Synthesis And In Vitro Biochemical Evaluation of Porphyrin Derivatives For Photodynamic Anticancer Therapy
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| Language: | English |
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University of Akron / OhioLINK
2021
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=akron1628023193002942 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-akron1628023193002942 |
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oai_dc |
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NDLTD |
| language |
English |
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Organic Chemistry Photodynamic Therapy PDT A549 AsPC-1 Porphyrins Curcumin Gemcitabine Capecitabine |
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Organic Chemistry Photodynamic Therapy PDT A549 AsPC-1 Porphyrins Curcumin Gemcitabine Capecitabine Abdelaziz, Mostafa A. Synthesis And In Vitro Biochemical Evaluation of Porphyrin Derivatives For Photodynamic Anticancer Therapy |
| author |
Abdelaziz, Mostafa A. |
| author_facet |
Abdelaziz, Mostafa A. |
| author_sort |
Abdelaziz, Mostafa A. |
| title |
Synthesis And In Vitro Biochemical Evaluation of Porphyrin Derivatives For Photodynamic Anticancer Therapy |
| title_short |
Synthesis And In Vitro Biochemical Evaluation of Porphyrin Derivatives For Photodynamic Anticancer Therapy |
| title_full |
Synthesis And In Vitro Biochemical Evaluation of Porphyrin Derivatives For Photodynamic Anticancer Therapy |
| title_fullStr |
Synthesis And In Vitro Biochemical Evaluation of Porphyrin Derivatives For Photodynamic Anticancer Therapy |
| title_full_unstemmed |
Synthesis And In Vitro Biochemical Evaluation of Porphyrin Derivatives For Photodynamic Anticancer Therapy |
| title_sort |
synthesis and in vitro biochemical evaluation of porphyrin derivatives for photodynamic anticancer therapy |
| publisher |
University of Akron / OhioLINK |
| publishDate |
2021 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=akron1628023193002942 |
| work_keys_str_mv |
AT abdelazizmostafaa synthesisandinvitrobiochemicalevaluationofporphyrinderivativesforphotodynamicanticancertherapy |
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1719472572696887296 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-akron16280231930029422021-08-27T05:10:01Z Synthesis And In Vitro Biochemical Evaluation of Porphyrin Derivatives For Photodynamic Anticancer Therapy Abdelaziz, Mostafa A. Organic Chemistry Photodynamic Therapy PDT A549 AsPC-1 Porphyrins Curcumin Gemcitabine Capecitabine Photodynamic therapy (PDT) has attracted significant attention as an alternative approach to traditional cancer therapies such as radiotherapy, chemotherapy, and surgery. PDT involves irradiating a drug (the photosensitizer) with a photon of light to generate singlet oxygen (1O2) that then proceeds to kill cancer cells. Porphyrin-based photosensitizers have been widely used in PDT. Porphyrins have a significant absorption in the visible region (400-700 nm), little dark toxicity, and long-lived triplet states that can lead to high singlet oxygen production. Porphyrins are known to accumulate in tumor cells in high concentrations, but aggregation, resulting from π-π stacking, often leads to a reduction in fluorescence and 1O2 quantum yields. Porphyrins are also highly hydrophobic, leading to low bioavailability and making intravenous administration difficult. Ground state curcumin analogs have been shown to have significant anti-cancer activity against various cancer lines, although these molecules have a low bioavailability due to poor absorption and fast metabolism. Four novel porphyrin-curcumin analog conjugates (1-4) have been synthesized (Figure 1) for use as photosensitizers in the photodynamic treatment of pancreatic ductal adenocarcinoma (PDAC) and lung cancer. Porphyrin-curcumin analog conjugates have several advantages over the individual components: (1) improvement of stability, bioavailability, and tumor site accumulation of curcumin analogs, (2) the presence of two flexibly connected chromophores that will prevent aggregation of the porphyrin component, improving both fluorescence and 1O2 quantum yields, (3) the presence of two chromophores that may maximize triplet-triplet energy transfer with 3O2 and improve 1O2 generation efficiency.Capecitabine (Xeloda) and Gemcitabine (Gemzar) are standard chemotherapeutic agents for pancreatic cancer patients. However, Capecitabine and Gemcitabine are highly water-soluble drugs; so, they are rapidly removed from the blood circulation in addition to being rapidly metabolized to inactive intermediates. So, they have a poor accumulation in tumor cells because of high hydrophilicity. In our study, two novel porphyrin-capecitabine and porphyrin-gemcitabine derivatives (5-6) were synthesized for use as photosensitizers in the photodynamic treatment of different types of cancer. Introduction of the porphyrin ring makes capecitabine and gemcitaqbine more hydrophobic and thus enhances the accumulation in tumor sites, in addition to the added advantage of being photochemically active. When the modified drugs accumulate in the tumor site, they will be irradiated by light of proper wavelength matching absorption maxima of porphyrin, generating a diradical that is expected to abstract H-atoms from biological molecules generating free radicals that disrupt cell replication and thereby kill the cancer cells.The photophysical properties of those derivatives were evaluated and it was found out that the fluorescence quantum yields of the target compounds are very close to Tetraphenylporphyrin (TPP)standard. The singlet oxygen quantum yields were also calculated, and it was found out that they are close to methylene blue standard. The cytotoxicity of compounds 1-6 was evaluated, under dark conditions and after light irradiation at an appropriate wavelength, against A549 lung cancer cells and AsPC-1 pancreatic cancer cells. The cellular uptake was also evaluated by Flow Cytometry Cell Sorting (FACS) analysis. It was found out that the target compounds have little or almost no dark toxicity. On the other side, they have significant cytotoxicity against A549 cells and AsPC-1 cells with a significant cellular uptake because of the up-regulation of LDL receptors on the cancer cells that are responsible for the transport of porphyrin derivatives. Fluorescence imaging experiments show that the significant cytotoxicity of the target compounds is also caused by their localization on the mitochondria, leading to cellular death. 2021-08-26 English text University of Akron / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=akron1628023193002942 http://rave.ohiolink.edu/etdc/view?acc_num=akron1628023193002942 restricted--full text unavailable until 2023-08-26 This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |