Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Oct 10;263:120-131.
doi: 10.1016/j.jconrel.2017.03.017. Epub 2017 Mar 11.

MR Image-Guided Delivery of Cisplatin-Loaded Brain-Penetrating Nanoparticles to Invasive Glioma With Focused Ultrasound

Affiliations
Free PMC article

MR Image-Guided Delivery of Cisplatin-Loaded Brain-Penetrating Nanoparticles to Invasive Glioma With Focused Ultrasound

Kelsie F Timbie et al. J Control Release. .
Free PMC article

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 barriers with 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 ~60nm fluorescent tracer BPN across the blood-tumor barrier in both the 9L (6-fold improvement) gliosarcoma and 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 circulation into 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: Blood-brain barrier; Blood-tumor barrier; Cisplatin; Focused ultrasound; Glioma; Nanoparticle.

Figures

Figure 1
Figure 1. Physiochemical properties and diffusion behaviors of CDDP -loaded nanoparticles
(A) Transmission electron micrograph of CDDP -BPN (upper panel) and CDDP-UPN (lower panel). Scale bars = 100 nm. (B) Stability of CDDP -BPN and CDDP-UPN in ACSF and media with 10% FBS over time. (C) In vitro drug release kinetics of CDDP-BPN in PBS (pH 7.0) at 37°C (n=3). (D) In vitro cytotoxicity of carrier-free CDDP and CDDP-BPN in F98 rat GBM cells (n=3); *** p < 0.005. (E) Representative trajectories of CDDP-BPN and CDDP-UPN diffusing in rat brain tissue ex vivo. (F) Median MSD of CDDP-BPN and CDDP-UPN at a timescale of t = 1 s in at least n = 3 rat brain tissues (> 100 particles tracked in individual samples). *P< 0.05. (G) In vivo distribution of CDDP-BPN (red) and CDDP-UPN (green) in rat brain striatum following administration via CED. Cell nuclei are stained by DAPI (blue). Scale bar = 1 mm. (H) Volume of in vivo distribution of CDDP-BPN and CDDP-UPN in rat hemispheres (n > 3 rats).
Figure 2
Figure 2. Activation of microbubbles with MRgFUS opens the BTB in F98 gliomas, as well as the BBB in surrounding brain tissue
Representative contrast enhanced T1-weighted MR images of F98 glioma before (Pre-FUS) and after (Post-FUS) MRgFUS activation of microbubbles using a 9 spot grid pattern. BTB/BBB opening is indicated by increases in both the intensity and area of contrast enhancement.
Figure 3
Figure 3. MRgFUS markedly enhances the delivery of 60 nm PS-PEG-BPN across the BTB and BBB in 9L and F98 tumors
(A) Representative confocal microscopic images of 9L tumor cross-sections from FUS treated (FUS+) and untreated (FUS) rats. PS-PEG-BPN (red) are shown in relation to tumor endothelium (green). (B) Bar graph of PS-PEG-BPN delivery to 9L tumors and tumor edge regions. N=6 per group. *P<0.05 vs. FUS in same region. **P<0.05 vs. FUS+ in Edge region. (C) Representative confocal microscopic images of F98 tumor cross-sections from FUS treated (FUS+) and untreated (FUS) rats. PS-PEG-BPN (red) are shown in relation to tumor endothelium (green). (D) Bar graph of PS-PEG-BPN delivery to F98 tumors and tumor edge regions. N=4 per group. *P<0.05 vs. FUS in same region. **P<0.05 vs. FUS+ in Edge region. (E) Line graph of PS-PEG-BPN delivery to MRgFUS treated (FUS+) 9L and F98 tumors as a function of % Vascular Area. *P<0.05 vs. all other points within the 9L group.
Figure 4
Figure 4. MR image-guided delivery of CDDP-BPN to F98 gliomas with 0.8 MPa FUS inhibits tumor growth and improves survival
(A) Representative contrast-enhanced T1 weighted MR images taken before FUS application on Days 14, 21, and 28. Images show enhancing tumor volumes in untreated Control, CDDP-BPN, FUSlo + CDDP-BPN, and FUShi + CDDP-BPN treated rats. (B) Line graph of enhancing tumor volumes, taken from T1 weighted contrast MR images, for the 4 groups denoted in panel A. *P<0.05 vs. Control and CDDP-BPN groups. (C) Kaplan-Meier survival curves. *P<0.05 vs. Control. N≥4 for all groups.
Figure 5
Figure 5. MR image-guided delivery of CDDP-BPN with FUS reduces the invasiveness of F98 gliomas
(A) Representative contrast enhanced T1 weighted MR images taken from untreated Control, CDDP-BPN, FUSlo + CDDP-BPN, and FUShi + CDDP-BPN groups on Day 28. Insets show that the edge of the contrast enhancing region is more defined in the FUShi +CDDP-BPN treated F98 tumor when compared to the other 3 groups. (B) Radial intensity profiles acquired from the contrast MR images shown in the left column of panel A. Note that the linear region of the sigmoidal radial intensity profile from the FUShi + CDDP-BPN treated F98 glioma is considerably steeper than for the other 3 groups. Meanwhile, the width of the radial intensity profile is also reduced, indicating less infiltration into surrounding brain tissue. (C) Bar graph of tumor edge thickness for all 4 groups. *P<0.05 vs. all other groups. (D) Bar graph of tumor edge sharpness for all 4 groups. *P<0.05 vs. all other groups. (E) Representative transmitted light microscopic images of H&E stained cross-sections through F98 tumors from the CDDP-BPN and FUShi + CDDP-BPN groups. Note that the tumor border in the FUShi + CDDP-BPN image is well-defined compared to the CDDP-BPN image. Infiltrating tumor nodules are denoted with black arrows. (F) Bar graph of infiltrating tumor nodules per field of view (F.o.V.). **P<0.01 vs. all other groups. N≥4 for all groups.

Similar articles

See all similar articles

Cited by 13 articles

See all "Cited by" articles

MeSH terms

Feedback