Convection enhanced delivery of cisplatin-loaded brain penetrating nanoparticles cures malignant glioma in rats

被引:90
作者
Zhang, Clark [1 ,2 ]
Nance, Elizabeth A. [1 ,3 ]
Mastorakos, Panagiotis [1 ,4 ,5 ]
Chisholm, Jane [1 ,6 ]
Berry, Sneha [1 ,7 ]
Eberhart, Charles [8 ]
Tyler, Betty [5 ]
Brem, Henry [2 ,4 ,5 ,9 ]
Suk, Jung Soo [1 ,4 ]
Hanes, Justin [1 ,2 ,4 ,5 ,6 ,9 ]
机构
[1] Johns Hopkins Univ, Sch Med, Ctr Nanomed, Wilmer Eye Inst, Baltimore, MD 21231 USA
[2] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA
[3] Johns Hopkins Univ, Sch Med, Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA
[4] Johns Hopkins Univ, Wilmer Eye Inst, Dept Ophthalmol, Sch Med, Baltimore, MD 21231 USA
[5] Johns Hopkins Univ, Dept Neurosurg, Sch Med, Baltimore, MD 21231 USA
[6] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA
[7] Johns Hopkins Univ, Zanvyl Krieger Sch Arts & Sci, Ctr Biotechnol Educ, Baltimore, MD 21218 USA
[8] Johns Hopkins Univ, Dept Pathol, Sch Med, Baltimore, MD 21287 USA
[9] Johns Hopkins Univ, Dept Oncol, Sch Med, Baltimore, MD 21231 USA
基金
美国国家卫生研究院;
关键词
Brain tumor; Convection enhanced delivery; Cisplatin; Therapeutic nanoparticle; Non-adhesive surface; CENTRAL-NERVOUS-SYSTEM; PHASE-III TRIAL; GLIOBLASTOMA-MULTIFORME; ADJUVANT TEMOZOLOMIDE; DNA NANOPARTICLES; RADIATION-THERAPY; GENE-THERAPY; SOLID TUMORS; CARMUSTINE; RADIOTHERAPY;
D O I
10.1016/j.jconrel.2017.03.007
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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). (C) 2017 Published by Elsevier B.V.
引用
收藏
页码:112 / 119
页数:8
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