title: Quinacrine Mediated Sensitization of Glioblastoma (GBM) Cells to TRAIL through MMP-Sensitive PEG Hydrogel Carriers.
abstract: Overcoming drug resistance is a major challenge for cancer therapy. Tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) is a potent therapeutic as an activator of apoptosis, particularly in tumor but not in healthy cells. However, its efficacy is limited by the resistance of tumor cell populations to the therapeutic substance. Here, we have addressed this limitation through the development of a controlled release system, matrix-metalloproteinase (MMP)-sensitive and arg-gly-asp-ser (RGDS) peptide functionalized poly (ethylene-glycol) (PEG) particles which are synthesized via visible-light-induced water-in-water emulsion polymerization. Quinacrine (QC), a recently discovered TRAIL sensitizer drug, is loaded into the hydrogel carriers and the influence of this system on the apoptosis of a malignant type of brain cancer, glioblastoma multiforme (GBM), has been investigated in detail. The results suggest that MMP-sensitive particles are cytocompatible and superior to promote TRAIL-induced apoptosis in GBM cells when loaded with QC. Compared to QC and TRAIL alone, combination of QC-loaded PEG hydrogel and TRAIL demonstrates synergistic apoptotic inducing behavior. Furthermore, QC-loaded particles, but not QC or PEG-hydrogels alone, enhance apoptosis as is measured through expression of apoptosis-related genes. This system is promising to significantly improve the efficacy of chemotherapeutic drugs and suggests a combination treatment for GBM therapy.
authors.affiliation: Biomedical Sciences and Engineering, Koc University, 34450, Sariyer, Istanbul, Turkey.
authors.forename: Pelin
authors.initials: P
authors.lastname: Erkoc
authors.affiliation: School of Medicine, Koc University, 34450, Sariyer, Istanbul, Turkey.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Cingöz
authors.affiliation: Biomedical Sciences and Engineering, Koc University, 34450, Sariyer, Istanbul, Turkey.|School of Medicine, Koc University, 34450, Sariyer, Istanbul, Turkey.
authors.forename: Tugba Bagci
authors.initials: TB
authors.lastname: Onder
authors.affiliation: Biomedical Sciences and Engineering, Koc University, 34450, Sariyer, Istanbul, Turkey.|Chemical and Biological Engineering, Koc University, 34450, Sariyer, Istanbul, Turkey.
authors.forename: Seda
authors.initials: S
authors.lastname: Kizilel
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers; D065546:Drug Liberation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D018625:Microscopy, Atomic Force; D010455:Peptides / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry*; D058105:Polymerization; D011796:Quinacrine / Q000494:pharmacology / Q000627:therapeutic use*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000627:therapeutic use*; D014961:X-Ray Diffraction
chemical_list: D004337:Drug Carriers; D020100:Hydrogels; D010455:Peptides; D053221:TNF-Related Apoptosis-Inducing Ligand; D011092:Polyethylene Glycols; D020778:Matrix Metalloproteinase 2; D011796:Quinacrine
keywords: MMP-sensitive hydrogel; PEG hydrogel carriers; TRAIL; TRAIL resistance; quinacrine; water-in-water emulsion