title: TRAIL conjugated to nanoparticles exhibits increased anti-tumor activities in glioma cells and glioma stem cells in vitro and in vivo.
abstract: Glioblastomas (GBM) are characterized by resistance to chemotherapy and radiotherapy, and therefore, alternative therapeutic approaches are needed. TRAIL induces apoptosis in cancer but not in normal cells and is considered to be a promising anti-tumor agent. However, its short in vivo half-life and lack of efficient administration modes are serious impediments to its therapeutic efficacy. Nanoparticles (NP) have been used as effective delivery tools for various anticancer drugs. TRAIL was conjugated to magnetic ferric oxide NP by binding the TRAIL primary amino groups to activated double bonds on the surface of the NP. The effect of NP-TRAIL was examined on the apoptosis of glioma cells and self-renewal of glioma stem cells (GSCs). In addition, the ability of the NP-TRAIL to track U251 cell-derived glioma xenografts and to affect cell apoptosis, tumor volume, and survival among xenografted rats was also examined. Conjugation of TRAIL to NP increased its apoptotic activity against different human glioma cells and GSCs, as compared with free recombinant TRAIL. Combined treatment with NP-TRAIL and γ-radiation or bortezomib sensitized TRAIL-resistant GSCs to NP-TRAIL. Using rhodamine-labeled NP and U251 glioma cell-derived xenografts, we demonstrated that the NP-TRAIL were found in the tumor site and induced a significant increase in glioma cell apoptosis, a decrease in tumor volume, and increased animal survival. In summary, conjugation of TRAIL to NP increased its apoptotic activity both in vitro and in vivo. Therefore, NP-TRAIL represents a targeted anticancer agent with more efficient action for the treatment of GBM and the eradication of GSCs.
authors.affiliation: Department of Chemistry, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Benny
authors.initials: B
authors.lastname: Perlstein
authors.forename: Susan A
authors.initials: SA
authors.lastname: Finniss
authors.forename: Cathie
authors.initials: C
authors.lastname: Miller
authors.forename: Hana
authors.initials: H
authors.lastname: Okhrimenko
authors.forename: Gila
authors.initials: G
authors.lastname: Kazimirsky
authors.forename: Simona
authors.initials: S
authors.lastname: Cazacu
authors.forename: Hae Kyung
authors.initials: HK
authors.lastname: Lee
authors.forename: Nancy
authors.initials: N
authors.lastname: Lemke
authors.forename: Shlomit
authors.initials: S
authors.lastname: Brodie
authors.forename: Felix
authors.initials: F
authors.lastname: Umansky
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Rempel
authors.forename: Mark
authors.initials: M
authors.lastname: Rosenblum
authors.forename: Tom
authors.initials: T
authors.lastname: Mikklesen
authors.forename: Shlomo
authors.initials: S
authors.lastname: Margel
authors.forename: Chaya
authors.initials: C
authors.lastname: Brodie
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D015153:Blotting, Western; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D005260:Female; D005290:Ferric Compounds / Q000737:chemistry; D005720:Gamma Rays; D005910:Glioma / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D053758:Nanoparticles; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011719:Pyrazines / Q000627:therapeutic use; D051381:Rats; D011923:Rats, Nude; D011994:Recombinant Proteins / Q000627:therapeutic use*; D015996:Survival Rate; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D005290:Ferric Compounds; D011719:Pyrazines; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C000499:ferric oxide; D000069286:Bortezomib