C. The role of the blood-brain barrier (BBB) in drug delivery.

The delivery of chemotherapeutics to brain metastases is ineffective, due to an often intact BBB with low passive transcellular permeability. In a previous study we detected and characterized small brain metastases using intracardial injections of tumor cells followed by multimodal imaging (Fig. 3). Only small sized tracers (around 250D) were able to leak into tumor tissue at early stages of tumor development (D-Luciferin or ¹⁸F-FLT). Gadolinium-based MRI tracers (MW 559D and 2.066kD) extravasated relatively late (at 5 weeks), and PET imaging showed tumor permeability to large sized molecules such as ⁶⁴Cu-BSA (MW 65.55kD) at very late stages of tumor progression (9, 10).

In upcoming studies, we will permeabilise the BBB using microbubbles and focused ultrasound (FUS). Nod/scid mice will be injected intracardially with melanoma brain metastasis cells. When the animals develop tumors, they will be i.v. administered with gas microbubbles coated with drug/contrast agent-loaded PBCA nanoparticles, and exposed to FUS.