The synthesis and characterisation of Sn(IV) porphyrin derivatives and their potential application in anti-cancer and antimicrobial photodynamic therapy
- Authors: Dingiswayo, Somila
- Date: 2021-10
- Subjects: Porphyrins , Photochemotherapy , Cancer Photochemotherapy , Active oxygen Physiological effect , Aromaticity (Chemistry) , Tetrapyrroles , Magnetic circular dichroism , Corroles , Chlorins , Photodynamic antimicrobial chemotherapy (PACT)
- Language: English
- Type: Masters theses , text
- Identifier: http://hdl.handle.net/10962/188843 , vital:44791
- Description: In photodynamic therapy (PDT), the activation of light-sensitive drugs in tumour cells produces reactive singlet oxygen species, which cause tumour destruction through a cascade of biochemical reactions. Over the years, the wavelength of activation has been shown to be a critical factor in the penetration of light. Hence the properties of photosensitiser dyes in this context shape their ability to treat deep-seated tumours. In this study, the synthesis, structural characterisation and photophysicochemical properties of a series of Sn(IV) porphyrins with meso-methylthiophenyl rings that have been prepared to study their PDT and photodynamic antimicrobial chemotherapy (PACT) activity properties are reported. The series of Sn(IV) complexes is comprised of a porphyrin (1-Sn), a corrole (2-Sn), a chlorin (3-Sn) and an N-confused porphyrin (4-Sn). Herein, the low symmetry Sn(IV) porphyrin derivatives are shown to have excellent singlet oxygen generation capabilities, and lifetimes of the triplet excited states were in the microsecond range. For example, 4-Sn had a singlet oxygen quantum yield (ФΔ) and an excited triplet state lifetime (τT) of 0.88 and 27 μs, respectively. The complexes were studied using UV-visible and magnetic circular dichroism (MCD) spectroscopies. Interestingly, the positive-to-negative sign sequences of the Faraday B0 terms of 2-Sn and 3-Sn reveal that the structural modifications involved break the degeneracy of the MOs derived from the 1eg* LUMO of the porphyrin 1-Sn. In contrast, a conventional negative-to-positive sign sequence is observed for 4-Sn, since the confusion of a pyrrole moiety also results in a large separation of the 1a1u and 1a2u MOs of the porphyrin 1-Sn that are derived from the HOMO of a C16H162−parent hydrocarbon perimeter. The trends in the electronic structures of the Sn(IV) complexes were further investigated through a series of time-dependent density functional theory calculations, so that the suitability of the different types of complex for use in singlet oxygen applications could be further explored. During in vitro photodynamic antimicrobial chemotherapy (PACT) studies, chlorin derivative 3-Sn had the highest activity towards S. aureus and E. coli with log10 reductions of 10.5 and 8.74, respectively. The unusually high activity of 3-Sn against E.coli suggests that the interaction of neutral photosensitisers with gram-negativebacteria is more complex than previously understood. Anti-cancer PDT studies demonstrated that the photosensitisers had negligible dark cytotoxicity. Upon photoirradiation, the Sn(IV) complexes consistently exhibited IC50 values lower than 15 μM against MCF-7 adenocarcinoma cells. An IC50 value of 1.4 μM for 4-Sn after activation at the deep-red region of the spectrum demonstrates that complexes of this type merit further in-depth investigation. The results provide evidence that the low-symmetry Sn(IV) chlorins and N-confused porphyrins merit further in-depth study for use in singlet oxygen applications. , Thesis (MSc) -- Faculty of Science, Chemistry, 2021
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- Date Issued: 2021-10
Echogenic liposomes for ultrasound-triggered drug delivery
- Authors: Izuchukwu, Ezekiel Charles
- Date: 2021-10
- Subjects: Liposomes , Drug delivery systems , Colon (Anatomy) Cancer Treatment , Transmission electron microscopy , Fourier transform infrared spectroscopy , Liquid chromatography , Echogenic liposomes , Ultrasound-triggered drug delivery
- Language: English
- Type: Masters theses , text
- Identifier: http://hdl.handle.net/10962/188997 , vital:44805
- Description: Colorectal cancer is one of common cancers worldwide. It is the third most diagnosed cancer and the second leading cause of death. The use of 5-fluorouracil (5-FU) alone or in a chemotherapy regime has been the effective treatment of colorectal cancer patients. The efficacy of 5-FU in colorectal cancer treatment is significantly limited by drug resistance, gastrointestinal, and bone marrow toxicity through high-level expression of thymidylate synthase, justifying a need to improve its therapeutic index. Liposomes are colloidal membranes comprising of one or more lipid bilayers enclosing an aqueous core. They have been used to improve the therapeutic index of many anti-cancer drugs by changing drug absorption, elongating biological half-life, reducing metabolism, and reducing toxicity to healthy tissues. Echogenic liposomes are specifically designed to respond to external triggering like ultrasound stimulation by entrapping a gas or an emulsion that can vaporize. A liposome's unique property is that it can entrap both hydrophobic and hydrophilic substances simultaneously in the lipid bilayer and the aqueous core, respectively. These stimuli-responsive liposomes can be triggered externally with ultrasound, to release the chemotherapeutic cargo only at the required site. This research aims to formulate echogenic liposomes encapsulating 5-FU for potential ultrasound triggered release (echogenic). Liposome formulations wereprepared with lipid composition of crude soybean lecithin and cholesterol by thin-filmhydration method and the drug was passively loaded in the formulation. The 5-FU loadedliposomes were evaluated by dynamic light scattering (DLS) for particle size, polydispersityindex, and zeta potential and transmission electron microscopy (TEM) for morphology.Encapsulated liposomal formulations were also evaluated using physicochemical techniquesincluding thermogravimetric analysis (TGA), differential scanning calorimetry (DSC),Fourier-transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). Theencapsulation efficiency and release kinetics were studied using a validated high-performanceliquid chromatography (HPLC) method. Echogenic properties were explored by entrapping abiocompatible gas (argon) at the same time as the drug (5-FU) using a pressure/freezemethodology. The liposomal formulations were typically spherical with a size of about 150 nmand encapsulation efficiency of 62%. Low-frequency ultrasound (20 kHz) was used to triggerthe drug release from the complete formulation at 10%, 15%, and 20% amplitude and exposuretime of 5 min and 10 min. The rate of drug release from the nano-carrier was a function of theultrasound amplitude and exposure time and reached a maximum of 65% release under theconditions investigated. The cumulative release was investigated, with and without theapplication of ultrasound. It was demonstrated that the application of ultrasound resulted in complete release (99%) after 12 h while this dropped to 70% without ultrasound. These results are encouraging for optimizing ultrasound parameters for triggered and controlled release of the 5-FU, for conditions such as the management of cancer where low-power ultrasound can be applied. , Thesis (MSc) -- Faculty of Science, Chemistry, 2021
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- Date Issued: 2021-10