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J Control Release. 2017 Dec 28;268:92-101. doi: 10.1016/j.jconrel.2017.10.012. Epub 2017 Oct 16.

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

Author information

1
Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Pediatric Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
2
Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA.
3
Department of Hematology, First Affiliated Hospital, Harbin Medical University, Harbin 150081, China.
4
Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
5
Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: hshen@houstonmethodist.org.

Abstract

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 3days. 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.

KEYWORDS:

Arsenic trioxide; Bone marrow; Decitabine; Delivery; Myelodysplastic syndrome; Nanoparticle

PMID:
29042320
PMCID:
PMC5722672
DOI:
10.1016/j.jconrel.2017.10.012
[Indexed for MEDLINE]
Free PMC Article

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