Experiment research of focused ultrasound combined with drug and microbubble for treatment of central nervous system leukemia.

It has been shown that low frequency ultrasound in the presence of microbubble can effectively open the blood brain barrier (BBB) to allow the drugs to be delivered into the brain with an increased concentration. We aim to apply this method to increase the efficacy of Cytarabine (Ara-c) to treat central nervous system leukemia (CNSL). In the present study, we validated this ultrasound contrast agent Sonovue® targeting treatment via in vivo and in vitro experiments. The results showed that Sonovue® combined with Cytarabine could significantly inhibit K562 cell (chronic myeloid leukemia cell line) proliferation. In the animal experiments, it has been shown that high dose Ara-c chemotherapy could prevent and cure CNSL effectively and the drug concentration in the brain was much higher compared with low dose Ara-c chemotherapy group. We certified that under ultrasound exposure Sonovue® combined with low dose Cytarabine achieved an effective drug concentration in the rat brain, and brain tissue had no significant damage. Further animal experiments will be conducted to confirm these results in a leukemia animal model, considering the blood brain barrier is destroyed at different levels by leukemia cells. We hope this method will reduce the side effects of high-dose Cytarabine and improve the clinically high recurrence and poor prognosis of the central nervous system leukemia.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To evaluate whether Sonovue® microbubble-assisted low-frequency ultrasound can enhance delivery and efficacy of Cytarabine to the brain for treatment of central nervous system leukemia by opening the blood–brain barrier.

Animal model / Human subject Rat (strain not specified; age not specified; sex not specified)

Disease model central nervous system leukemia (CNSL)

Cargo name and characteristics Cytarabine (Ara-C): small-molecule chemotherapeutic antimetabolite (deoxycytidine analog) used to treat leukemia; tested at low and high doses in the study.

Outcomes and Safety

Summary of Outcomes Ultrasound (1.48 W/cm2, duty ratio 1:4, 5 min) combined with Sonovue (1.7 mg/ml) and Cytarabine increased K562 cell apoptosis and growth inhibition in vitro and noninvasively opened the blood–brain barrier in rats to raise brain Cytarabine levels (low-dose 10 mg/kg + US+Sonovue: 41.18 ng/ml vs low-dose alone 23.44 ng/ml and high-dose 150 mg/kg 32.41 ng/ml) without apparent brain tissue damage.

Duration of biological effect 24 and 48 hours

Safety-related matter The authors report that focused ultrasound combined with Sonovue® opened the BBB and achieved effective brain Ara-c concentrations without observable brain tissue or blood vessel damage (no significant damage on HE staining) and cite prior in vitro and in vivo studies indicating safety; they also note that this approach could reduce the severe side effects associated with high‑dose Cytarabine, while contrasting harms of current alternatives (invasive intrathecal injection, radiotherapy).

Brain Region

Visualization unavailable

Ultrasound Parameters

Focal Characteristics focal depth: None; focal length: None; aperture size: None

We are open to feedback. If you see a mistake or have a suggestion, please contact us.