Glycyrrhetinic Acid Functionalized Graphene Oxide

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Category: Biology
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2021/03/16
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Glycyrrhetinic Acid Functionalized Graphene Oxide essay

Introduction

Graphene and graphene oxide Graphene is an ultra-thin single layer of carbon where the carbon atoms are arranged in a hexagonal lattice. Graphene most common structures are carbon nanotubes (rolled up graphene sheets) and graphite (graphene layers are stacked and held together by weak forces, mainly Van der Vaals) which are becoming more used day by day in all sorts of different applications such as energy storage, thermal applications, mechanical strength and it is starting to develop in biomedicine, like graphene oxide nanoparticles (GONPs) in nanobiotechnology?1?.

Graphene oxides (GO) are a relatively recently discovered carbon nano-structures made from graphite oxidation where carbon atoms are arranged in single layer hexagonal pattern as graphene, but laced with oxygen-containing groups on nanoparticles edges such as carboxyl, hydroxyl, carbonyl or epoxy?2?. Due to GO group’s hydrophilicity, they can be dissolved in water or other solvents allowing the formation of thin films (single carbon atomic layer), making GO potentially useful for micro-electronics?3?.

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GONPs hydrophilicity and easy modifiable and specific surface allows GONPs functionalization with different biocompatible polymers such as polyethylene glycol (PEG) or chitosan amongst others. Many current applications of this GONPs in nanomedicine are emerging, especially the ones related to antimicrobialthera pies, drug delivery and cancer therapies?4?.

Drug delivery in cancer In the field of nanobiotechnology, one of the main branches of study is drug delivery. There are plenty of investigations targeted especially to cancer treatment. For instance, using functionalized graphene oxide.

An ideal design for cancer treatment would be through mitochondria-mediated apoptosis (MMA). Mitochondria are highly important in cellular processes, either essential or pathological. In cancer, cells acquire the ability of not responding to the apoptotic signals of mitochondria, therefore they are able to avoid apoptosis. If mitochondria cell-suicide factors are stimulated, apoptosis will be triggered. Hence, the interest in targeting mitochondria for drug delivery against these kind of pathologies.

However, there is a major challenge, mitochondria permeability is quite low. A way to overcome this limitation could be using ligands targeted to mitochondria. Conjugating our drug of interest to the ligand, we could achieve a proper delivery and presumably, develop a treatment. The widest and most diverse source of such ligands is nature, more specifically, plants.

In the study, Glycyrrhetinic acid (GA) was used due previous studies demonstrating its antitumor activity. In hepatocellular carcinoma cells, protein kinase C ? (PKC ?) is overexpressed and it happens to be the main binding site of GA.

Also, GA interacts with the mitochondrial respiratory chain stimulating the production of hydrogen peroxide. This chemical compound oxidizes pyridine nucleotides and thiol groups, which causes the switch of permeability, opening the mitochondrial pores. In this study they functionalized GO with GA in order to act as a nanocarrier for doxorubicin (DOX), a common drug used in chemotherapy treatments ?6?.

Functionalization

GO’s good biocompatibility and drug loading capacity were critical points taken into account to prepare the GA-functionalized GO. The reaction between –NH2 group of pegylated GA and –COOH group of GO using a cross-linking reagent allows GA-GO conjugation (figure 3), was demonstrated by Fourier transformed infrared (FTIR) spectroscopy. –COOH absorbance peak of GO group (1730 cm?-1?) disappeared in GA-GO, as a new absorbance peak of 1620 cm?-1 corresponding to the –NH2 group of peglated GA appeared confirming the GA-GO conjugation.

GA-GO lateral size of 200 nm and a thickness of less than 10 nm was measured by atomic force microscopy (AFM). Zeta potential measured value was -37.6 mV for GA-GO, significantly more negative than GO zeta potential value(-11.3 mV) at pH 7.4.

In vivo results

The in vivo assay was performed on HepG2-bearing nude mice (HepG2 is a strain of well-differentiated hepatocellular carcinoma cells, non-carcinogenic in nude mice). Bax is a protein that is found in higher proportions in the cytosolic side, but when inserted in the mitochondrial membrane it triggers cytochrome-c release into cytosol. Bcl-2 is an anti-apoptotic protein and acts inhibiting the pro-apoptotic molecules such as Bax. Expression of Bax and Bcl-2 ratio was observed by IHC and the following results were obtained: They performed TUNEL in order to confirm apoptosis and there were indeed stronger signals in those that [email protected] was administered.

Biodistribution

They observed where DOX concentration was higher, and conclude that DOX was elevated mainly in the liver and tumor-site in those administered [email protected], and also higher concentration respect to the other administration forms, DOX·HCl and [email protected] It was also tested that this kind of administration decreased tumor weight, stating its apoptotic effect in tumoral cells. This was also confirmed by HxE and Ki67 stainings.

Safety Evaluation

As doxorubicin in its free form is cardiotoxic, they emphasized if it would produce the same effect when given as [email protected] They tested ?in vitro ?its toxicity in 2 cell lines: H9c2 cardiomyocytes and L02 hepatic cells. The inhibitory effect was significantly lower at several doses (2.0-16?g/mL) on those injected [email protected] but high in tumoral cells.

Blood chemistry analysis (including liver markers ALT, AAT & alkaline phosphatase) were performed 21d after injection of [email protected] and they weren’t different from the control sample only administered saline solution. This indicates that the NP doesn’t give rise to hepatic or systemic toxicity, and that the liver function is not damaged.

Conclusions

Combining inorganic materials with biological ligands and features is a strategy that presents a wide variety of applications. Through nanobiotechnological advances and techniques we can achieve important goals such as a proper drug delivery, as seen through this assay in which functionalizing graphene oxide with the glycyrrhetinic acid ligand allowed accurate target of mitochondria. This proposal could potentially be a future therapeutic cancer treatment and also an inspirational approach for similar unsolved problems.

References

  1. Randviir, E. P., Brownson, D. A. C., & Banks, C. E. (2014). A decade of graphene research: Production, applications and outlook. ?Materials Today?, ?17?(9), 426–432.
  2. Kumar Gupta, D., Singh Rajaura, R., & Sharma, K. (2015). Synthesis and Characterization of Graphene Oxide Nanoparticles and their Antibacterial Activity. Science and Technology?, ?1?(1), 16–24.
  3. Dimiev, A. M., & Tour, J. M. (2014). Mechanism of graphene oxide formation. ?ACS Nano?, ?8?(3), 3060–3068.
  4. Wu, S. Y., An, S. S. A., & Hulme, J. (2015). Current applications of graphene oxide in nanomedicine. ?International Journal of Nanomedicine?, ?10?, 9–24.
  5. Gerani, K., Mortaheb, H. R., & Mokhtarani, B. (2017). Enhancement in Performance of Sulfonated PES Cation-Exchange Membrane by Introducing Pristine and Sulfonated Graphene Oxide Nanosheets Synthesized through Hummers and Staudenmaier Methods. Polymer – Plastics Technology and Engineering. https://doi.org/10.1080/03602559.2016.1233260
  6. Zhang, C., Liu, Z., Zheng, Y., Geng, Y., Han, C., Shi, Y., Kong, L. (2018). Glycyrrhetinic Acid Functionalized Graphene Oxide for Mitochondria Targeting and Cancer Treatment In Vivo. Small. https://doi.org/10.1002/smll.201703306
 

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Glycyrrhetinic Acid Functionalized Graphene Oxide. (2021, Mar 16). Retrieved from https://papersowl.com/examples/glycyrrhetinic-acid-functionalized-graphene-oxide/