Application of stimuli-responsive cysteine-based organogels as a drug delivery system for chemotherapy drugs

Date

2023-8-24

Author

Zare, Diba

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Cancer is one of the deadliest diseases and researchers are trying to replace chemotherapy as an aggressive treatment with safer treatments for instance immunotherapy. Chemotherapy is the main clinical treatment for malignancies, even though most chemotherapeutic medicines, including doxorubicin, have poor water solubility, resulting in low bioavailability and significant side effects. There has been much research into identifying and developing stimulus-sensitive agents to deliver chemotherapeutic medications to the target area and release therapeutic quantities of these drugs in the cancer area safely and efficiently. For the past few decades, stimuli-responsive organogels grabbed more attention as a potential drug delivery system for chemotherapy drugs. Cysteine derivatives having disulfide bonds (-S-S-) in their side chain can be used as stimuli-responsive organogelators as the disulfide bond can be cleaved in the presence of certain reducing agents such as thiol derivatives like tris (2- carboxyethyl) phosphine hydrochloride (TCEP), beta-mercaptoethanol (BME), dithiothreitol (DTT), and glutathione (GSH). Glutathione is a tripeptide that consists of cysteine, glutamic acid, and glycine. Studies show that cells of certain cancers have higher levels of glutathione due to increased production of reactive oxygen species (ROS). Some of the classical tumor promoters also activate GSH synthesis and turnover mechanisms. This feature allows targeted cancer therapy using glutathione-responsive drug delivery systems. This thesis studied the drug delivery property of cysteine-based organogelators like L-Cys(t-dodecyl-sulfanyl)-OH and L-Cys-(StBu)-OH with a disulfide bond in their side chain that can be cleaved in the presence of glutathione. the organogels were prepared using sunflower oil as the nonpolar solvent and doxorubicin was used as the chemotherapy drug. The drug release property of these organogels was measured in the presence of different concentrations of GSH and was compared with the drug release property of L-Cys-(tBu)-OH based organogel which does not contain a disulfide bond in its side chain in sunflower oil as the negative control group. Furthermore, the biocompatibility of the organogelators was measured in vitro using the L929 cell line and the characterization of the organogels was measured using TEM imaging, XRD, and Rheological measurements. The results indicated that both L-Cys(t-dodecyl-sulfanyl)-OH and L-Cys-(StBu)-OH can form organogels in sunflower oil and can release doxorubicin in the presence of GSH. Also, the characterization studies confirmed their gel form criteria. Moreover, the in vitro biocompatibility studies did not show significant toxicity to the L929 cells for all the concentrations of L-Cys-(StBu)-OH and low concentrations of LCys(t-dodecyl-sulfanyl)-OH.

Subject Keywords

drug delivery systems, doxorubicin, low molecular weight organogelator, glutathione

URI

https://hdl.handle.net/11511/105253

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Graduate School of Natural and Applied Sciences, Thesis