期刊
CANCER LETTERS
卷 369, 期 1, 页码 250-258出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2015.08.022
关键词
Nanocomplex; Targeted delivery; Temozolomide resistance; Glioblastoma multiforme; Cancer stem cells
类别
资金
- NCI [5R01CA13201202]
- NCI SBIR [HHSN261201400038C]
- National Foundation for Cancer Research [HU0001]
- SynerGene Therapeutics Inc.
- NCI Cancer Center [2P30CA51008]
- U.S. Public Health Service [151ORR15768-01]
- Research Facilities Improvement grant from the National Center for Research Resources, NIH [C06RR14567]
Although temozolomide (TMZ) is the current first-line chemotherapy for glioblastoma multiforme (GBM), most patients either do not respond or ultimately fail TMZ treatment. Both intrinsic tumor resistance and limited access of TMZ to brain tumors as a result of the blood-brain barrier (BBB) contribute to poor response and ultimately to poor prognosis for GBM patients. We have developed a dual-targeting nanomedicine that both actively crosses the BBB and actively targets cancer cells once in the brain parenchyma. This nanomedicine (termed scL-TMZ) is sized similar to 40 nm and comprised of a cationic liposome (DOTAP:DOPE) encapsulating TMZ. The surface of liposome is decorated with anti-transferrin receptor single-chain antibody fragments to facilitate the crossing of the BBB by the scL-TMZ in addition to targeting GBM in the brain. This novel formulation was found to be markedly more effective than standard TMZ in both TMZ-resistant and TMZ-sensitive GBM. Encapsulation of TMZ also markedly enhanced its efficacy in killing a variety of non-GBM tumor cells. The scL-TMZ nanocomplex was shown to target cancer stem cells, which have been linked to both drug resistance and recurrence in GBM. Most significantly, systemically administered scL-TMZ significantly prolonged survival in mice bearing intracranial GBM tumors. The improved efficacy of scL-TMZ compared to standard TMZ was accompanied by reduced toxicity, so we conclude that the scL-TMZ nanomedicine holds great promise as a more effective therapy for GBM and other tumor types. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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