Study on Transportation of Arsenic Trioxide Nanoparticles Across Blood-Brain Barrier in ICR Mice

Abstract 4292

With the progress of leukemia therapy and the improvement of supportive treatment, all-trans-retinoic acid (ATRA) and arsenic trioxide (As₂O₃) are extensively used in clinical. In recent years, remission rate of acute promyelocytic leukemia (APL) is obviously improved, and the survival is gradually extended. However, the incidence rate of central nervous system leukemia (CNSL) is increasing, and the therapeutic effect and prognosis are poor. This will severely influence the survival of the patients, and it is also one of the important reasons of leukemia relapse.

The method for prevention of CNSL is intrathecal injection. However, it will cause discomfort to the patients, and also has some adverse reaction and certain risk. With the increase of the incidence of CNSL, new methods are urgently needed. We developed new Arsenic trioxide Nanoparticles (ASN), which are easier to penetrate blood-brain barrier (BBB).

Previous studies showed that ASN had a stronger anti-tumor activity compared with traditional Arsenic trioxide. The underlying reason may be associated with physical and chemical properties of the nanoparticles. When material processed into nanometer scale (0.1 ~ 100 nm), it will present a new physical and chemical characteristics, which may gift the drug new biological characteristics and functions. In the present study, we found that ASN could pass through blood brain barrier more easily than traditional arsenic trioxide. In this study, we evaluate the penetrability of ASN across BBB with ICR mice.

Arsenic trioxide nanopaticles (ASN) were prepared with sol-gel method, about 40nm in diameter. And the Electronic differential system (EDS) showed that these nanopaticles were arsenic trioxide. Healthy ICR mice were chosen, and then they were divided into ASN group and arsenic acids group. The mice were gavaged with ASN or arsenic acids at the dose of 1 mg/kg body weight. After treated with different drugs, the mice were sacrificed in different time. The brain tissue was removed for analysis. Ultimately, atomic fluorescence spectrometry was utilized to determine the concentration of As in cerebral tissues. All the experiments were performed in accordance with the Regulations of Experimental Animal Administration issued by the State Committee of Science and Technology of People’s Republic of China.

Compare with arsenic acids group, the concentration of As was evidently higher in cerebral tissues of ASN group in 1□‘4 hour (P<0.01) after treatment. In ASN group, the concentration of As in brains reached the peak about 171.2061 ± 43.1 ng/g at two hours after administration, and then declined. In contrast, the peak concentration of As in brain tissue was only 69.6563 ± 14.9 ng/g (vs. ASN group P=0.028) at two hour after treatment in arsenic acids group. There was no significant difference of the As concentration in CSF at 8□‘24 hour. Hence, the nanoparticles were easier to pass through the BBB.

The penetrability of nanoparticle across of BBB was increased and the drug could quickly reach therapeutic concentration. The metabolism characteristics of ASN suggested that ASN may have less unfavorable effect.