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CpG expedites regression of local and systemic tumors when combined with activatable nanodelivery

Kheirolomoom, Azadeh, Ingham, Elizabeth S., Mahakian, Lisa M., Tam, Sarah M., Silvestrini, Matthew T., Tumbale, Spencer K., Foiret, Josquin, Hubbard, Neil E., Borowsky, Alexander D., Murphy, William J., Ferrara, Katherine W.
Journal of Controlled Release 2015 v.220 pp. 253-264
adjuvants, breast neoplasms, copper, doxorubicin, drug therapy, mice, nanoparticles, suppressor cells, ultrasonics
Ultrasonic activation of nanoparticles provides the opportunity to deliver a large fraction of the injected dose to insonified tumors and produce a complete local response. Here, we evaluate whether the local and systemic response to chemotherapy can be enhanced by combining such a therapy with locally-administered CpG as an immune adjuvant. In order to create stable, activatable particles, a complex between copper and doxorubicin (CuDox) was created within temperature-sensitive liposomes. Whereas insonation of the CuDox liposomes alone has been shown to produce a complete response in murine breast cancer after 8 treatments of 6mg/kg delivered over 4weeks, combining this treatment with CpG resolved local cancers within 3 treatments delivered over 7days. Further, contralateral tumors regressed as a result of the combined treatment, and survival was extended in systemic disease. In both the treated and contralateral tumor site, the combined treatment increased leukocytes and CD4+ and CD8+ T-effector cells and reduced myeloid-derived suppressor cells (MDSCs). Taken together, the results suggest that this combinatorial treatment significantly enhances the systemic efficacy of locally-activated nanotherapy.