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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.[1][2]

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.[3][4]Tumor cells present higher levels of cytosolic GSH with respect to normal cells.[5] 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.[6]

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.[7] 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. [8] 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.[9][10] 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.[11]

Novel Drug Delivery Systems (NDDS) Numerous novel drug delivery systems (NDDS) have been studied using advanced technologies for more convenient, controlled, and targeted delivery.[12] Each DDS has unique characteristics that determine its release rate and mechanism, largely due to differences in physical, chemical, and morphological properties.[13]

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).[14] 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.[15][16]

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.[17][18] 

             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.

References

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  1. ^ Pompella A, Visvikis A, Paolicchi A, De Tata V, Casini AF (October 2003). "The changing faces of glutathione, a cellular protagonist". Biochemical Pharmacology. 66 (8): 1499–1503. doi:10.1016/S0006-2952(03)00504-5. PMID 14555227.
  2. ^ Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr. 2004;134(3):489-492. doi:10.1093/jn/134.3.489
  3. ^ Giustarini D, Milzani A, Dalle-Donne I, Rossi R. How to Increase Cellular Glutathione. Antioxidants (Basel). 2023 May 13;12(5):1094. doi: 10.3390/antiox12051094. PMID: 37237960; PMCID: PMC10215789
  4. ^ Ru Cheng, Fang Feng, Fenghua Meng, Chao Deng, Jan Feijen, Zhiyuan Zhong, Glutathione-responsive nano-vehicles as a promising platform for targeted intracellular drug and gene delivery, Journal of Controlled Release, Volume 152, Issue 1, 2011, Pages 2-12, ISSN 0168-3659, https://doi.org/10.1016/j.jconrel.2011.01.030.
  5. ^ West K.R., Otto S., 2005, Reversible covalent chemistry in drug delivery, Curr. Drug Discov. Technol., 2:123–160.
  6. ^ Gamcsik MP, Kasibhatla MS, Teeter SD, Colvin OM. Glutathione levels in human tumors. Biomarkers. 2012 Dec;17(8):671-91. doi: 10.3109/1354750X.2012.715672. Epub 2012 Aug 20. PMID: 22900535; PMCID: PMC3608468.
  7. ^ "Drug Delivery Systems". www.nibib.nih.gov. Retrieved 2021-04-25
  8. ^ COMMON ROUTES OF DRUG ADMINISTRATION". media.lanecc.edu. Archived from the original on 2021-10-15. Retrieved 2021-04-20.
  9. ^ Park, Kinam (September 2014). "Controlled drug delivery systems: Past forward and future back". Journal of Controlled Release. 190: 3–8. doi:10.1016/j.jconrel.2014.03.054. PMC 4142099. PMID 24794901.
  10. ^ ltd, Research and Markets. "Pharmaceutical Drug Delivery Market Forecast to 2027 - COVID-19 Impact and Global Analysis by Route of Administration; Application; End User, and Geography". www.researchandmarkets.com. Retrieved 2021-04-24.
  11. ^ Yun, Yeon Hee; Lee, Byung Kook; Park, Kinam (December 2015). "Controlled Drug Delivery: Historical perspective for the next generation". Journal of Controlled Release. 219: 2–7. doi:10.1016/j.jconrel.2015.10.005. PMC 4656096. PMID 26456749.
  12. ^ Li, Chong; Wang, Jiancheng; Wang, Yiguang; Gao, Huile; Wei, Gang; Huang, Yongzhuo; Yu, Haijun; Gan, Yong; Wang, Yongjun; Mei, Lin; Chen, Huabing; Hu, Haiyan; Zhang, Zhiping; Jin, Yiguang (2019-11-01). "Recent progress in drug delivery". Acta Pharmaceutica Sinica B. 9 (6): 1145–1162. doi:10.1016/j.apsb.2019.08.003. ISSN 2211-3835. PMC 6900554. PMID 31867161.
  13. ^ Madhusudana Rao, Kummara; Krishna Rao, Kummari S.V.; Ha, Chang-Sik (2018-01-01). "Functional stimuli-responsive polymeric network nanogels as cargo systems for targeted drug delivery and gene delivery in cancer cells". Design of Nanostructures for Theranostics Applications: 243–275. doi:10.1016/B978-0-12-813669-0.00006-3. ISBN 9780128136690.
  14. ^ Patra, Jayanta Kumar; Das, Gitishree; Fraceto, Leonardo Fernandes; Campos, Estefania Vangelie Ramos; Rodriguez-Torres, Maria del Pilar; Acosta-Torres, Laura Susana; Diaz-Torres, Luis Armando; Grillo, Renato; Swamy, Mallappa Kumara; Sharma, Shivesh; Habtemariam, Solomon (December 2018). "Nano based drug delivery systems: recent developments and future prospects". Journal of Nanobiotechnology. 16 (1): 71. doi:10.1186/s12951-018-0392-8. ISSN 1477-3155. PMC 6145203. PMID 30231877
  15. ^ Li, Yulin; Maciel, Dina; Rodrigues, João; Shi, Xiangyang; Tomás, Helena (2015-08-26). "Biodegradable Polymer Nanogels for Drug/Nucleic Acid Delivery". Chemical Reviews. 115 (16): 8564–8608. doi:10.1021/cr500131f. ISSN 0009-2665. PMID 26259712. S2CID 1651110.
  16. ^ Glutathione-Sensitive Nanogels for Drug Release, Giulio Ghersi and Clelia Dispenza and Marianna Sabatino and Natascia Grimaldi and Giorgia Adamo and Simona Campora, Chemical engineering transactions, 2014, 38
  17. ^ Gilbert, H. F. (1990). "Molecular and Cellular Aspects of Thiol–Disulfide Exchange". Advances in Enzymology and Related Areas of Molecular Biology. Advances in Enzymology and Related Areas of Molecular Biology. Vol. 63. pp. 69–172. doi:10.1002/9780470123096.ch2. ISBN 9780470123096. PMID 2407068.
  18. ^ Gilbert, H. F. (1995). "Thiol/disulfide exchange equilibria and disulfide bond stability". Biothiols, Part A: Monothiols and Dithiols, Protein Thiols, and Thiyl Radicals. Methods in Enzymology. Vol. 251. pp. 8–28. doi:10.1016/0076-6879(95)51107-5. ISBN 9780121821524. PMID 7651233.
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