Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States.
Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, MD 21205, United States.
J Control Release. 2017 Oct 10;263:112-119. doi: 10.1016/j.jconrel.2017.03.007. Epub 2017 Mar 7.
Glioblastoma multiforme (GBM) is highly invasive and uniformly fatal, with median survival<20months 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 (70nm 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=40days), cisplatin alone (median survival=12days) or saline-treated controls (median survival=28days).
多形性胶质母细胞瘤（GBM）具有高度侵袭性，且普遍致命，即使采用最激进的治疗方法，包括手术、放疗和全身化疗，中位生存期仍<20 个月。顺铂是一种特别有效的化疗药物，但由于严重的全身毒性和即使在标准递送系统中直接置于大脑内，也无法有效渗透脑肿瘤组织，其在治疗 GBM 中的应用受到限制。我们描述了载顺铂纳米颗粒的开发，这些纳米颗粒足够小（直径 70nm），可以在细胞间的多孔细胞外基质中移动，并且具有密集的聚乙二醇（PEG）冠，可防止它们在通过脑肿瘤实质移动时被黏附捕获。结果，与没有密集 PEG 冠的纳米颗粒相比，这些“穿透大脑的纳米颗粒”在局部通过手动注射或对流增强递送后，能够更深地渗透到脑肿瘤组织中。纳米颗粒还以有效浓度持续释放顺铂，以杀死它们到达的肿瘤细胞，而不会在没有递送系统时将顺铂注入大脑中观察到的毒性相关死亡。与顺铂在常规非 PEG 化颗粒（中位生存期=40 天）、顺铂单独（中位生存期=12 天）或生理盐水治疗对照组（中位生存期=28 天）中相比，顺铂在穿透大脑的纳米颗粒中给药时，荷原位脑胶质瘤大鼠的中位生存期显著延长（未达到中位生存期；80%的长期幸存者）。
