EACR25-1291

Activity of a platinum(IV)–flurbiprofen conjugate free and immobilized into mesoporous nanostructured silica on colon cancer

T. Komazec1, D. Bovan1, M. Mojić1, N. Radulović1, E. Mihajlović1, S. Mijatović1, I. Predarska2, E. Hey-Hawkins3, G. Kaluđerović4, D. Maksimović-Ivanić1
1Institute for Biological Research "Siniša Stanković" National Institute of the Republic of Serbia University of Belgrade, Belgrade, Serbia
2Institute of Bioanalytical Chemistry, Leipzig University, Germany, Mainz, Germany
3Institute of Bioanalytical Chemistry, Leipzig University, Germany, Leipzig, Germany
4University of Applied Sciences Merseburg, Germany, Leipzig, Germany
Introduction:

Prostaglandin E2 (PGE2), a main mediator of inflammation, is a product of cyclooxygenase-2 (COX-2) activation, whose expression is increased in human colorectal cancer. In addition to its role in inflammation, PGE2 also acts as a mitogenic signaling molecule released by dying tumor cells and is thus involved in the repopulation of tumors. To improve the effect of chemotherapy by elimination of the mitogenic signal mediated by PGE2, a drug with cisplatin core – platinum(IV) complex was synthesized bearing the anti-inflammatory drug flurbiprofen. Additionally, the conjugate was immobilized into mesoporous silica nanostructural material SBA-15 in order to enable improved delivery of the drug into tumor tissue. The cytotoxicity was assessed in 2D and 3D culture system, as well in vivo using a syngeneic mouse model of colon cancer.

Material and method:

The potential cytotoxicity of free and immobilized platinum(IV)-flurbiprofen conjugate was determined in murine cell lines 4T1, B16, CT26, and MC38 using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and crystal violet as viability assays. Organoids were established from MC38-induced tumors in C57BL/6 mice which were then isolated, digested and further propagated. A CellTiter-Glo™ luminescent cell viability assay was employed to evaluate the antitumor effect of the drugs on organoids. The in vivo efficacy of the drugs was investigated in tumor-bearing C57BL/6 mice.

Result and discussion:

All tumor cell lines showed a dose-dependent decrease in viability after treatment with the drug conjugate and the corresponding SBA-15 formulation. MC38 cells were selected for further studies as they proved to be very sensitive to the applied treatments. Colon cancer organoids, which better simulate the architecture of tumor tissue than 2D cultures, showed a remarkable decrease in viability after 6 days of treatment with both drug formulations, while IC50 values were approximately several times higher than those obtained in 2D cultures. Finally, administration of both the drug conjugate and the corresponding nanostructured material to tumor-bearing C57BL/6 mice in a therapeutic regimen resulted in a statistically significant reduction in tumor volume compared to the control group.

Conclusion:

The strong antitumor potential of the platinum(IV)-flurbiprofen conjugate free and immobilized into SBA-15 in a model of mice colon cancer opens up many opportunities for further research.