title: A nanoparticle carrying the p53 gene targets tumors including cancer stem cells, sensitizes glioblastoma to chemotherapy and improves survival.
abstract: Temozolomide (TMZ)-resistance in glioblastoma multiforme (GBM) has been linked to upregulation of O(6)-methylguanine-DNA methyltransferase (MGMT). Wild-type (wt) p53 was previously shown to down-modulate MGMT. However, p53 therapy for GBM is limited by lack of efficient delivery across the blood brain barrier (BBB). We have developed a systemic nanodelivery platform (scL) for tumor-specific targeting (primary and metastatic), which is currently in multiple clinical trials. This self-assembling nanocomplex is formed by simple mixing of the components in a defined order and a specific ratio. Here, we demonstrate that scL crosses the BBB and efficiently targets GBM, as well as cancer stem cells (CSCs), which have been implicated in recurrence and treatment resistance in many human cancers. Moreover, systemic delivery of scL-p53 down-modulates MGMT and induces apoptosis in intracranial GBM xenografts. The combination of scL-p53 and TMZ increased the antitumor efficacy of TMZ with enhanced survival benefit in a mouse model of highly TMZ-resistant GBM. scL-p53 also sensitized both CSCs and bulk tumor cells to TMZ, increasing apoptosis. These results suggest that combining scL-p53 with standard TMZ treatment could be a more effective therapy for GBM.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University , Washington, D. C. 20057, United States.
authors.forename: Sang-Soo
authors.initials: SS
authors.lastname: Kim
authors.forename: Antonina
authors.initials: A
authors.lastname: Rait
authors.forename: Eric
authors.initials: E
authors.lastname: Kim
authors.forename: Kathleen F
authors.initials: KF
authors.lastname: Pirollo
authors.forename: Maki
authors.initials: M
authors.lastname: Nishida
authors.forename: Natalia
authors.initials: N
authors.lastname: Farkas
authors.forename: John A
authors.initials: JA
authors.lastname: Dagata
authors.forename: Esther H
authors.initials: EH
authors.lastname: Chang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D001812:Blood-Brain Barrier / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm; D015316:Genetic Therapy / Q000379:methods; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D051379:Mice; D018625:Microscopy, Atomic Force; D050997:Nanomedicine; D053758:Nanoparticles / Q000737:chemistry*; D009364:Neoplasm Recurrence, Local; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects; D000077204:Temozolomide; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003606:Dacarbazine; D000077204:Temozolomide