TY - JOUR
T1 - CpG expedites regression of local and systemic tumors when combined with activatable nanodelivery
AU - Kheirolomoom, Azadeh
AU - Ingham, Elizabeth S.
AU - Mahakian, Lisa M.
AU - Tam, Sarah M.
AU - Silvestrini, Matthew T.
AU - Tumbale, Spencer K.
AU - Foiret, Josquin
AU - Hubbard, Neil
AU - Borowsky, Alexander D
AU - Murphy, William J
AU - Ferrara, Katherine W.
PY - 2015/12/28
Y1 - 2015/12/28
N2 - 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 6 mg/kg delivered over 4 weeks, combining this treatment with CpG resolved local cancers within 3 treatments delivered over 7 days. 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.
AB - 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 6 mg/kg delivered over 4 weeks, combining this treatment with CpG resolved local cancers within 3 treatments delivered over 7 days. 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.
KW - CpG
KW - Doxorubicin
KW - Immunotherapy
KW - Temperature-sensitive liposome
KW - Ultrasound
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UR - http://www.scopus.com/inward/citedby.url?scp=84946131338&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2015.10.016
DO - 10.1016/j.jconrel.2015.10.016
M3 - Article
C2 - 26471394
AN - SCOPUS:84946131338
VL - 220
SP - 253
EP - 264
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -