Bone-targeting nanoparticle to co-deliver decitabine and arsenic trioxide for effective therapy of myelodysplastic syndrome with low systemic toxicity

JOURNAL OF CONTROLLED RELEASE

卷:268

Article

Wu, Xiaoyan^1,2  Hu, Zhenhua¹  Nizzero, Sara¹  Zhang, Guodong¹  Ramirez, Maricela R.¹  Shi, Ce³  Zhou, Jin³  Ferrari, Mauro^1,4  Shen, Haifa¹ 

[1] Houston Methodist Res Inst, Dept Nanomed, 6670 Bertner Ave, Houston, TX 77030 USA

[2] Huazhong Univ Sci & Technol, Union Hosp, Dept Pediat Hematol, Tongji Med Coll, Wuhan 430022, Hubei, Peoples R China

[3] Harbin Med Univ, Affiliated Hosp 1, Dept Hematol, Harbin 150081, Heilongjiang, Peoples R China

[4] Weill Cornell Med Coll, Dept Med, New York, NY USA

关键词: Myelodysplastic syndrome;    Bone marrow;    Delivery;    Nanoparticle;    Decitabine;    Arsenic trioxide;   

DOI  :  10.1016/j.jconrel.2017.10.012

来源: Elsevier

【 摘 要 】

Myelodysplastic syndromes (MDS) are a diverse group of bone marrow disorders and clonal hematopoietic stem cell disorders characterized by abnormal blood cells, or reduced peripheral blood cell count. Recent clinical studies on combination therapy of decitabine (DAC) and arsenic trioxide (ATO) have demonstrated synergy on MDS treatment, but the treatment can cause significant side effects to patients. In addition, both drugs have to be administered on a daily basis due to their short half-lives. In addressing key issues of reducing toxic side effects and improving pharmacokinetic profiles of the therapeutic agents, we have developed a new formulation by co-packaging DAC and ATO into alendronate-conjugated bone-targeting nanoparticles (BTNPs). Our pharmacokinetic studies revealed that intravenously administered BTNPs increased circulation time up to 3 days. Biodistribution analysis showed that the BTNP facilitated DAC and ATO accumulation in the bone, which is 6.7 and 7.9 times more than untargeted NP. Finally, MDS mouse model treated with BTNPs showed better restoration of complete blood count to normal level, and significantly longer median survival as compared to free drugs or untargeted NPs treatment. Our results support bone-targeted co-delivery of DAC and ATO for effective treatment of MDS.

【 授权许可】

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