Abstract
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.
Highlights
Central nervous system leukemia (CNSL) is a fatal leukemia complication companied with clinical symptoms in nervous system due to the infiltration of leukemia cells into duramater, spinal cord, brain parenchyma and nervous system [1]
It has been shown that high dose Ara-c chemotherapy could prevent and cure central nervous system leukemia (CNSL) effectively and the drug concentration in the brain was much higher compared with low dose Ara-c chemotherapy group
(1) Enhanced apoptosis effect on k562 cells was detected at 24 hours after intervention with ultrasound combined with Sonovue® and Cytarabine, and the effect was stronger than that in the groups with ultrasound, Sonovue®, Cytarabine individually used or combination of two, as shown in Figures 1D, 2 and 3A
Summary
Central nervous system leukemia (CNSL) is a fatal leukemia complication companied with clinical symptoms in nervous system due to the infiltration of leukemia cells into duramater, spinal cord, brain parenchyma and nervous system [1]. CNSL is an indispensable factor for the treatment of acute leukemia and other hematological malignancies [2]. It’s necessary to find a new, safe and effective treatment method to prevent and control CNSL or other hematological malignancies infiltrating central nervous system. Blood brain barrier may participate in forming and maintaining the CNS immune evasion [6], which is the basis of recurrence that leukemia cells and other tumor cells hide in the “shelter-central nervous system” to “escape” the damage of chemotherapy drugs [6]. For CNSL or other hematological malignancies central nervous system infiltration treatment, a new drug delivery system by which the drug can effectively pass through the BBB is indispensable
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