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Mechanistic Insights into the Action of Histamine-Functionalized PLA Nanoparticles Loaded with 5-Fluorouracil Against
Patrycja Jaroniek1,2, Marek Brzeziński3, Zuzanna Świniarska2,3
1Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland.
Abstract:
Gastric cancer is among the leading causes of cancer-related deaths worldwide. Modern treatment approaches include nanoparticles (NPs) designed to target cancer cells, which release a therapeutic cargo facilitating the inhibition of their expansion, thereby improving anti-tumor therapies. The success of NPs, created to deliver anticancer agents and biologically active compounds, may depend on selecting the way to target cancer cells. This study focused on examining the effects of NPs made of polylactic acid (PLA) with histamine (His) end groups and loaded with 5-fluorouracil (5-FU), a known anticancer drug (PLA-His-5-FU), on human gastric cancer AGS cells in vitro. The incubation of AGS cells with PLA-His-FU NPs resulted in diminished mitochondrial membrane potential and the induction of cell apoptosis, along with cell cycle arrest and the reduction of cell proliferation. Furthermore, the NPs tested provoked the secretion of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1β by AGS cells and induced the activation of the nuclear factor kappa B (NF-κB) signaling pathway in THP-1 blue monocytes, which indicates the ability to promote the development of a milieu for the infiltration and activation of immunocompetent cells. NPs did not increase intracellular adhesion molecule (ICAM-1) deposition on AGS cells, thus potentially preventing the distribution of cancer cells. In conclusion, PLA-His-5-FU NPs show promising anticancer activity for gastric cancer AGS cells in vitro, better than PLA-OH-5-FU, and can be used in further in vivo studies to confirm this activity.
Insights
Polylactic acid nanoparticles with histamine and 5-fluorouracil (PLA-His-5-FU NPs) effectively target gastric cancer cells. These nanoparticles induce apoptosis, arrest cell cycle, and reduce proliferation, showing promise for gastric cancer treatment.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Gastric cancer is a leading cause of cancer mortality globally.
- Nanoparticles (NPs) offer targeted delivery of anticancer agents to inhibit tumor growth.
- The efficacy of NPs depends on effective cancer cell targeting strategies.
Purpose of the Study:
- To evaluate the in vitro anticancer effects of polylactic acid nanoparticles with histamine end groups loaded with 5-fluorouracil (PLA-His-5-FU) on human gastric cancer AGS cells.
- To compare the efficacy of PLA-His-5-FU NPs with PLA-OH-5-FU NPs.
Main Methods:
- Human gastric cancer AGS cells were incubated with PLA-His-5-FU NPs.
- Assays were performed to assess mitochondrial membrane potential, apoptosis, cell cycle, proliferation, cytokine secretion (TNF-α, IL-1β), NF-κB pathway activation, and ICAM-1 deposition.
Main Results:
- PLA-His-5-FU NPs diminished mitochondrial membrane potential and induced apoptosis in AGS cells.
- NPs caused cell cycle arrest and reduced cell proliferation.
- Pro-inflammatory cytokines TNF-α and IL-1β were secreted, and the NF-κB pathway was activated in monocytes.
- No increase in ICAM-1 deposition was observed, potentially hindering cancer cell dissemination.
Conclusions:
- PLA-His-5-FU NPs demonstrate significant in vitro anticancer activity against gastric cancer AGS cells.
- These NPs show superior efficacy compared to PLA-OH-5-FU NPs.
- The findings support further in vivo investigation of PLA-His-5-FU NPs for gastric cancer therapy.
