Doxorubicin (DOX) is a powerful anti-cancer drug, and efforts have been made to design nanostructures to deliver it to cancer cells. The nanostructures increase the cytotoxic effects of DOX on cancer cells, while reducing the negative effects on healthy cells.
Study: Multifunctional Green Synthesized Cu-Al Layered Double Hydroxide (LDH) Nanoparticles: Anti-Cancer and Antibacterial Activities. Image Credit: CI Photos / Shutterstock.com
In a research article published in the journal Scientific reportslayered double hydroxide (LDH) nanostructures were developed to administer DOX efficiently.
Figure 1. FTIR spectra of the synthesized nanomaterials (A, B). XRD results of the synthesized nanomaterials (C). S1 partially (C) stands for one of the POs. © Kiani, M., Bagherzadeh, M., Ghadiri, AM, Makvandi, P., & Rabiee, N. (2022).
Cancer and how nanotechnology can help
Cancer accounts for the second highest mortality after heart disease, with susceptibility to tumor development determined by several factors such as age, family history and carcinogenic exposure.
Chemotherapy is the most commonly used cancer treatment. However, complex encounters in the cancer microenvironment, as well as the ability of cancer cells to multiply and switch between molecular pathways to ensure their preservation, have led to the tumors developing resistance to treatments.
Doxorubicin (DOX) is widely used in tumor therapy because it can limit DNA replication by reducing the action of topoisomerase enzymes, suppressing cell cycle progression, and ultimately directing tumors toward cell death.
Resistance to DOX has been caused by a number of factors, including doxorubicin release of P-glycoprotein from tumor cells, Bcl-2 overexpression, apoptotic suppression, and abnormal expression of epigenetic and genetic variables. As a result, research has focused on developing nanostructured delivery mechanisms for doxorubicin to increase its anti-cancer efficacy.
The benefits of LDH as a drug delivery system
Nanotechnology offers new promises to reduce resistance to treatments and improve the effectiveness of chemotherapy drugs in cancer treatment.
Layered double hydroxides (LDHs) are nanoscale multilayer structures and anion clays with a hydrotalcite crystalline structure generated by two metal ions, including a trivalent and a divalent metal ion, an -OH group, an H2O-molecule and an interlayer anion.
Due to their distinctive multilayer architecture and anion exchange capacity between layers, LDH nanostructures have paved the way in the biomedical domain. One of the most important uses for LDH nanostructures in drug administration is the incorporation of a specific chemical into LDH through an anionic exchange between the layers.
LDH has excellent ability to charge drugs, a large surface area, great durability and anion exchange ability. These properties make them preferable for drug administration, especially compared to other nanostructures such as polymer nanoparticles (NPs).
More significantly, because LDH has a soluble bulk layer at pH 5.0 (around the acidity level in the cancer microenvironment), they are major challengers for drug administration against tumors.
Benefits of Plantago Ovata
Plantago ovata (PO) is a classic botanical remedy with bioactive polysaccharides. It is an organically produced substance with advantages such as sustainable production, low cost, availability and a good safety profile.
PO was used from the beginning to treat wounds. Subsequent research showed that PO extracts have a variety of medicinal properties, such as antioxidants, anti-inflammatory, immunomodulatory and analgesic properties.
Figure 2. Drug release at pH 4.5 (A), pH 5.5 (B) and pH 7.2 (C). The modification of nanoparticles with PO promotes drug release capacity and they resulted in delayed release of DOX. The DOX release was stable after 250 hours. Highest release occurred at pH 5.5 and lowest release was observed at pH 4.5. © Kiani, M., Bagherzadeh, M., Ghadiri, AM, Makvandi, P., & Rabiee, N. (2022).
Important results of the study
PO was used to modify the surfaces of nanoscale Cu-Al LDH structures to increase their ability as nanoscale drug delivery systems. Doxorubicin, an anti-cancer drug, was stacked on NP when prepared, and characterization procedures showed correct manufacturing and drug content.
The drug release analysis indicated pH-sensitive releases of doxorubicin from LDH NPs, with the largest release of anticancer drugs occurring at pH 5.5 and the least amount of drug release at pH 4.5, perhaps due to the detrimental effect of lower and strongly acidic pH on NP- architectures.
The MTT experiment showed high cytocompatibility of PO-incorporated Cu-Al LDH nanostructures, showing partial and low cytotoxicity to HEK-293 and PC12 cells, while decreasing the viability of MCF-7 and HT-29 cells as cancer cells.
Notably, the decrease in viability of HT-29 and MCF-7 cells was less in PO-incorporated LDH NPs than LDH nanoscale carriers without PO, which should be further investigated in future studies. CLSM data showed that LDH NP delivered doxorubicin to the nucleus and cytoplasm of HEK-293 and MCF-7 cells.
Histological examination of renal tissue revealed no cellular deterioration, adequate cellular and tubular architecture, and zero circulatory obstruction. This indicates the high cytocompatibility of PO-incorporated LDH nanostructures.
Antimicrobial testing showed that Cu-Al LDH nanoparticles showed biotoxicity against gram-negative and gram-positive bacteria, and they can be used to treat microbial diseases in future experiments.
Figure 3. The CLSM images of the drug loaded nanocarriers coated with leaf extracts treated with HEK-293 cell lines. The concentration of the nanoparticles used: 17.5 μg / mL. © Kiani, M., Bagherzadeh, M., Ghadiri, AM, Makvandi, P., & Rabiee, N. (2022).
Kiani, M., Bagherzadeh, M., Ghadiri, AM, Makvandi, P., & Rabiee, N. (2022). Multifunctional green synthesized Cu-Al layered double hydroxide (LDH) nanoparticles: anti-cancer and antibacterial activities. Scientific reports, 12. Available on: https://doi.org/10.1038/s41598-022-13431-7
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