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Enhanced Cytotoxicity of Folic Acid-Targeted Liposomes Co-Loaded with C6 Ceramide and Doxorubicin: In Vitro Evaluation on HeLa, A2780-ADR, and H69-AR Cells.
Mol Pharm. 2016 Feb 01; 13(2):428-37.MP

Abstract

Current research in cancer therapy is beginning to shift toward the use of combinational drug treatment regimens. However, the efficient delivery of drug combinations is governed by a number of complex factors in the clinical setting. Therefore, the ability to synchronize the pharmacokinetics of the individual therapeutic agents present in combination not only to allow for simultaneous tumor accumulation but also to allow for a synergistic relationship at the intracellular level could prove to be advantageous. In this work, we report the development of a novel folic acid-targeted liposomal formulation simultaneously co-loaded with C6 ceramide and doxorubicin [FA-(C6+Dox)-LP]. In vitro cytotoxicity assays showed that the FA-(C6+Dox)-LP was able to significantly reduce the IC50 of Dox when compared to that after the treatment with the doxorubicin-loaded liposomes (Dox-LP) as well as the untargeted drug co-loaded (C6+Dox)-LP on HeLa, A2780-ADR, and H69-AR cells. The analysis of the cell cycle distribution showed that while the C6 liposomes (C6-LP) did not cause cell cycle arrest, all the Dox-containing liposomes mediated cell cycle arrest in HeLa cells in the G2 phase at Dox concentrations of 0.3 and 1 μM and in the S phase at the higher concentrations. It was also found that this arrest in the S phase precedes the progression of the cells to apoptosis. The targeted FA-(C6+Dox)-LP were able to significantly enhance the induction of apoptotic events in HeLa cell monolayers as compared to the other treatment groups. Next, using time-lapse phase holographic imaging microscopy, it was found that upon treatment with the FA-(C6+Dox)-LP, the HeLa cells underwent rapid progression to apoptosis after 21 h as evidenced by a drastic drop in the average area of the cells after loss of cell membrane integrity. Finally, upon evaluation in a HeLa spheroid cell model, treatment with the FA-(C6+Dox)-LP showed significantly higher levels of cell death compared to those with C6-LP and Dox-LP. Overall, this study clearly shows that the co-delivery of C6 ceramide and Dox using a liposomal platform significantly correlates with an antiproliferative effect due to cell cycle regulation and subsequent induction of apoptosis and thus warrants its further evaluation in preclinical animal models.

Authors+Show Affiliations

Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University , Boston, Massachusetts 02115, United States.Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University , Boston, Massachusetts 02115, United States.Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University , Boston, Massachusetts 02115, United States.Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University , Boston, Massachusetts 02115, United States.Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University , Boston, Massachusetts 02115, United States. Department of Biochemistry, Faculty of Science, King Abdulaziz University , Jeddah, Saudi Arabia.

Pub Type(s)

Evaluation Study
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

26702994

Citation

Sriraman, Shravan Kumar, et al. "Enhanced Cytotoxicity of Folic Acid-Targeted Liposomes Co-Loaded With C6 Ceramide and Doxorubicin: in Vitro Evaluation On HeLa, A2780-ADR, and H69-AR Cells." Molecular Pharmaceutics, vol. 13, no. 2, 2016, pp. 428-37.
Sriraman SK, Pan J, Sarisozen C, et al. Enhanced Cytotoxicity of Folic Acid-Targeted Liposomes Co-Loaded with C6 Ceramide and Doxorubicin: In Vitro Evaluation on HeLa, A2780-ADR, and H69-AR Cells. Mol Pharm. 2016;13(2):428-37.
Sriraman, S. K., Pan, J., Sarisozen, C., Luther, E., & Torchilin, V. (2016). Enhanced Cytotoxicity of Folic Acid-Targeted Liposomes Co-Loaded with C6 Ceramide and Doxorubicin: In Vitro Evaluation on HeLa, A2780-ADR, and H69-AR Cells. Molecular Pharmaceutics, 13(2), 428-37. https://doi.org/10.1021/acs.molpharmaceut.5b00663
Sriraman SK, et al. Enhanced Cytotoxicity of Folic Acid-Targeted Liposomes Co-Loaded With C6 Ceramide and Doxorubicin: in Vitro Evaluation On HeLa, A2780-ADR, and H69-AR Cells. Mol Pharm. 2016 Feb 1;13(2):428-37. PubMed PMID: 26702994.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhanced Cytotoxicity of Folic Acid-Targeted Liposomes Co-Loaded with C6 Ceramide and Doxorubicin: In Vitro Evaluation on HeLa, A2780-ADR, and H69-AR Cells. AU - Sriraman,Shravan Kumar, AU - Pan,Jiayi, AU - Sarisozen,Can, AU - Luther,Ed, AU - Torchilin,Vladimir, Y1 - 2016/01/08/ PY - 2015/12/26/entrez PY - 2015/12/26/pubmed PY - 2016/12/21/medline KW - A2780-ADR KW - C6 ceramide KW - H69-AR KW - HeLa KW - apoptosis KW - cancer KW - cancer cell spheroids KW - cell cycle arrest KW - combination drug therapy KW - doxorubicin KW - drug resistance KW - folic acid targeting KW - imaging cytometry KW - liposomes KW - nanomedicine KW - nanoparticles KW - phase holographic imaging KW - receptor targeting SP - 428 EP - 37 JF - Molecular pharmaceutics JO - Mol Pharm VL - 13 IS - 2 N2 - Current research in cancer therapy is beginning to shift toward the use of combinational drug treatment regimens. However, the efficient delivery of drug combinations is governed by a number of complex factors in the clinical setting. Therefore, the ability to synchronize the pharmacokinetics of the individual therapeutic agents present in combination not only to allow for simultaneous tumor accumulation but also to allow for a synergistic relationship at the intracellular level could prove to be advantageous. In this work, we report the development of a novel folic acid-targeted liposomal formulation simultaneously co-loaded with C6 ceramide and doxorubicin [FA-(C6+Dox)-LP]. In vitro cytotoxicity assays showed that the FA-(C6+Dox)-LP was able to significantly reduce the IC50 of Dox when compared to that after the treatment with the doxorubicin-loaded liposomes (Dox-LP) as well as the untargeted drug co-loaded (C6+Dox)-LP on HeLa, A2780-ADR, and H69-AR cells. The analysis of the cell cycle distribution showed that while the C6 liposomes (C6-LP) did not cause cell cycle arrest, all the Dox-containing liposomes mediated cell cycle arrest in HeLa cells in the G2 phase at Dox concentrations of 0.3 and 1 μM and in the S phase at the higher concentrations. It was also found that this arrest in the S phase precedes the progression of the cells to apoptosis. The targeted FA-(C6+Dox)-LP were able to significantly enhance the induction of apoptotic events in HeLa cell monolayers as compared to the other treatment groups. Next, using time-lapse phase holographic imaging microscopy, it was found that upon treatment with the FA-(C6+Dox)-LP, the HeLa cells underwent rapid progression to apoptosis after 21 h as evidenced by a drastic drop in the average area of the cells after loss of cell membrane integrity. Finally, upon evaluation in a HeLa spheroid cell model, treatment with the FA-(C6+Dox)-LP showed significantly higher levels of cell death compared to those with C6-LP and Dox-LP. Overall, this study clearly shows that the co-delivery of C6 ceramide and Dox using a liposomal platform significantly correlates with an antiproliferative effect due to cell cycle regulation and subsequent induction of apoptosis and thus warrants its further evaluation in preclinical animal models. SN - 1543-8392 UR - https://www.unboundmedicine.com/medline/citation/26702994/Enhanced_Cytotoxicity_of_Folic_Acid_Targeted_Liposomes_Co_Loaded_with_C6_Ceramide_and_Doxorubicin:_In_Vitro_Evaluation_on_HeLa_A2780_ADR_and_H69_AR_Cells_ L2 - https://doi.org/10.1021/acs.molpharmaceut.5b00663 DB - PRIME DP - Unbound Medicine ER -