Introduction: Blood-brain barrier (BBB) hamper the delivery of drug carriers into brain. Recently, focused ultrasound (FUS) has been recognized as an emerging technique to overcome BBB. With the combination with microbubbles, FUS transiently opens gaps in BBB to enhance small drug permeation. For applying this technique for nanoparticle delivery, an important question is how large the opened BBB gaps are, and how long these gaps last. In this study, FUS-assisted BBB permeation of gold nanoparticles (AuNPs) with different size are examined in vitro and in vivo for elucidating the optimum design of NPs for brain drug delivery. Materials and Methods: 3, 15, and 120 nm AuNPs were applied to bEnd3 cells cultured on Transwell® in vitro, and ICR mice via i.v. injection in vivo under existence of Sonazoid® microbubbles, followed by FUS irradiation. TEER was measured to evaluate the barrier function of the in vitro BBB model. The amount of permeated AuNPs was measured using ICP-MS. Results and discussion: TEER measurement indicated that gaps are transiently opened for 4 h in the in vitro BBB model by FUS. The amount of permeated AuNPs in vitro was significantly increased by FUS for 3 and 15 nm NPs, while no significant difference was observed for 120 nm NPs. The permeated amount increased with decreasing NP size. FUS irradiation also significantly increased the NP delivery efficiency to brain in vivo. In the case of 0.7 MPa FUS, the efficiency increased by ca. 3-10 times. It was found that smaller NPs are not necessarily better, and 15 nm NPs showed the highest efficiency. We consider that this optimum size is determined by the competition between permeation through disrupted BBB gaps and blood half-life; while smaller NPs are better for the permeation through narrow gaps, they are rapidly excreted from blood by renal clearance. This hypothesis was supported by our kinetic model calculation that can express NP size-dependent permeation and clearance.

Size-dependent delivery of nanoparticles to brain assisted by focused ultrasound-mediated BBB disruption

256th National Meeting (2018)

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