Literature DB >> 24818768

Bone marrow endothelium-targeted therapeutics for metastatic breast cancer.

Junhua Mai1, Yi Huang2, Chaofeng Mu1, Guodong Zhang1, Rong Xu1, Xiaojing Guo3, Xiaojun Xia1, David E Volk4, Ganesh L Lokesh4, Varatharasa Thiviyanathan4, David G Gorenstein4, Xuewu Liu1, Mauro Ferrari5, Haifa Shen6.   

Abstract

Effective treatment of pan class="Disease">cancer metastasis to the bone relies on bone marrow drug accumulation. The surface proteins in the bone marrow vascular endothelium provide docking sites for targeted drug delivery. We have developed a n>an class="Chemical">thioaptamer that specifically binds to E-selectin that is overexpressed in the vasculature of tumor and inflammatory tissues. In this study, we tested targeted delivery of therapeutic siRNA loaded in the E-selectin thioaptamer-conjugated multistage vector (ESTA-MSV) drug carrier to bone marrow for the treatment of breast cancer bone metastasis. We evaluated tumor type- and tumor growth stage-dependent targeting in mice bearing metastatic breast cancer in the bone, and carried out studies to identify factors that determine targeting efficiency. In a subsequent study, we delivered siRNA to knock down expression of the human STAT3 gene in murine xenograft models of human MDA-MB-231 breast tumor, and assessed therapeutic efficacy. Our studies revealed that the CD31(+)E-selectin(+) population accounted for 20.8%, 26.4% and 29.9% of total endothelial cells respectively inside the femur of mice bearing early, middle and late stage metastatic MDA-MB-231 tumors. In comparison, the double positive cells remained at a basal level in mice with early stage MCF-7 tumors, and jumped to 23.9% and 28.2% when tumor growth progressed to middle and late stages. Accumulation of ESTA-MSV inside the bone marrow correlated with the E-selectin expression pattern. There was up to 5-fold enrichment of the targeted MSV in the bone marrow of mice bearing early or late stage MDA-MB-231 tumors and of mice with late stage, but not early stage, MCF-7 tumors. Targeted delivery of STAT3 siRNA in ESTA-MSV resulted in knockdown of STAT3 expression in 48.7% of cancer cells inside the bone marrow. Weekly systemic administration of ESTA-MSV/STAT3 siRNA significantly extended survival of mice with MDA-MB-231 bone metastasis. In conclusion, targeting the overexpressed E-selectin provides an effective approach for tissue-specific drug delivery to the bone marrow. Tumor growth in the bone can be effectively inhibited by blockage of the STAT3 signaling.
Copyright © 2014 Elsevier B.V. All rights reserved.

Entities:  

Keywords:  Bone metastasis; Breast cancer; E-selectin; Silicon particle; Targeted siRNA delivery; Thioaptamer

Mesh:

Substances:

Year:  2014        PMID: 24818768      PMCID: PMC4109393          DOI: 10.1016/j.jconrel.2014.04.057

Source DB:  PubMed          Journal:  J Control Release        ISSN: 0168-3659            Impact factor:   9.776


  45 in total

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