directly synthesised from endo-bicyclo[2.2.2]octa-5-ene-2,3-dicarboxylic anhydride and p-methoxyaniline.
The pH-rate profile of (1) was established over the pH range of 3-10, covering rapid hydrolysis of un-ionised acid-amide at lower pH but slower imide formation above pH 8 from the ionised acid-amide. From the kinetic data were calculated the dissociation constant for (1) (pKa: 5.1 at 30 C) and limiting lower pH rate constant for hydrolysis of (1) in its fully neutral form (klim: 0.44 min-1 at 30 C). The data in the pH range of 8-10 provided klow (0.067 min-1) representing formation of (2) from fully ionised (1).
The following equilibrium reaction was also investigated at high pH, at which (1) was in its fully ionised amide carboxylate form, by kinetic studies on (2) in hydroxide solutions.
Imide + OH- Amide carboxylate
The second order rate constant for the forward reaction, kf, was 74 L mol-1 min-1 which with klow for the reverse reaction gave K as 1100 L mol-1.

year: 2010

title: Policy and law in development of relationship property legislation in New Zealand

authors: Wilson, Margaret

abstract: The central theme of this paper is an analysis of the relationship between policy and law in the context of relationship property. The focus of the paper is on the development of the policy that provided the basis for the Property Relationships Act (PRA). At the outset I acknowledge a personal long term involvement in the campaign for legal recognition of women's right to entitlement of an equal share of the assets accumulated during the marriage or relationship.

text: Policy and law in development of relationship property legislation in New Zealand The central theme of this paper is an analysis of the relationship between policy and law in the context of relationship property. The focus of the paper is on the development of the policy that provided the basis for the Property Relationships Act (PRA). At the outset I acknowledge a personal long term involvement in the campaign for legal recognition of women's right to entitlement of an equal share of the assets accumulated during the marriage or relationship.

year: 2017

title: Mai ngā pouwhirinaki - The experiences of whānau caring for Māori tangata whaiora with traumatic brain injury in the Waikato

authors: Silveira, Maia

subjects: Traumatic brain injury

abstract: In Aotearoa today, Māori have a disproportionate experience of Traumatic Brain Injury (TBI) in the community and in prisons compared to non-Māori. Furthermore, Māori have higher mortality rates following TBI, and are more likely to have a prolonged stay in hospital then be discharged without community support services compared with non-Māori. Currently, many of the post-acute rehabilitation services are located in the Auckland region which causes undue pressure of whānau needs, finances, and work commitments for many whānau and individuals with TBI from the Waikato region. My research focuses on the experiences of whānau navigators experience of caring for Māori tangata whaiora with TBI in the Waikato region. Whānau navigators for this thesis refers to members of the whānau who have familial obligations of care. Within this thesis I consult and engage with whānau about post-acute rehabilitation services. This is a qualitative based research project, which draws upon narrative inquiry, and a Kaupapa Māori research paradigm. Documenting these experiences will provide empirical evidence to highlight the invaluable role whānau have within recovery and the value of whānau support. This research can be used to identify the dynamic needs of whānau and encourage the healthcare system to provide a service that is consistent with Kaupapa Māori health frameworks and practices which at present is non- existent. As a result, the project will help inform the development of a service model within TBI that can better reflect and support the needs of whānau and Māori communities, that is a locally derived practice and more applicable and appropriate for Māori. Mauri ora!

text: Mai ngā pouwhirinaki - The experiences of whānau caring for Māori tangata whaiora with traumatic brain injury in the Waikato In Aotearoa today, Māori have a disproportionate experience of Traumatic Brain Injury (TBI) in the community and in prisons compared to non-Māori. Furthermore, Māori have higher mortality rates following TBI, and are more likely to have a prolonged stay in hospital then be discharged without community support services compared with non-Māori. Currently, many of the post-acute rehabilitation services are located in the Auckland region which causes undue pressure of whānau needs, finances, and work commitments for many whānau and individuals with TBI from the Waikato region. My research focuses on the experiences of whānau navigators experience of caring for Māori tangata whaiora with TBI in the Waikato region. Whānau navigators for this thesis refers to members of the whānau who have familial obligations of care. Within this thesis I consult and engage with whānau about post-acute rehabilitation services. This is a qualitative based research project, which draws upon narrative inquiry, and a Kaupapa Māori research paradigm. Documenting these experiences will provide empirical evidence to highlight the invaluable role whānau have within recovery and the value of whānau support. This research can be used to identify the dynamic needs of whānau and encourage the healthcare system to provide a service that is consistent with Kaupapa Māori health frameworks and practices which at present is non- existent. As a result, the project will help inform the development of a service model within TBI that can better reflect and support the needs of whānau and Māori communities, that is a locally derived practice and more applicable and appropriate for Māori. Mauri ora!

year: 2022