TY - JOUR
T1 - Bone marrow endothelium-targeted therapeutics for metastatic breast cancer
AU - Mai, Junhua
AU - Huang, Yi
AU - Mu, Chaofeng
AU - Zhang, Guodong
AU - Xu, Rong
AU - Guo, Xiaojing
AU - Xia, Xiaojun
AU - Volk, David E.
AU - Lokesh, Ganesh L.
AU - Thiviyanathan, Varatharasa
AU - Gorenstein, David G.
AU - Liu, Xuewu
AU - Ferrari, Mauro
AU - Shen, Haifa
N1 - Funding Information:
The authors acknowledge financial support from the following sources: Department of Defense grants W81XWH-09-1-0212 and W81XWH-12-1-0414 , National Institute of Health grants U54CA143837 and U54CA151668 , the State of Texas CPRIT grant RP121071 , the Ernest Cockrell Jr. Distinguished Endowed Chair , and Golfers Against Cancer .
PY - 2014/8/10
Y1 - 2014/8/10
N2 - Effective treatment of 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 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.
AB - Effective treatment of 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 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.
KW - Bone metastasis
KW - Breast cancer
KW - E-selectin
KW - Silicon particle
KW - Targeted siRNA delivery
KW - Thioaptamer
UR - http://www.scopus.com/inward/record.url?scp=84901768538&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84901768538&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2014.04.057
DO - 10.1016/j.jconrel.2014.04.057
M3 - Article
C2 - 24818768
AN - SCOPUS:84901768538
SN - 0168-3659
VL - 187
SP - 22
EP - 29
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -