Photodynamic anticancer and antimicrobial activities of aza-BODIPY and porphyrinbased photosensitisers and their non-linear properties
- Authors: Molupe, Nthabeleng Regina
- Date: 2024-10-11
- Subjects: Photochemotherapy , Anti-infective agents , Nonlinear optics , Cancer Treatment , BODIPY , Porphyrins
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/466603 , vital:76758 , DOI https://doi.org/10.21504/10962/466603
- Description: New aza-BODIPY dyes and porphyrins were synthesised and characterised so that photodynamic therapy (PDT) and photodynamic antimicrobial chemotherapy (PACT) activity studies could be performed. Several strategies were explored to achieve targeted nanoplatforms or biocompatible nanoplatforms to enhance the suitability of these compounds for use in PDT. Following earlier MSc research on the encapsulation of halogenated boron dipyrromethene (BODIPY) dyes into Pluronic® micelles, similar nanomicelles were prepared to encapsulate halogenated boron aza-dipyrromethene (aza-BODPY) dyes to enhance their aqueous solubility. However, the 1,7-dimethylthiophenyl- 2,6-diiodo-3,5-diphenyl (1) and 1,7-di-methylthiophenyl-2,6-diiodo- 3,5-dithien-3-yl (2) aza-BODIPY dyes that were prepared in this context were found to degrade when encapsulated. A different strategy was then followed in which gold nanoparticles (AuNPs) were conjugated to 1 and 2 via Au-S interactions to form biocompatible aza-BODIPY-AuNP conjugates (1-AuNP and 2-AuNP). This strategy was successful, and favourable IC50 values of 3.60 and 10.0 μM for 1-AuNP and 2- AuNP were obtained during in vitro PDT activity studies against MCF-7 human breast cancer cells, respectively, while values of 11.0 and 12.8 μM were obtained for 1 and 2. To further explore the preparation of better-targeted aza-BODIPY photosensitiser dyes, folic acid (FA) was conjugated to 1,7-dihydroxyphenyl-2,6-diiodo-3,5-di-4- bromophenyl (3) and 1,7-di-4-bromo-2,6-diiodo-3,5-dihydroxyphenylphenyl (4) aza- BODIPYs via ester bonds. Not only was the conjugation to form 3-FA and 4-FA successful, but the conjugated dyes are water-soluble, which is advantageous for drug transport in the context of PDT. These conjugates were applied in vitro against MCF-7 cancer cells and were found to have relatively high activities with IC50 values of 0.91 and 7.48 μM for 3-FA and 4-FA, respectively, while values of 11.3 and 13.0 μM were obtained for the non-conjugated 3 and 4 dyes. In a similar manner, tin (IV) and indium (III) tetrapyridylporphyrins (5 and 6) were axially conjugated to folic acid via ester bonds (5-FA and 6-FA). The conjugation was successful and enhanced the PDT activities of the dyes MCF-7 cancer cells in vitro from 48.2 to 29.6 μM for 5 and 5-FA, and from 43.9 to 13.3 μM for 6 and 6-FA. Relatively high dark toxicity was observed for 6-FA of 26.1 μM. When the nitrogen atoms of the meso-pyridyl rings were quaternized (5-FAQ and 6-FAQ) to further enhance the aqueous solubility of the complexes, it was not possible to calculate an IC50 value. When octanol-water partition coefficients (Log P) were calculated by the shake flask method, values of −0.70 and −1.70 were obtained for 5-FAQ and 6-FAQ, respectively. This provides evidence that the dyes are too water-soluble and not sufficiently lipophilic. The PACT activity properties of the synthesised diiodinated aza-BODIPYs were studied against Staphylococcus aureus (S. aureus) through photoirradiation for 60 min with Thorlabs M660L4 (280 mW.cm−2) and M730L4 (160 mW.cm−2) light emitting diodes (LEDs) mounted on the illumination chamber of Modulight® 7710-680 medical laser system providing doses at the well-plate of 100 and 57 J.cm−2.min−1. Aza- BODIPYs 2, 3 and 4 all inhibited the growth of S. aureus but with relatively low Log10 reductions of 1.37, 1.20 and 0.20. In contrast, aza-BODIPY 1 was found to have a Log10 reduction of 7.82. The PACT activities of free base and Sn(IV) 5-[4-(3- bromoethylcarboxyamidyl)phenyl]-10,15,20-triphenylporphyrins (7 and 8) prepared by Dr Balaji Babu (New Journal of Chemistry 2022, 46, 5288-5295) were tested against S. aureus to determine whether adding a triphenylphosphonium moiety to form free base and Sn(IV) 5-[4-(triphenylphosphonium)ethylcarboxyamidyl)phenyl]-10,15,20- triphenylporphyrin (18 and 19) enhances the photo-induced antibacterial activity, in addition to optimising the PDT properties due to its mitochondria-targeting properties. The PACT activities obtained against S. aureus were not favourable, but 18 exhibited enhanced activity across the studied concentration range. The potential utility of aza-BODIPY dyes 1-4 and their non-iodinated analogues (1a- 4a) for optical limiting applications was analysed by carrying out a series of Z-scan measurements, since dyes of this type have large ground state dipole moments, and this can enhance the non-linear optical limiting response. All the aza-BODIPY dyes under investigation exhibited intense non-linear absorption (NLA) behaviour with Zscan profiles that contain significant reverse saturable absorption (RSA) responses. Aza-BODIPYs 1, 2a, 2, 3, 4a, and 4 decreased the transmitted intensity of the strong laser beam to less than 50% of the linear response in organic solutions with a fixed absorbance of 1.8 for the main aza-BODIPY spectral band and a laser pulse input energy of 42 μJ. Higher second-order hyperpolarizability (γ) values were obtained for iodinated dyes 1, 2, 3 and 4. The highest value of 3.15×10−29 esu was obtained for 1. A comparative study involving the four non-iodinated dyes 1, 2, 3 and 4 and seven 1,3,5,7-tetraaryl aza-BODIPY dyes reported previously in the PhD thesis of Gugu Kubheka at Rhodes University demonstrated that there was no clear trend correlation between the γ values calculated from the Z-scan measurements and calculated dipole moments. , Thesis (PhD) -- Faculty of Science, Chemistry, 2024
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- Authors: Molupe, Nthabeleng Regina
- Date: 2024-10-11
- Subjects: Photochemotherapy , Anti-infective agents , Nonlinear optics , Cancer Treatment , BODIPY , Porphyrins
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/466603 , vital:76758 , DOI https://doi.org/10.21504/10962/466603
- Description: New aza-BODIPY dyes and porphyrins were synthesised and characterised so that photodynamic therapy (PDT) and photodynamic antimicrobial chemotherapy (PACT) activity studies could be performed. Several strategies were explored to achieve targeted nanoplatforms or biocompatible nanoplatforms to enhance the suitability of these compounds for use in PDT. Following earlier MSc research on the encapsulation of halogenated boron dipyrromethene (BODIPY) dyes into Pluronic® micelles, similar nanomicelles were prepared to encapsulate halogenated boron aza-dipyrromethene (aza-BODPY) dyes to enhance their aqueous solubility. However, the 1,7-dimethylthiophenyl- 2,6-diiodo-3,5-diphenyl (1) and 1,7-di-methylthiophenyl-2,6-diiodo- 3,5-dithien-3-yl (2) aza-BODIPY dyes that were prepared in this context were found to degrade when encapsulated. A different strategy was then followed in which gold nanoparticles (AuNPs) were conjugated to 1 and 2 via Au-S interactions to form biocompatible aza-BODIPY-AuNP conjugates (1-AuNP and 2-AuNP). This strategy was successful, and favourable IC50 values of 3.60 and 10.0 μM for 1-AuNP and 2- AuNP were obtained during in vitro PDT activity studies against MCF-7 human breast cancer cells, respectively, while values of 11.0 and 12.8 μM were obtained for 1 and 2. To further explore the preparation of better-targeted aza-BODIPY photosensitiser dyes, folic acid (FA) was conjugated to 1,7-dihydroxyphenyl-2,6-diiodo-3,5-di-4- bromophenyl (3) and 1,7-di-4-bromo-2,6-diiodo-3,5-dihydroxyphenylphenyl (4) aza- BODIPYs via ester bonds. Not only was the conjugation to form 3-FA and 4-FA successful, but the conjugated dyes are water-soluble, which is advantageous for drug transport in the context of PDT. These conjugates were applied in vitro against MCF-7 cancer cells and were found to have relatively high activities with IC50 values of 0.91 and 7.48 μM for 3-FA and 4-FA, respectively, while values of 11.3 and 13.0 μM were obtained for the non-conjugated 3 and 4 dyes. In a similar manner, tin (IV) and indium (III) tetrapyridylporphyrins (5 and 6) were axially conjugated to folic acid via ester bonds (5-FA and 6-FA). The conjugation was successful and enhanced the PDT activities of the dyes MCF-7 cancer cells in vitro from 48.2 to 29.6 μM for 5 and 5-FA, and from 43.9 to 13.3 μM for 6 and 6-FA. Relatively high dark toxicity was observed for 6-FA of 26.1 μM. When the nitrogen atoms of the meso-pyridyl rings were quaternized (5-FAQ and 6-FAQ) to further enhance the aqueous solubility of the complexes, it was not possible to calculate an IC50 value. When octanol-water partition coefficients (Log P) were calculated by the shake flask method, values of −0.70 and −1.70 were obtained for 5-FAQ and 6-FAQ, respectively. This provides evidence that the dyes are too water-soluble and not sufficiently lipophilic. The PACT activity properties of the synthesised diiodinated aza-BODIPYs were studied against Staphylococcus aureus (S. aureus) through photoirradiation for 60 min with Thorlabs M660L4 (280 mW.cm−2) and M730L4 (160 mW.cm−2) light emitting diodes (LEDs) mounted on the illumination chamber of Modulight® 7710-680 medical laser system providing doses at the well-plate of 100 and 57 J.cm−2.min−1. Aza- BODIPYs 2, 3 and 4 all inhibited the growth of S. aureus but with relatively low Log10 reductions of 1.37, 1.20 and 0.20. In contrast, aza-BODIPY 1 was found to have a Log10 reduction of 7.82. The PACT activities of free base and Sn(IV) 5-[4-(3- bromoethylcarboxyamidyl)phenyl]-10,15,20-triphenylporphyrins (7 and 8) prepared by Dr Balaji Babu (New Journal of Chemistry 2022, 46, 5288-5295) were tested against S. aureus to determine whether adding a triphenylphosphonium moiety to form free base and Sn(IV) 5-[4-(triphenylphosphonium)ethylcarboxyamidyl)phenyl]-10,15,20- triphenylporphyrin (18 and 19) enhances the photo-induced antibacterial activity, in addition to optimising the PDT properties due to its mitochondria-targeting properties. The PACT activities obtained against S. aureus were not favourable, but 18 exhibited enhanced activity across the studied concentration range. The potential utility of aza-BODIPY dyes 1-4 and their non-iodinated analogues (1a- 4a) for optical limiting applications was analysed by carrying out a series of Z-scan measurements, since dyes of this type have large ground state dipole moments, and this can enhance the non-linear optical limiting response. All the aza-BODIPY dyes under investigation exhibited intense non-linear absorption (NLA) behaviour with Zscan profiles that contain significant reverse saturable absorption (RSA) responses. Aza-BODIPYs 1, 2a, 2, 3, 4a, and 4 decreased the transmitted intensity of the strong laser beam to less than 50% of the linear response in organic solutions with a fixed absorbance of 1.8 for the main aza-BODIPY spectral band and a laser pulse input energy of 42 μJ. Higher second-order hyperpolarizability (γ) values were obtained for iodinated dyes 1, 2, 3 and 4. The highest value of 3.15×10−29 esu was obtained for 1. A comparative study involving the four non-iodinated dyes 1, 2, 3 and 4 and seven 1,3,5,7-tetraaryl aza-BODIPY dyes reported previously in the PhD thesis of Gugu Kubheka at Rhodes University demonstrated that there was no clear trend correlation between the γ values calculated from the Z-scan measurements and calculated dipole moments. , Thesis (PhD) -- Faculty of Science, Chemistry, 2024
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Liposomal formulations of metallophthalocyanines-nanoparticle conjugates for hypoxic photodynamic therapy and photoelectrocatalysis
- Authors: Nwahara, Nnamdi Ugochinyere
- Date: 2023-10-13
- Subjects: Liposomes , Photochemotherapy , Phthalocyanines , Photoelectrochemistry , Cancer Treatment
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/432159 , vital:72847 , DOI 10.21504/10962/432159
- Description: This thesis investigates new strategies to enhance the efficacy of photodynamic therapy (PDT) under hypoxic conditions using in-vitro cancer cell models. Phthalocyanines are chosen as viable photosensitizer complexes owing to the favourable absorption properties. To this end, this thesis reports on the synthesis and photophysicochemical properties of various zinc and silicon phthalocyanines (Pcs). To afford better photophysicochemical properties, the reported Pcs were conjugated to different nanoparticles (NPs) through chemisorption as well as amide bond formation to yield Pc-NP conjugates. All the studied Pcs showed relatively high triplet and singlet oxygen quantum yields corresponding to their low fluorescence quantum yields. The various mechanisms for hypoxic response include (i) Type I PDT, (ii) PDT coupled with oxygen-independent therapy and (iii) in-situ oxygen generation using catalase-mimicking nanoparticles which serve to supplement in-vitro oxygen concentrations using MPcs or MPc-NPs conjugates. The mechanisms were assessed using electrochemical, computational techniques and catalase mimicking experiments. The as-synthesised Pcs or Pc-NPs were subjected to liposomal loading before PDT studies which led to enhanced biocompatibility and aqueous dispersity. The in-vitro dark cytotoxicity tests and photodynamic therapy activities of the fabricated Pc-liposomes and Pc-NPs-liposomes on either Henrietta Lacks (HeLa) or Michigan Cancer Foundation-7 (MCF-7) breast cancer cells are presented herein. This work further showed that folic acid (FA) functionalization of liposomes could be exploited for active drug delivery and herein led to an almost 3-fold increase in drug uptake vs non-FA functionalised liposomes in accordance with folate receptor (FR) expression levels between HeLa and MCF-7 cells. The in-vitro dark cytotoxicity and photodynamic therapy of selected Pc complexes and conjugates were accessed using MCF-7 and HeLa cell lines. The various mechanisms; (i) Type I PDT, (ii) PDT coupled with oxygen -independent therapy and (iii) in-situ oxygen generation using catalase-mimicking nanoparticles were shown to adequately compensate for the otherwise attenuation of PDT activity under hypoxia. , Thesis (PhD) -- Faculty of Science, Chemistry, 2023
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- Authors: Nwahara, Nnamdi Ugochinyere
- Date: 2023-10-13
- Subjects: Liposomes , Photochemotherapy , Phthalocyanines , Photoelectrochemistry , Cancer Treatment
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/432159 , vital:72847 , DOI 10.21504/10962/432159
- Description: This thesis investigates new strategies to enhance the efficacy of photodynamic therapy (PDT) under hypoxic conditions using in-vitro cancer cell models. Phthalocyanines are chosen as viable photosensitizer complexes owing to the favourable absorption properties. To this end, this thesis reports on the synthesis and photophysicochemical properties of various zinc and silicon phthalocyanines (Pcs). To afford better photophysicochemical properties, the reported Pcs were conjugated to different nanoparticles (NPs) through chemisorption as well as amide bond formation to yield Pc-NP conjugates. All the studied Pcs showed relatively high triplet and singlet oxygen quantum yields corresponding to their low fluorescence quantum yields. The various mechanisms for hypoxic response include (i) Type I PDT, (ii) PDT coupled with oxygen-independent therapy and (iii) in-situ oxygen generation using catalase-mimicking nanoparticles which serve to supplement in-vitro oxygen concentrations using MPcs or MPc-NPs conjugates. The mechanisms were assessed using electrochemical, computational techniques and catalase mimicking experiments. The as-synthesised Pcs or Pc-NPs were subjected to liposomal loading before PDT studies which led to enhanced biocompatibility and aqueous dispersity. The in-vitro dark cytotoxicity tests and photodynamic therapy activities of the fabricated Pc-liposomes and Pc-NPs-liposomes on either Henrietta Lacks (HeLa) or Michigan Cancer Foundation-7 (MCF-7) breast cancer cells are presented herein. This work further showed that folic acid (FA) functionalization of liposomes could be exploited for active drug delivery and herein led to an almost 3-fold increase in drug uptake vs non-FA functionalised liposomes in accordance with folate receptor (FR) expression levels between HeLa and MCF-7 cells. The in-vitro dark cytotoxicity and photodynamic therapy of selected Pc complexes and conjugates were accessed using MCF-7 and HeLa cell lines. The various mechanisms; (i) Type I PDT, (ii) PDT coupled with oxygen -independent therapy and (iii) in-situ oxygen generation using catalase-mimicking nanoparticles were shown to adequately compensate for the otherwise attenuation of PDT activity under hypoxia. , Thesis (PhD) -- Faculty of Science, Chemistry, 2023
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The development of ionic zinc(II) phthalocyanines for sono-photodynamic combination therapy of cervical and breast cancer
- Authors: Nene, Lindokuhle Cindy
- Date: 2023-03-31
- Subjects: Phthalocyanines , Sonochemistry , Photochemotherapy , Cancer Treatment
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/422565 , vital:71958 , DOI 10.21504/10962/422565
- Description: This study focuses on the development of the sono-photodynamic combination therapy (SPDT) activity of phthalocyanines (Pcs) on the cervical and breast cancer cell lines in vitro. The SPDT technique utilizes ultrasound in combination with light to elicit cytotoxic effects for cancer eradication. In this work, a selection of tetra-peripherally substituted Zn(II) cationic and zwitterionic Pcs were prepared. The photophysical parameters of the Pcs were determined including their fluorescence behaviours and efficiency of the triplet excited state population. The effects of the ultrasonic parameters (frequencies (MHz) and power (W.cm-2)) on the stability of the Pcs were evaluated. Four parameters were evaluated: Par I (1 MHz: 1 W.cm-2), Par II (1 MHz: 2 W.cm-2), Par III (3 MHz: 1 W.cm-2) and Par IV (3 MHz: 2 W.cm-2). The stability of the Pcs reduced with the increase in the ultrasonic power (for Par II and Par IV). The Par I showed the least degradation compared to the other parameters and was therefore used for the SPDT treatments. The sonodynamic (SDT), photodynamic (PDT) therapy activities of the Pcs were studied and compared to their SPDT efficacies. The Pcs showed reactive oxygen species generation during the SDT, PDT and SPDT treatments. For the SDT and SPDT, singlet oxygen (1O2) and hydroxyl radicals (•OH) were detected. For PDT, only the 1O2 were detected. The cell cytotoxicity studies for the Pcs showed relatively higher therapeutic efficacies for the SDT treatments compared to the PDT treatments, where the SPDT showed higher therapeutic efficacies compared to both the SDT and PDT monotreatments on both the cell lines in vitro. Overall, the combination treatments were better compared to the monotreatments. The activities of the Pcs were compared by their differences in structures, including the type of R-group, type of quaternizing agent and type of nanoparticle conjugates. , Thesis (PhD) -- Faculty of Science, Chemistry, 2023
- Full Text:
- Authors: Nene, Lindokuhle Cindy
- Date: 2023-03-31
- Subjects: Phthalocyanines , Sonochemistry , Photochemotherapy , Cancer Treatment
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/422565 , vital:71958 , DOI 10.21504/10962/422565
- Description: This study focuses on the development of the sono-photodynamic combination therapy (SPDT) activity of phthalocyanines (Pcs) on the cervical and breast cancer cell lines in vitro. The SPDT technique utilizes ultrasound in combination with light to elicit cytotoxic effects for cancer eradication. In this work, a selection of tetra-peripherally substituted Zn(II) cationic and zwitterionic Pcs were prepared. The photophysical parameters of the Pcs were determined including their fluorescence behaviours and efficiency of the triplet excited state population. The effects of the ultrasonic parameters (frequencies (MHz) and power (W.cm-2)) on the stability of the Pcs were evaluated. Four parameters were evaluated: Par I (1 MHz: 1 W.cm-2), Par II (1 MHz: 2 W.cm-2), Par III (3 MHz: 1 W.cm-2) and Par IV (3 MHz: 2 W.cm-2). The stability of the Pcs reduced with the increase in the ultrasonic power (for Par II and Par IV). The Par I showed the least degradation compared to the other parameters and was therefore used for the SPDT treatments. The sonodynamic (SDT), photodynamic (PDT) therapy activities of the Pcs were studied and compared to their SPDT efficacies. The Pcs showed reactive oxygen species generation during the SDT, PDT and SPDT treatments. For the SDT and SPDT, singlet oxygen (1O2) and hydroxyl radicals (•OH) were detected. For PDT, only the 1O2 were detected. The cell cytotoxicity studies for the Pcs showed relatively higher therapeutic efficacies for the SDT treatments compared to the PDT treatments, where the SPDT showed higher therapeutic efficacies compared to both the SDT and PDT monotreatments on both the cell lines in vitro. Overall, the combination treatments were better compared to the monotreatments. The activities of the Pcs were compared by their differences in structures, including the type of R-group, type of quaternizing agent and type of nanoparticle conjugates. , Thesis (PhD) -- Faculty of Science, Chemistry, 2023
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