Nanoparticle conjugates of a highly potent toxin enhance safety and circumvent platinum resistance in ovarian cancer

Ruogu Qi, Yongheng Wang, Peter M. Bruno, Haihua Xiao, Yingjie Yu, Ting Li, Sam Lauffer, Wei Wei, Qixian Chen, Xiang Kang, Haiqin Song, Xi Yang, Xing Huang, Alexandre Detappe, Ursula Matulonis, David Pepin, Michael T. Hemann, Michael J. Birrer () and P. Peter Ghoroghchian ()
Additional contact information
Ruogu Qi: Koch Institute for Integrative Cancer Research at MIT
Yongheng Wang: Koch Institute for Integrative Cancer Research at MIT
Peter M. Bruno: Koch Institute for Integrative Cancer Research at MIT
Haihua Xiao: Koch Institute for Integrative Cancer Research at MIT
Yingjie Yu: Koch Institute for Integrative Cancer Research at MIT
Ting Li: Koch Institute for Integrative Cancer Research at MIT
Sam Lauffer: Massachusetts General Hospital
Wei Wei: Massachusetts General Hospital
Qixian Chen: Koch Institute for Integrative Cancer Research at MIT
Xiang Kang: Koch Institute for Integrative Cancer Research at MIT
Haiqin Song: Koch Institute for Integrative Cancer Research at MIT
Xi Yang: Koch Institute for Integrative Cancer Research at MIT
Xing Huang: Koch Institute for Integrative Cancer Research at MIT
Alexandre Detappe: Koch Institute for Integrative Cancer Research at MIT
Ursula Matulonis: Dana Farber Cancer Institute
David Pepin: Massachusetts General Hospital
Michael T. Hemann: Koch Institute for Integrative Cancer Research at MIT
Michael J. Birrer: Massachusetts General Hospital
P. Peter Ghoroghchian: Koch Institute for Integrative Cancer Research at MIT

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Advanced-stage epithelial ovarian cancers are amongst the most difficult to treat tumors and have proven to be refractory to most cytotoxic, molecularly targeted, or immunotherapeutic approaches. Here, we report that nanoparticle-drug conjugates (NDCs) of monomethyl auristatin E (MMAE) significantly increase loading on a per-vehicle basis as compared to antibody-drug conjugates (ADCs). Their intraperitoneal administration enabled triggered release of the active MMAE toxin to inhibit tumor growth and to extend animal survival to >90 days in a cell-line xenograft model of disseminated ovarian cancer. In a patient-derived xenograft model of advanced-stage and platinum-resistant ovarian cancer, an MMAE-based NDC doubled the duration of tumor growth inhibition as compared to cisplatin. NDCs of highly potent toxins thus introduce a translatable platform that may be exploited to maximize the safety and efficacy of cytotoxic chemotherapies, combining the best features of ADCs with those of nanoparticle-based therapeutics.

Date: 2017
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DOI: 10.1038/s41467-017-02390-7

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