Encapsulation of temozolomide in a tumor-targeting nanocomplex enhances anti-cancer efficacy and reduces toxicity in a mouse model of glioblastoma.
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 ~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.
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, WA 20057, USA.
Sang-Soo
SS
Kim
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, WA 20057, USA.
Antonina
A
Rait
SynerGene Therapeutics, Inc., Potomac, MD 20854, USA.
Eric
E
Kim
SynerGene Therapeutics, Inc., Potomac, MD 20854, USA.
James
J
DeMarco
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, WA 20057, USA.
Kathleen F
KF
Pirollo
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, WA 20057, USA. Electronic address: change@georgetown.edu.
Esther H
EH
Chang
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000633:toxicity; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008819:Mice, Nude; D053769:Nanocapsules / Q000008:administration & dosage* / Q000633:toxicity; D000077204:Temozolomide; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D053769:Nanocapsules; D003606:Dacarbazine; D000077204:Temozolomide
Cancer stem cells; Glioblastoma multiforme; Nanocomplex; Targeted delivery; Temozolomide resistance