Draft:The Role of Glutathione in Degradation of Drug Delivery Systems

The Role of Glutathione in Degradation of Drug Delivery Systems Overview of Glutathione (GSH) Glutathione (GSH) is a naturally occurring antioxidant in the body, produced by the liver and nerve cells in the central nervous system. It is composed of three amino acids: glycine, L-cysteine, and L-glutamate. Glutathione plays a crucial role in metabolizing toxins, neutralizing free radicals, and supporting immune function, among other vital processes.

Cellular Glutathione Levels The concentration of glutathione in the cytoplasm is significantly higher (ranging from 0.5-10 mM) compared to extracellular fluids (2-20 μM), reaching levels up to 1000 times greater. Tumor cells present higher levels of cytosolic GSH with respect to normal cells. Among various types of cancer, lung cancer, larynx cancer, mouth cancer, and breast cancer exhibit higher concentrations (10-40 mM) of GSH compared to healthy cells. [https://ibb.co/7Jrwffc Cellular glutathione levels of healthy cells and some cancer cells. Created with BioRender. ]

Drug Delivery Systems Drug delivery systems (DDS) are technological frameworks designed to formulate and store drug molecules in appropriate forms, such as tablets or solutions, for administration. These systems expedite drug delivery to specific target sites within the body, enhancing therapeutic efficacy and minimizing off-target effects. Drugs can be administered through various routes including oral, buccal, sublingual, nasal, ophthalmic, transdermal, subcutaneous, anal, transvaginal, and intravesical.

Over the past decades, DDS have significantly advanced disease treatment and health improvement by enhancing systemic circulation and controlling pharmacological effects. Controlled-release formulations, first approved in the 1950s, release drugs at a predetermined rate over a specific period, unaffected by physiological conditions. These systems can last from days to years, providing spatial control over drug release and improving solubility, target site accumulation, efficacy, pharmacological activity, pharmacokinetic properties, patient acceptance, and compliance, while reducing drug toxicity. Novel Drug Delivery Systems (NDDS) Numerous novel drug delivery systems (NDDS) have been studied using advanced technologies for more convenient, controlled, and targeted delivery. Each DDS has unique characteristics that determine its release rate and mechanism, largely due to differences in physical, chemical, and morphological properties.

Glutathione in Degradation of DDS Among these innovative systems, drug delivery systems containing disulfide bonds, typically cross-linked micro-nanogels, stand out for their ability to degrade in the presence of high concentrations of glutathione (GSH). This degradation process releases the drug payload specifically into cancerous or tumorous tissue, leveraging the significant difference in redox potential between the oxidizing extracellular environment and the reducing intracellular cytosol.

When internalized by endocytosis, nanogels encounter high concentrations of GSH inside the cancer cell. GSH, a potent reducing agent, donates electrons to disulfide bonds in the nanogels, initiating a thiol-disulfide exchange reaction. This reaction breaks the disulfide bonds, converting them into two thiol groups, and facilitates targeted drug release where it is needed most. This reaction is called a thiol-disulfide exchange reaction. R−S−S−R′+ 2GSH → R−SH + R′−SH + GSSG where R and R' are parts of the micro-nanogel structure, and GSSG is oxidized glutathione (glutathione disulfide).

The breaking of disulfide bonds causes the nanogel to degrade into smaller fragments. This degradation process leads to the release of encapsulated drugs. The released drug molecules can then exert their therapeutic effects, such as inducing apoptosis in cancer cells.