TY - JOUR
T1 - Convection enhanced delivery of cisplatin-loaded brain penetrating nanoparticles cures malignant glioma in rats
AU - Zhang, Clark
AU - Nance, Elizabeth A.
AU - Mastorakos, Panagiotis
AU - Chisholm, Jane
AU - Berry, Sneha
AU - Eberhart, Charles
AU - Tyler, Betty
AU - Brem, Henry
AU - Suk, Jung Soo
AU - Hanes, Justin
N1 - Funding Information:
The funding for this work was provided by the National Institutes of Health (R01CA164789, R01EB020147, R01CA197111, R01CA204968 and P30EY001765) and Focused Ultrasound Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We also thank B. Schuster for his help in high-throughput MPT analysis.
Publisher Copyright:
© 2017
PY - 2017/10/10
Y1 - 2017/10/10
N2 - Glioblastoma multiforme (GBM) is highly invasive and uniformly fatal, with median survival < 20 months after diagnosis even with the most aggressive treatment that includes surgery, radiation, and systemic chemotherapy. Cisplatin is a particularly potent chemotherapeutic agent, but its use to treat GBM is limited by severe systemic toxicity and inefficient penetration of brain tumor tissue even when it is placed directly in the brain within standard delivery systems. We describe the development of cisplatin-loaded nanoparticles that are small enough (70 nm in diameter) to move within the porous extracellular matrix between cells and that possess a dense polyethylene glycol (PEG) corona that prevents them from being trapped by adhesion as they move through the brain tumor parenchyma. As a result, these “brain penetrating nanoparticles” penetrate much deeper into brain tumor tissue compared to nanoparticles without a dense PEG corona following local administration by either manual injection or convection enhanced delivery. The nanoparticles also provide controlled release of cisplatin in effective concentrations to kill the tumor cells that they reach without causing toxicity-related deaths that were observed when cisplatin was infused into the brain without a delivery system. Median survival time of rats bearing orthotopic glioma was significantly enhanced when cisplatin was delivered in brain penetrating nanoparticles (median survival not reached; 80% long-term survivors) compared to cisplatin in conventional un-PEGylated particles (median survival = 40 days), cisplatin alone (median survival = 12 days) or saline-treated controls (median survival = 28 days).
AB - Glioblastoma multiforme (GBM) is highly invasive and uniformly fatal, with median survival < 20 months after diagnosis even with the most aggressive treatment that includes surgery, radiation, and systemic chemotherapy. Cisplatin is a particularly potent chemotherapeutic agent, but its use to treat GBM is limited by severe systemic toxicity and inefficient penetration of brain tumor tissue even when it is placed directly in the brain within standard delivery systems. We describe the development of cisplatin-loaded nanoparticles that are small enough (70 nm in diameter) to move within the porous extracellular matrix between cells and that possess a dense polyethylene glycol (PEG) corona that prevents them from being trapped by adhesion as they move through the brain tumor parenchyma. As a result, these “brain penetrating nanoparticles” penetrate much deeper into brain tumor tissue compared to nanoparticles without a dense PEG corona following local administration by either manual injection or convection enhanced delivery. The nanoparticles also provide controlled release of cisplatin in effective concentrations to kill the tumor cells that they reach without causing toxicity-related deaths that were observed when cisplatin was infused into the brain without a delivery system. Median survival time of rats bearing orthotopic glioma was significantly enhanced when cisplatin was delivered in brain penetrating nanoparticles (median survival not reached; 80% long-term survivors) compared to cisplatin in conventional un-PEGylated particles (median survival = 40 days), cisplatin alone (median survival = 12 days) or saline-treated controls (median survival = 28 days).
KW - Brain tumor
KW - Cisplatin
KW - Convection enhanced delivery
KW - Non-adhesive surface
KW - Therapeutic nanoparticle
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U2 - 10.1016/j.jconrel.2017.03.007
DO - 10.1016/j.jconrel.2017.03.007
M3 - Article
C2 - 28279797
AN - SCOPUS:85015690633
SN - 0168-3659
VL - 263
SP - 112
EP - 119
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -