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Potential antitumor activity of novel DODAC/PHO-S liposomes
Arthur Cássio de Lima Luna1, Greice Kelle Viegas Saraiva2, Otaviano Mendonça Ribeiro Filho3
1Biochemistry and Biophysical Laboratory, Butantan Institute, University of Sao Paulo, Sao Paulo, Brazil; Department of Medical Sciences, Medical School, University of Sao Paulo, Sao Paulo, Brazil.
Abstract:
In recent studies, we showed that synthetic phosphoethanolamine (PHO-S) has a great potential for inducing cell death in several tumor cell lines without damage to normal cells. However, its cytotoxic effect and selectivity against tumor cells could increase with encapsulation in cationic liposomes, such as dioctadecyldimethylammonium chloride (DODAC), due to electrostatic interactions between these liposomes and tumor cell membranes. Our aim was to use cationic liposomes to deliver PHO-S and to furthermore maximize the therapeutic effect of this compound. DODAC liposomes containing PHO-S (DODAC/PHO-S), at concentrations of 0.3-2.0 mM, prepared by ultrasonication, were analyzed by scanning electron microscopy (SEM) and dynamic light scattering. The cytotoxic effect of DODAC/PHO-S on B16F10 cells, Hepa1c1c7 cells, and human umbilical vein endothelial cells (HUVECs) was assessed by MTT assay. Cell cycle phases of B16F10 cells were analyzed by flow cytometry and the morphological changes by SEM, after treatment. The liposomes were spherical and polydisperse in solution. The liposomes were stable, presenting an average of ∼ 50% of PHO-S encapsulation, with a small reduction after 40 days. DODAC demonstrated efficient PHO-S delivery, with the lowest values of IC50% (concentration that inhibits 50% of the growth of cells) for tumor cells, compared with PHO-S alone, with an IC50% value of 0.8 mM for B16F10 cells and 0.2 mM for Hepa1c1c7 cells, and without significant effects on endothelial cells. The Hepa1c1c7 cells showed greater sensitivity to the DODAC/PHO-S formulation when compared to B16F10 cells and HUVECs. The use of DODAC/PHO-S on B16F10 cells induced G2/M-phase cell cycle arrest, with the proportion significantly greater than that treated with PHO-S alone. The morphological analysis of B16F10 cells by SEM showed changes such as "bleb" formation, cell detachment, cytoplasmic retraction, and apoptotic bodies after DODAC/PHO-S treatment. Cationic liposomal formulation for PHO-S delivery promoted cytotoxicity more selectively and effectively against B16F10 and Hepa1c1c7 cells. Thus, the DODAC/PHO-S liposomal formulation presents great potential for preclinical studies.
Insights
Synthetic phosphoethanolamine (PHO-S) delivered via cationic DODAC liposomes shows enhanced tumor cell death. This PHO-S liposomal formulation effectively targets cancer cells, offering improved therapeutic potential with minimal impact on normal cells.
Area of Science:
- Biochemistry
- Nanotechnology
- Oncology
Background:
- Synthetic phosphoethanolamine (PHO-S) demonstrates potential for inducing tumor cell death.
- Cationic liposomes, like dioctadecyldimethylammonium chloride (DODAC), can enhance PHO-S's cytotoxic effect and selectivity through electrostatic interactions with tumor cell membranes.
Purpose of the Study:
- To utilize cationic DODAC liposomes for PHO-S delivery.
- To maximize the therapeutic efficacy of PHO-S through liposomal encapsulation.
Main Methods:
- DODAC liposomes encapsulating PHO-S (DODAC/PHO-S) were prepared via ultrasonication.
- Liposome characterization included scanning electron microscopy (SEM) and dynamic light scattering.
- Cytotoxicity was assessed using MTT assays on B16F10 and Hepa1c1c7 tumor cells, and HUVECs.
- Cell cycle analysis (flow cytometry) and morphological changes (SEM) were evaluated in B16F10 cells.
Main Results:
- DODAC/PHO-S liposomes were spherical, polydisperse, and stable, with approximately 50% PHO-S encapsulation.
- The formulation exhibited enhanced cytotoxicity against tumor cells compared to PHO-S alone, with lower IC50 values (0.8 mM for B16F10, 0.2 mM for Hepa1c1c7).
- No significant toxicity was observed in HUVECs, indicating selectivity.
- DODAC/PHO-S induced G2/M-phase cell cycle arrest in B16F10 cells and caused characteristic apoptotic morphological changes.
Conclusions:
- Cationic DODAC liposomes effectively deliver PHO-S, enhancing its selective cytotoxicity against B16F10 and Hepa1c1c7 tumor cells.
- The DODAC/PHO-S liposomal formulation demonstrates significant potential for preclinical cancer therapy development.
