Download Overcoming Acquired Tamoxifen-Resistance through

Overcoming Acquired Tamoxifen-Resistance through Simultaneous Delivery of Chemotherapeutic
Tamoxifen and Manganese Superoxide Dismutase Silencing Agent via Acid-Responsive Core-Shell
Nanoparticles
Jane Kim
Mentor: Young Jik Kwon
Approximately half of breast cancer patients treated with chemotherapeutic tamoxifen develop resistance to
the drug. Drug resistance leading to relapse during which the patient cannot be successfully treated with the
same chemotherapeutic agent is a significant problem in the clinic, and the co-administration of
chemotherapeutics and an appropriate agent for silencing resistance is a possible mechanism of counteracting
acquired drug resistance. This study demonstrated the successful silencing of acquired tamoxifen resistance in
tamoxifen-resistant MCF7-BK-TR breast cancer cells both in vitro and in vivo through simultaneous delivery of
tamoxifen and a resistance silencing agent, siRNA. The siRNA used silences a mitochondrial enzyme,
manganese superoxide dismutase (MnSOD), responsible for causing tamoxifen-resistance through producing
a reactive oxygen species that dismutates tamoxifen. For effective siRNA delivery, nanoparticles consisting of
siRNA/PAMAM dendriplexes encapsulated within a polyketalized shell were designed to be capable of
cleaving to release the encapsulated siRNA in acidic conditions associated with tumor cells. In vivo studies in
which MCF7-BK-TR breast cancer cells were implanted in mice showed that treatment with tamoxifen and
MnSOD siRNA nanoparticles caused an approximate 20% decrease in tumor weight over a seven-week
period as compared to the control. The results of this study validate the concept of overcoming drug
resistance using siRNA carrying nanoparticles in co-administration with the drug of interest.