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Anti-Melanoma Activity of Indomethacin Incorporated into Mesoporous Silica Nanoparticles

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Abstract

Melanoma is the deadliest type of skin cancer. Treatments that directly address tumor survival are required. Indomethacin (IND) is a well-known drug used worldwide. Although widely used as a therapeutic agent, IND has undesirable gastrointestinal effects.

Purpose

To investigate the antitumor efficacy of IND incorporated into mesoporous silica nanoparticles (MSNPs+IND), as well as its toxic potential in a syngeneic murine B16 melanoma model.

Methods

Antitumor activity was evaluated by measuring tumor size and weight and by histopathological analysis. Possible molecular signaling pathways involved in the antitumor activity were analyzed by Western blot in liver tissue and by immunohistochemistry in tumor tissue. The potential toxicity was evaluated by determining body and organ weights and by biochemical and genotoxic analysis.

Results

MSNPs+IND treatments inhibited tumor growth by up to 70.09% and decreased the frequency of mitosis in tumor tissues, which was up to 37.95% lower compared to the IND groups. In hepatic tissue, COX-2 levels decreased significantly after treatment with MSNPs+IND and IND. Additionally, MSNPs+IND and IND increased the levels of cleaved caspase-3 (156.25% and 137.50%, respectively), inducing tumor cell apoptosis. Genotoxicity was limited to the group treated with the higher concentration of IND, while MSNPs prevented IND-induced genotoxicity.

Conclusions

MSNPs may be promising for future applications in cancer therapy.

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Abbreviations

APTES:

3-Aminopropyltriethoxysilane alkoxide

B16F10:

Murine melanoma cells

BRAF :

Human oncogene

b.w.:

Body weight

Ca2+ :

Calcium

COX:

Cyclooxygenase

COX-1:

Cyclooxygenase, isoform 1

COX-2:

Cyclooxygenase, isoform 2

DAMPs:

Damage-associated molecular patterns

DMEM:

Dulbecco’s Modified Eagle’s Medium

DMSO:

Dimethylsulfoxide

DNA:

Deoxyribonucleic acid

EDTA:

Ethylenediamine tetraacetic acid

FDA:

Food and Drug Administration

HAM F10:

Nutrient Mixture F-10 Ham

HIF-1:

Hypoxia-inducible fator-1

IAP:

Inhibitors of apoptosis proteins

INCA:

Brazilian National Cancer Institute (Instituto Nacional do Câncer)

IND:

Indomethacin

MEK :

Human oncogene

MN:

Micronucleus

MNPCE:

Micronucleated polychromatic erythrocytes

MSNP:

Mesoporous silica nanoparticles

MSNP+IND:

Indomethacin incorporated into mesoporous silica nanoparticles

NCE:

Normochromatic erythrocytes

NDI:

Nuclear division index

NF-κB:

Nuclear factor kappa B

NK:

Natural killers cells

NM:

Nanomaterial

NO:

Nitric oxide

NP:

Nanoparticle

NSAIDs:

Non-steroidal anti-inflammatory drugs

O2 :

Oxygen

OECD:

Organization for Economic Co-operation and Development

PBS:

Phosphate-buffered saline

PGE2:

E2 prostaglandin

pH:

Hydrogenionic potential

RNA:

Ribonucleic acid

ROS:

Reactive oxygen species

RPMI:

Roswell Park Memorial Institute culture medium

SCGE:

Single cell gel electrophoresis

SD:

Standard deviation

Sol-gel:

Solution-Gel

STAT3:

Signal transducers and activators of transcription

TGA:

Thermogravimetric analysis

TGIR:

Tumor growth inhibition rate

TNF:

Tumor necrosis factor

USP:

São Paulo University (Universidade de São Paulo)

UV:

Ultraviolet

VEGF:

Vascular endothelial growth factor

WHO:

World Health Organization

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by the São Paulo Research Foundation (FAPESP, Brazil; grant # 2016/24269-7). Partial support was provided by the Coordination for the Improvement of Higher Education Personnel (CAPES, Brazil; Finance Code 001). The authors are grateful to the National Council for Scientific and Technological (CNPq, Brazil) for the fellowships granted. The authors declare no conflict of interest.

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Authors and Affiliations

  1. Universidade de Franca, Avenida Dr. Armando Salles Oliveira, 201 – Parque Universitário, Franca, São Paulo, 14404-600, Brazil

    Natália Helen Ferreira, Arthur Barcelos Ribeiro, Francisco Rinaldi-Neto, Fernanda Santos Fernandes, Samuel do Nascimento, Wilson Rodrigues Braz, Eduardo José Nassar & Denise Crispim Tavares

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  1. Natália Helen Ferreira
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Correspondence to Natália Helen Ferreira.

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Ferreira, N.H., Ribeiro, A.B., Rinaldi-Neto, F. et al. Anti-Melanoma Activity of Indomethacin Incorporated into Mesoporous Silica Nanoparticles. Pharm Res 37, 172 (2020). https://doi.org/10.1007/s11095-020-02903-y

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  • DOI: https://doi.org/10.1007/s11095-020-02903-y

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