Targeting microbubbles-carrying TGFβ1 inhibitor combined with ultrasound sonication induce BBB/BTB disruption to enhance nanomedicine treatment for brain tumors

Jun 7, 2015Journal of controlled release : official journal of the Controlled Release Society

Using ultrasound and microbubbles carrying a TGF-β1 blocker to open brain barriers and improve nanoparticle treatment for brain tumors

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Abstract

GMBL/US significantly increased the accumulation of superparamagnetic iron oxide nanoparticles in sonicated tumors.

GMBL is a conjugated microbubble designed to disrupt the blood-brain barrier and blood-tumor barrier.
In vitro studies indicated that GMBL remained stable for over one month.
The combination treatment of folate-conjugated polymersomal doxorubicin and GMBL/US improved anti-glioma effects.
Enhanced vascular permeability facilitated by GMBL/US allowed for greater nanoparticle accumulation in targeted tumor sites.
The combination treatment resulted in a significant increase in overall survival time for brain tumor-bearing mice.
GMBL/US demonstrates potential for non-invasive delivery of nanomedicine in treating central nervous system diseases.

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The clinical application of chemotherapy for brain cancer tumors remains a challenge due to difficulties in the transport of therapeutic agents across the blood-brain barrier/blood-tumor barrier (BBB/BTB). In this study, we developed des-octanoyl ghrelin-conjugated microbubbles (GMB) loaded with TGFβ1 inhibitor (LY364947) (GMBL) to induce BBB/BTB disruption for ultrasound (US) sonication with GMBL. The in-vitro stability study showed that GMB was pretty stable over one month. The in-vivo study showed that the accumulation of superparamagnetic iron oxide nanoparticles (SPION) in the sonicated tumor was significantly higher for focused US sonication in the presence of GMBL, indicating that GMBL/US can locally disrupt BBB/BTB to promote vascular permeability of nanoparticles. In addition, the combination of folate-conjugated polymersomal doxorubicin (FPD) and GMBL/US (FPD+GMBL/US) achieved the best anti-glioma effect and significant improvement in the overall survival time for brain tumor-bearing mice. When combined with focused US, GMBL facilitated local BBB/BTB disruption and simultaneously released LY364947 to decrease the pericyte coverage of the endothelium at the targeted brain tumor sites, resulting in enhanced accumulation and antitumor activity of FPD. The overall results indicate that GMBL/US owns a great potential for non-invasive targeting delivery of nanomedicine across the BBB to treat central nervous system (CNS) diseases.

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Targeting microbubbles-carrying TGFβ1 inhibitor combined with ultrasound sonication induce BBB/BTB disruption to enhance nanomedicine treatment for brain tumors

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