y Role of sphingomyelin on the interaction of the anticancer drug gemcitabine hydrochloride with cell membrane models

Author(s)

Materon, Elsa M. ^{[1, 2]} ; Nascimento, Gustavo F. ^[1] ; Shimizu, Flavio M. ^{[1, 3]} ; Camara, Amanda S. ^[1] ; Sandrino, Bianca ^[1] ; Faria, Ronaldo C. ^[2] ; Oliveira Jr, Osvaldo N.

Affiliation

^[1] Univ Sao Paulo, Sao Carlos Inst Phys, POB 369, BR-13560970 Sao Carlos, SP - Brazil

^[2] Univ Fed Sao Carlos, Chem Dept, CP 676, BR-13565905 Sao Carlos, SP - Brazil

^[3] Univ Campinas UNICAMP, Gleb Wataghin Inst Phys IFGW, Dept Appl Phys, BR-13083859 Campinas, SP - Brazil

• Document type: Journal article
• Source: COLLOIDS AND SURFACES B-BIOINTERFACES; v. 196, DEC 2020.
• Web of Science Citations: 0

Abstract

The fight against drug resistance in chemotherapy requires a molecular-level understanding of the drug interaction with cell membranes, which today is feasible with membrane models. In this study, we report on the interaction of gemcitabine (GEM), a pyrimidine nucleoside antimetabolite used to treat pancreatic cancer, with Langmuir films that mimic healthy and cancerous cell membranes. The cell membrane models were made with eight compositions of a quaternary mixture containing 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC), 1,2-dipalmitoyl-sn-glycero-3-phosphoserine (DPPS), sphingomyelin (SM), and cholesterol (CHOL). The relative concentration of SM was increased so that four of these compositions represented cancerous cells. GEM was found to increase the mean molecular area, also increasing their surface elasticity, with stronger interactions being observed for membranes corresponding to cancerous cells. More specifically, GEM penetrated deepest in the membrane with the highest SM concentration (40 mol%), as inferred from polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS). This finding was confirmed with molecular dynamics simulations that also indicated how GEM approaches the membrane, which could be useful for guiding the design of drug delivery systems. The experimental and simulation results are consistent with the preferential attachment of GEM onto cancerous cells and highlight the role of SM on drug-cell interactions. (AU)

• FAPESP's process: 12/15543-7 - Biosensors to detect Escherichia coli using the concept of an extended electronic tongue
• Grantee: Flavio Makoto Shimizu
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 17/24053-7 - Development of simple electrochemical methods for the detection of biomarkers for the diagnosis of diseases
• Grantee: Ronaldo Censi Faria
• Support type: Regular Research Grants
• FAPESP's process: 17/04712-6 - Study of the drug interactions of gemcitabine hydrochloride with lipid membrane models
• Grantee: Gustavo Freitas Do Nascimento
• Support type: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 18/22214-6 - Toward a convergence of technologies: from sensing and biosensing to information visualization and machine learning for data analysis in clinical diagnosis
• Grantee: Osvaldo Novais de Oliveira Junior
• Support type: Research Projects - Thematic Grants