MR image-guided delivery of cisplatin-loaded brain-penetrating nanoparticles to invasive glioma with focused ultrasound
2017
Abstract Systemically administered chemotherapeutic drugs are often ineffective in the treatment of invasive brain tumors due to poor
therapeutic index. Within gliomas, despite the presence of heterogeneously leaky microvessels, dense extracellular matrix and high interstitial pressure generate a “blood-tumor barrier” (BTB), which inhibits drug delivery and distribution. Meanwhile, beyond the contrast MRI-enhancing edge of the tumor, invasive cancer cells are protected by the intact
blood-brain barrier(BBB). Here, we tested whether brain-penetrating nanoparticles (BPN) that possess dense surface coatings of polyethylene glycol (PEG) and are loaded with cisplatin (CDDP) could be delivered across both the blood-tumor and
blood-brain barrierswith MR image-guided focused ultrasound (MRgFUS), and whether this treatment could control glioma growth and invasiveness. To this end, we first established that MRgFUS is capable of significantly enhancing the delivery of ~ 60 nm fluorescent tracer BPN across the blood-tumor barrier in both the 9 L (6-fold improvement)
gliosarcomaand invasive F98 (28-fold improvement) glioma models. Importantly, BPN delivery across the intact BBB, just beyond the tumor edge, was also markedly increased in both tumor models. We then showed that a CDDP loaded BPN formulation (CDDP-BPN), composed of a blend of
polyaspartic acid(PAA) and heavily PEGylated
polyaspartic acid(PAA-PEG), was highly stable, provided extended drug release, and was effective against F98 cells in vitro. These CDDP-BPN were delivered from the
systemic circulationinto orthotopic F98 gliomas using MRgFUS, where they elicited a significant reduction in tumor invasiveness and growth, as well as improved animal survival. We conclude that this therapy may offer a powerful new approach for the treatment invasive gliomas, particularly for preventing and controlling recurrence.
Keywords:
-
Correction
-
Source
-
Cite
-
Save
79
References
61
Citations
NaN
KQI