Temozolomide nanoparticles for targeted glioblastoma therapy.
Glioblastoma (GBM) is a deadly and debilitating brain tumor with an abysmal prognosis. The standard therapy for GBM is surgery followed by radiation and chemotherapy with Temozolomide (TMZ). Treatment of GBMs remains a challenge, largely because of the fast degradation of TMZ, the inability to deliver an effective dose of TMZ to tumors, and a lack of target specificity that may cause systemic toxicity. Here, we present a simple method for synthesizing a nanoparticle-based carrier that can protect TMZ from rapid degradation in physiological solutions and can specifically deliver them to GBM cells through the mediation of a tumor-targeting peptide chlorotoxin (CTX). Our nanoparticle, namely NP-TMZ-CTX, had a hydrodynamic size of <100 nm, exhibited sustained stability in cell culture media for up to 2 weeks, and could accommodate stable drug loading. TMZ bound to nanoparticles showed a much higher stability at physiological pH, with a half-life 7-fold greater than that of free TMZ. NP-TMZ-CTX was able to target GBM cells and achieved 2-6-fold higher uptake and a 50-90% reduction of IC50 72 h post-treatment as compared to nontargeted NP-TMZ. NP-TMZ-CTX showed great promise in its ability to deliver a large therapeutic dose of TMZ to GBM cells and could serve as a template for targeted delivery of other therapeutics.
†Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, United States.|‡Department of Materials Science and Engineering, University of Washington, Seattle, Washington 98195, United States.
Chen
C
Fang
‡Department of Materials Science and Engineering, University of Washington, Seattle, Washington 98195, United States.
Kui
K
Wang
‡Department of Materials Science and Engineering, University of Washington, Seattle, Washington 98195, United States.
Zachary R
ZR
Stephen
†Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, United States.|‡Department of Materials Science and Engineering, University of Washington, Seattle, Washington 98195, United States.
Qingxin
Q
Mu
§Department of Neurological Surgery, University of Washington, Seattle, Washington 98195, United States.
Forrest M
FM
Kievit
∥Department of Chemistry, University of Washington, Seattle, Washington 98195, United States.
Daniel T
DT
Chiu
†Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, United States.|⊥Departments of Medicine and Bioengineering, University of Washington, Seattle, Washington 98195, United States.
Oliver W
OW
Press
‡Department of Materials Science and Engineering, University of Washington, Seattle, Washington 98195, United States.|§Department of Neurological Surgery, University of Washington, Seattle, Washington 98195, United States.
Miqin
M
Zhang
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D000077204:Temozolomide
D000970:Antineoplastic Agents; D004337:Drug Carriers; D003606:Dacarbazine; D000077204:Temozolomide
MGMT; chlorotoxin; drug delivery; glioblastoma; nanomedicine; therapeutics