Ibuprofen delivered by poly(lactic-co-glycolic acid) (PLGA) nanoparticles to human gastric cancer cells exerts antiproliferative activity at very low concentrations

Patrizia Bonelli,¹ Franca M Tuccillo,¹ Antonella Federico,⁵ Maria Napolitano,² Antonella Borrelli,¹ Daniela Melisi,⁶ Maria G Rimoli,⁶ Raffaele Palaia,³ Claudio Arra,⁴ Francesco Carinci<sup>7

1</sup>Laboratory of Molecular Biology and Viral Oncogenesis; ²Department of Clinical Immunology; ³Department of Gastrointestinal-Hepatobiliary-Pancreatic Cancer Oncology Surgery; ⁴Animal Facility, National Cancer Institute G Pascale, Naples, Italy; ⁵Microtech Laboratory, Naples, Italy; ⁶Pharmaceutical and Toxicological Chemistry Department, School of Pharmacy, University "Federico II", Naples, Italy; ⁷Department of Maxillofacial Surgery, University of Ferrara, Ferrara, Italy

Purpose: Epidemiological, clinical, and laboratory studies have suggested that ibuprofen, a commonly used nonsteroidal anti-inflammatory drug, inhibits the promotion and proliferation of certain tumors. Recently, we demonstrated the antiproliferative effects of ibuprofen on the human gastric cancer cell line MKN-45. However, high doses of ibuprofen were required to elicit these antiproliferative effects in vitro. The present research compared the antiproliferative effects of ibuprofen delivered freely and released by poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) in MKN-45 cells.
Methods: MKN-45 human gastric adenocarcinoma cells were treated with ibuprofen-loaded PLGA NPs. The proliferation of MKN-45 cells was then assessed by cell counting. The uptake of NPs was imaged by fluorescence microscopy and flow cytometry. The release of ibuprofen from ibuprofen-loaded PLGA NPs in the cells was evaluated by gas chromatography–mass spectrometry.
Results: Dramatic inhibition of cellular proliferation was observed in cells treated with ibuprofen-loaded PLGA NPs versus those treated with free ibuprofen at the same concentration. The localization of NPs was cytoplasmic. The initiation of ibuprofen release was rapid, commencing within 2 hours, and then increased slowly over time, reaching a maximum concentration at 24 hours. The inhibition of proliferation was confirmed to be due to the intracellular release of ibuprofen from the NPs. Using PLGA NPs as carriers, ibuprofen exerted an antiproliferative activity at concentrations > 100 times less than free ibuprofen, suggesting greater efficiency and less cellular toxicity. In addition, when carried by PLGA NPs, ibuprofen more quickly induced the expression of transcripts involved in proliferation and invasiveness processes.
Conclusion: Ibuprofen exerted an antiproliferative effect on MKN-45 cells at low concentrations. This effect was achieved using PLGA NPs as carriers of low doses of ibuprofen.

Keywords: nonsteroidal anti-inflammatory drug (NSAID), proliferation, uptake, MKN-45 cells

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