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postgraduate thesis: Anti-cancer organoplatinum(II) N-heterocyclic carbene complexes and anti-amyloidogenic timosaponins : metabolism, nanoformulations and biological studies
Title | Anti-cancer organoplatinum(II) N-heterocyclic carbene complexes and anti-amyloidogenic timosaponins : metabolism, nanoformulations and biological studies |
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Authors | |
Advisors | |
Issue Date | 2018 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Wan, P. K. [溫佩琪]. (2018). Anti-cancer organoplatinum(II) N-heterocyclic carbene complexes and anti-amyloidogenic timosaponins : metabolism, nanoformulations and biological studies. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | The clinical success of cisplatin represents a milestone achievement in anti-cancer therapy. However, the problems of chemoresistance and severe side effects are believed due to its inherent instability and toxic metabolites generated during biostranformation. Such adversities have spurred a pressing need for development of new and stable platinum-based therapeutic agents with improved efficacy, safety profile, and alternative mechanistic actions. A recently reported example is the luminescent and physiologically stable cyclometalated platinum(II) complex [Pt(C^N^N)(NHCnBu)]PF6 (Pt1a) with strong σ-donating N-heterocyclic carbene (NHC) ligand. This thesis describes detailed studies of in vivo metabolism, pharmacokinetic disposition, target engagement of Pt1a and the formulations by harnessing PEGylation. The related studies were also extended to the bioactive natural products timosaponins.
By using UPLC-QTOF tandem mass spectrometry, the predominant metabolic pathways of Pt1a in in vitro rat/human liver microsomes and in vivo mouse model were proposed to be hydroxylation and glucuronidation. The hydrophilic metabolites displayed lower cytotoxicity towards cancer and normal cells, and being eliminated readily via urinary excretion compared with Pt1a. Thereby, two polymeric nanoformulations (M1P and Pt1a-NP) were prepared with an intention to modulate the pharmacokinetic profiles of Pt(II)-NHC complexes. M1P and Pt1a-NP were found to exhibit prolonged plasma retention, increased tumor accumulation and reduced platinum deposition in normal tissues compared to Pt1a. Both M1P and Pt1a-NP also displayed effective in vivo anti-tumor activities in tumor-bearing mice without causing apparent systemic toxicity, whereas cisplatin induced significant body weight loss and severe nephrotoxicity at equivalent platinum dosage.
Target engagement of Pt1a with the putative protein targets identified previously was studied by cellular thermal shift assay. Vimentin, a cytoskeletal protein, was found to exhibit the greatest stabilization against heat denaturation by Pt1a treatment. The unique [Pt(C^N^N)(NHC)]+ scaffold imparted stronger binding interaction between Pt1a and vimentin compared with that of HSP60 or other Pt(II) derivatives with alternative pincer or isocyanide coordination. Pt1a significantly promoted vimentin aggregation as revealed by TEM and immunofluorescence studies. The perturbation of cellular cytoskeletal structure was associated with the potent anti-migratory and anti-metastatic activities of Pt1a in vimentin-overexpressing cancer cells. Additionally, a panel of cyclometalated Pt(IV)-NHC complexes were synthesized and characterized. The favorable reductive activation, higher lipophilicity and cellular uptake conferred the comparable anti-cancer and anti-tumor properties of the Pt(IV)-NHC complexes to Pt1a, demonstrating the possibility of using Pt(IV) prodrug for Pt1a delivery.
The molecular target and metabolism analyses were also extended to the study of bioactive natural products timosaponins. The inhibition of production of β-amyloid (Aβ) peptide is a key approach in the development of therapeutics for treatment of Alzheimer’s disease. The natural products timosaponins and their synthesized derivatives containing sarsasapogenin (SSG) as the aglycone were demonstrated to effectively lower the Aβ production and markedly stimulate neurtite outgrowth. Mechanistic studies on timosaponins treatment revealed modulation of amyloid precursor protein processing through suppression of β-cleavage and preferential reducing of the Aβ42 levels without affecting γ-secretase activity. Moreover, mice administered with SSG and “SSG-aglyconed” timosaponins lowered the brain Aβ42 levels. The timosaponins and their deglycosylated metabolites were also detected in mouse plasma and brain. (499 words) |
Degree | Doctor of Philosophy |
Subject | Organoplatinum compounds - Therapeutic use Natural products - Therapeutic use |
Dept/Program | Chemistry |
Persistent Identifier | http://hdl.handle.net/10722/308651 |
DC Field | Value | Language |
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dc.contributor.advisor | Che, CM | - |
dc.contributor.advisor | Lok, CN | - |
dc.contributor.author | Wan, Pui Ki | - |
dc.contributor.author | 溫佩琪 | - |
dc.date.accessioned | 2021-12-06T01:04:07Z | - |
dc.date.available | 2021-12-06T01:04:07Z | - |
dc.date.issued | 2018 | - |
dc.identifier.citation | Wan, P. K. [溫佩琪]. (2018). Anti-cancer organoplatinum(II) N-heterocyclic carbene complexes and anti-amyloidogenic timosaponins : metabolism, nanoformulations and biological studies. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/308651 | - |
dc.description.abstract | The clinical success of cisplatin represents a milestone achievement in anti-cancer therapy. However, the problems of chemoresistance and severe side effects are believed due to its inherent instability and toxic metabolites generated during biostranformation. Such adversities have spurred a pressing need for development of new and stable platinum-based therapeutic agents with improved efficacy, safety profile, and alternative mechanistic actions. A recently reported example is the luminescent and physiologically stable cyclometalated platinum(II) complex [Pt(C^N^N)(NHCnBu)]PF6 (Pt1a) with strong σ-donating N-heterocyclic carbene (NHC) ligand. This thesis describes detailed studies of in vivo metabolism, pharmacokinetic disposition, target engagement of Pt1a and the formulations by harnessing PEGylation. The related studies were also extended to the bioactive natural products timosaponins. By using UPLC-QTOF tandem mass spectrometry, the predominant metabolic pathways of Pt1a in in vitro rat/human liver microsomes and in vivo mouse model were proposed to be hydroxylation and glucuronidation. The hydrophilic metabolites displayed lower cytotoxicity towards cancer and normal cells, and being eliminated readily via urinary excretion compared with Pt1a. Thereby, two polymeric nanoformulations (M1P and Pt1a-NP) were prepared with an intention to modulate the pharmacokinetic profiles of Pt(II)-NHC complexes. M1P and Pt1a-NP were found to exhibit prolonged plasma retention, increased tumor accumulation and reduced platinum deposition in normal tissues compared to Pt1a. Both M1P and Pt1a-NP also displayed effective in vivo anti-tumor activities in tumor-bearing mice without causing apparent systemic toxicity, whereas cisplatin induced significant body weight loss and severe nephrotoxicity at equivalent platinum dosage. Target engagement of Pt1a with the putative protein targets identified previously was studied by cellular thermal shift assay. Vimentin, a cytoskeletal protein, was found to exhibit the greatest stabilization against heat denaturation by Pt1a treatment. The unique [Pt(C^N^N)(NHC)]+ scaffold imparted stronger binding interaction between Pt1a and vimentin compared with that of HSP60 or other Pt(II) derivatives with alternative pincer or isocyanide coordination. Pt1a significantly promoted vimentin aggregation as revealed by TEM and immunofluorescence studies. The perturbation of cellular cytoskeletal structure was associated with the potent anti-migratory and anti-metastatic activities of Pt1a in vimentin-overexpressing cancer cells. Additionally, a panel of cyclometalated Pt(IV)-NHC complexes were synthesized and characterized. The favorable reductive activation, higher lipophilicity and cellular uptake conferred the comparable anti-cancer and anti-tumor properties of the Pt(IV)-NHC complexes to Pt1a, demonstrating the possibility of using Pt(IV) prodrug for Pt1a delivery. The molecular target and metabolism analyses were also extended to the study of bioactive natural products timosaponins. The inhibition of production of β-amyloid (Aβ) peptide is a key approach in the development of therapeutics for treatment of Alzheimer’s disease. The natural products timosaponins and their synthesized derivatives containing sarsasapogenin (SSG) as the aglycone were demonstrated to effectively lower the Aβ production and markedly stimulate neurtite outgrowth. Mechanistic studies on timosaponins treatment revealed modulation of amyloid precursor protein processing through suppression of β-cleavage and preferential reducing of the Aβ42 levels without affecting γ-secretase activity. Moreover, mice administered with SSG and “SSG-aglyconed” timosaponins lowered the brain Aβ42 levels. The timosaponins and their deglycosylated metabolites were also detected in mouse plasma and brain. (499 words) | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Organoplatinum compounds - Therapeutic use | - |
dc.subject.lcsh | Natural products - Therapeutic use | - |
dc.title | Anti-cancer organoplatinum(II) N-heterocyclic carbene complexes and anti-amyloidogenic timosaponins : metabolism, nanoformulations and biological studies | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Chemistry | - |
dc.description.nature | published_or_final_version | - |
dc.date.hkucongregation | 2018 | - |
dc.identifier.mmsid | 991044448916703414 | - |