Ultrasound-mediated delivery and distribution of polymeric nanoparticles in the normal brain parenchyma and melanoma metastases

Baghirov H., Snipstad S., Sulheim E., Berg S., Hansen R., Thorsen F., Morch Y., De Lange Davies C.
Cancer Research2017
The blood-brain barrier (BBB) prevents the passage of nearly all drugs into the brain, hindering brain cancer treatment. Nanoparticles (NPs) have emerged as promising drug delivery vehicles, due to incorporation of poorly soluble drugs, functionalization for controlled and sustained release and combination of drug delivery with imaging. Transport of NPs across the BBB, however, is equally complicated and can benefit from versatile BBB opening techniques. Focused ultrasound (FUS) in combination with microbubbles (MBs) ensures safe and reversible opening of the BBB. Here we used FUS with a novel platform based on MBs stabilized by poly(isohexyl cyanoacrylate) (PIHCA) NPs to permeabilize the BBB and transport NPs into the brain in a melanoma metastasis model. Intracardiac injection of patient-derived human melanoma cells was performed in immunodeficient mice. Brain melanoma metastases developed four weeks post-injection. A novel ultrasound system able to generate 1.1 MHz and 7.8 MHz FUS during the same experiment was used for FUS treatments. Selection of the treatment area was guided by magnetic resonance imaging. BBB was disrupted by FUS at 1.1 MHz, while FUS at 7.8 MHz was used to enable acoustic radiation force and, hopefully, push NPs farther into the extracellular matrix away from blood vessels. Successful BBB opening was verified using a gadolinium-based contrast agent. After the FUS treatment, the brains were either frozen or fixed in formalin for histological examination. NP transport across the BBB and distribution in the brain parenchyma were assessed using confocal microscopy with advanced image analysis. Levels of P-glycoprotein (P-gp), an integral component of the BBB, were determined using immunohistochemistry. FUS in combination with PIHCA NP-MBs successfully opened the BBB with an acoustic pressure of 0.38 MPa. NPs were transported across the BBB and distributed in the brain parenchyma in a manner dependent on the extent of BBB opening. NP were also delivered to melanoma metastases, although at this stage of tumor development their accumulation in metastases was limited compared to the surrounding tissue, possibly due to reduced vascularization of metastases. Little effect of 7.8 MHz FUS was observed, possibly because FUS at 1.1 MHz already increased NP distribution in the brain tissue. FUS exposure induced some extent of red blood cell extravasation. P-gp levels were not altered immediately after sonication. Overall, our results indicate that combining NPs and MBs in a single unit, such as the one used in our study, can be used to deliver NPs across the BBB in a substantial amount, showing its potential in NP-aided drug delivery to the brain.

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