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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 Glutathione, commonly referred to as GSH, is a naturally occurring antioxidant in the body. It is produced by the liver and nerve cells in the central nervous system. 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]

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

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. They expedite the delivery of drugs to specific target sites within the body, thereby enhancing therapeutic efficacy and minimizing off-target accumulation.[5] [6] Drugs can be administered through various routes, including oral [7] , buccal and sublingual[8] , nasal and ophthalmic[9] [10] , transdermal and subcutaneous [11][12], anal and transvaginal [13][14], and intravesical[15]. The components of the drug determine its physicochemical properties and the changes it induces in the body. Over recent decades, DDS have been effectively employed in disease treatment and health improvement by enhancing systemic circulation and controlling the pharmacological effects of drugs. Advances in pharmacology and pharmacokinetics have underscored the importance of drug release in determining therapeutic effectiveness, leading to the concept of controlled release [16]. Controlled-release formulations, first approved in the 1950s, have gained significant attention due to their advantages over conventional drugs. These formulations release drugs at a predetermined rate over a specific period, unaffected by physiological conditions, and can last from days to years. They also provide spatial control over drug release, with consistent or variable release rates[17]. Furthermore, controlled-release systems improve drug solubility, target site accumulation, efficacy, pharmacological activity, pharmacokinetic properties, patient acceptance, and compliance, while reducing drug toxicity. Recently, numerous novel drug delivery systems (NDDS) have been developed 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 which affect their affinities for various drug substances[18]. Studies have identified diffusion, chemical reaction, solvent reaction, and stimuli control as major release mechanisms[19][20] 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), thereby releasing their drug payload specifically into cancerous or tumorous tissue. This release mechanism leverages the significant difference in redox potential between the oxidizing extracellular environment and the reducing intracellular cytosol[21]. Once internalized by endocytosis, the 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. In this reaction, GSH breaks the disulfide bonds, converting them into two thiol groups. This degradation process facilitates targeted drug release precisely where it is needed most. The reaction can be summarized as follows: 

             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.

Advantages of GSH-Sensitive Drug Carriers

Targeted Drug Release: The high concentration of GSH in cancer cells compared to healthy cells ensures that drug release occurs predominantly in the target cells, minimizing side effects on normal tissues.

Controlled Degradation: The disulfide bonds provide a mechanism for controlled degradation. The rate of degradation and drug release can be fine-tuned by adjusting the cross-linking density and the type of disulfide bonds used.

Enhanced Drug Efficacy: By ensuring that the drug is released specifically in the cancer cells, the efficacy of the treatment is increased, and lower doses of the drug may be needed, reducing potential toxicity.

References

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  1. ^ 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
  2. ^ 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.
  3. ^ West K.R., Otto S., 2005, Reversible covalent chemistry in drug delivery, Curr. Drug Discov. Technol., 2:123–160.
  4. ^ 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.
  5. ^ Rayaprolu B.M., Strawser J.J., Anyarambhatla G. Excipients in parenteral formulations: selection considerations and effective utilization with small molecules and biologics. Drug Dev. Ind. Pharm. 2018;44:1565–1571. doi: 10.1080/03639045.2018.1483392.
  6. ^ Vargason A.M., Anselmo A.C., Mitragotri S. The evolution of commercial drug delivery technologies. Nat. Biomed. Eng. 2021;5:951–967. doi: 10.1038/s41551-021-00698-w.
  7. ^ Alqahtani M.S., Kazi M., Alsenaidy M.A., Ahmad M.Z. Advances in oral drug delivery. Front. Pharmacol. 2021;12 doi: 10.3389/fphar.2021.618411.
  8. ^ Morales J.O., Vuddanda P.R., Velaga S. Fundam. Drug Deliv. 2021. Controlled drug delivery via the buccal and sublingual routes; pp. 433–448.
  9. ^ Hussein N.R., Omer H.K., Elhissi A.M.A., Ahmed W. In: Chapter 15 - Advances in Nasal Drug Delivery Systems. Ahmed W., Phoenix D.A., Jackson M.J., in M. C.P.B.T.-A., Charalambous S.E., editors. Academic Press; 2020. pp. 279–311.
  10. ^ Chauhan A., Fitzhenry L., Serro A.P. Recent Advances in Ophthalmic Drug Delivery. 2022:1–5.
  11. ^ Thirunavukkarasu A., Nithya R., Jeyanthi J. Transdermal drug delivery systems for the effective management of type 2 diabetes mellitus: a review. Diabetes Res. Clin. Pract. 2022 doi: 10.1016/j.diabres.2022.109996.
  12. ^ Sharma P., Gajula K., Dingari N.N., Gupta R., Gopal S., Rai B., Iacocca R.G. Subcutaneous drug delivery: a review of the state-of-the-art modelling and experimental techniques. J. Biomech. Eng. 2022 doi: 10.1115/1.4055758.
  13. ^ Misbah Ul Haq M., Razzak M., Uddin M.A., Ahmed N., Shahidulla D. Rectal drug delivery system: an overview. Clin. Pharmacol. Biopharm. 2021;10
  14. ^ Mahant S., Sharma A.K., Gandhi H., Wadhwa R., Dua K., Kapoor D.N. Emerging trends and potential prospects in vaginal drug delivery. Curr. Drug Deliv. 2022 doi: 10.2174/1567201819666220413131243.
  15. ^ Cho M., Joo M., Kim K., Wook Y., Lee S., Mi Y., Ho I. Biochemical and Biophysical Research Communications the immunotherapeutic effects of recombinant Bacillus rin resistant to antimicrobial peptides on Calmette-Gu e bladder cancer cells. Biochem. Biophys. Res. Commun. 2018 doi: 10.1016/j.bbrc.2018.12.097.
  16. ^ Verma R., Garg S. 2001. Current Status of Drug Delivery Technologies and Future Directions.
  17. ^ Keraliya R.A., Patel C., Patel P., Keraliya V., Soni T.G., Patel R.C., Patel M.M. Osmotic drug delivery system as a part of modified release dosage form. ISRN Pharm. 2012 doi: 10.5402/2012/528079. 2012.
  18. ^ Mattos B.D., Rojas O.J., Magalh W.L.E. Biogenic silica nanoparticles loaded with neem bark extract as green. slow-release biocide. 2017;142:4206–4213. doi: 10.1016/j.jclepro.2016.11.183.
  19. ^ Ding C., Li Z. A review of drug release mechanisms from nanocarrier systems. Mater. Sci. Eng. C. 2017;76:1440–1453. doi: 10.1016/j.msec.2017.03.130.
  20. ^ Chen K., Chen X. 2010. Design and Development of Molecular Imaging Probes; pp. 1227–1236.
  21. ^ 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
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