TY - JOUR
T1 - Bioorthogonal two-component drug delivery in HER2(+) breast cancer mouse models
AU - Hapuarachchige, Sudath
AU - Kato, Yoshinori
AU - Artemov, Dmitri
N1 - Funding Information:
This work was mainly supported by research grants KG100594 from Susan G. Komen for the Cure and partly supported by CA154738 from the National Institutes of Health. The authors are thankful to Mr. Desmond Jacob for intravital multiphoton imaging, and Ms. Mary McAllister for editorial assistance to prepare the manuscript. The authors also thank trainee students Miss Karin Umfrey and Jessica Kahan for helping with lab experiments.
PY - 2016/4/12
Y1 - 2016/4/12
N2 - The HER2 receptor is overexpressed in approximately 20% of breast cancers and is associated with tumorigenesis, metastasis, and a poor prognosis. Trastuzumab is a first-line targeted drug used against HER2(+) breast cancers; however, at least 50% of HER2(+) tumors develop resistance to trastuzumab. To treat these patients, trastuzumab-based antibody-drug conjugates (ACDs) have been developed and are currently used in the clinic. Despite their high efficacy, the long circulation half-life and non-specific binding of cytotoxic ADCs can result in systemic toxicity. In addition, standard ADCs do not provide an image-guided mode of administration. Here, we have developed a two-component, two-step, pre-targeting drug delivery system integrated with image guidance to circumvent these issues. In this strategy, HER2 receptors are pre-labeled with a functionalized trastuzumab antibody followed by the delivery of drug-loaded nanocarriers. Both components are cross-linked by multiple bioorthogonal click reactions in situ on the surface of the target cell and internalized as nanoclusters. We have explored the efficacy of this delivery strategy in HER2(+) human breast cancer models. Our therapeutic study confirms the high therapeutic efficacy of the new delivery system, with no significant toxicity.
AB - The HER2 receptor is overexpressed in approximately 20% of breast cancers and is associated with tumorigenesis, metastasis, and a poor prognosis. Trastuzumab is a first-line targeted drug used against HER2(+) breast cancers; however, at least 50% of HER2(+) tumors develop resistance to trastuzumab. To treat these patients, trastuzumab-based antibody-drug conjugates (ACDs) have been developed and are currently used in the clinic. Despite their high efficacy, the long circulation half-life and non-specific binding of cytotoxic ADCs can result in systemic toxicity. In addition, standard ADCs do not provide an image-guided mode of administration. Here, we have developed a two-component, two-step, pre-targeting drug delivery system integrated with image guidance to circumvent these issues. In this strategy, HER2 receptors are pre-labeled with a functionalized trastuzumab antibody followed by the delivery of drug-loaded nanocarriers. Both components are cross-linked by multiple bioorthogonal click reactions in situ on the surface of the target cell and internalized as nanoclusters. We have explored the efficacy of this delivery strategy in HER2(+) human breast cancer models. Our therapeutic study confirms the high therapeutic efficacy of the new delivery system, with no significant toxicity.
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U2 - 10.1038/srep24298
DO - 10.1038/srep24298
M3 - Article
C2 - 27068794
AN - SCOPUS:84964337048
SN - 2045-2322
VL - 6
JO - Scientific reports
JF - Scientific reports
M1 - 24298
ER -