Volume 54, Issue 45 pp. 13307-13311
Communication

Enzyme-Instructed Intracellular Molecular Self-Assembly to Boost Activity of Cisplatin against Drug-Resistant Ovarian Cancer Cells

Jie Li

Jie Li

Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)

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Yi Kuang

Yi Kuang

Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)

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Junfeng Shi

Junfeng Shi

Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)

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Jie Zhou

Jie Zhou

Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)

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Jamie E. Medina

Jamie E. Medina

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 (USA)

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Rong Zhou

Rong Zhou

Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)

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Dan Yuan

Dan Yuan

Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)

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Cuihong Yang

Cuihong Yang

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192 (P.R. China)

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Huaimin Wang

Huaimin Wang

State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin 300071 (China)

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Prof. Zhimou Yang

Prof. Zhimou Yang

State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin 300071 (China)

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Prof. Jianfeng Liu

Prof. Jianfeng Liu

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192 (P.R. China)

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Prof. Dr. Daniela M. Dinulescu

Corresponding Author

Prof. Dr. Daniela M. Dinulescu

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 (USA)

Daniela M. Dinulescu, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 (USA)

Bing Xu, Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)

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Prof. Dr. Bing Xu

Corresponding Author

Prof. Dr. Bing Xu

Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)

Daniela M. Dinulescu, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 (USA)

Bing Xu, Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)

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First published: 14 September 2015
Citations: 164

Graphical Abstract

Cisplatin-boosting nanofibers: The design and synthesis is reported of small peptide precursors that can be cleaved by carboxylesterase (CES) to form peptides that self-assemble in water to form molecular nanofibers. The precursors themselves are innocuous to cells at optimal concentrations, but they double or triple the activity of cisplatin against drug-resistant ovarian cancer cells.

Abstract

Anticancer drug resistance demands innovative approaches that boost the activity of drugs against drug-resistant cancers without increasing the systemic toxicity. Here we show the use of enzyme-instructed self-assembly (EISA) to generate intracellular supramolecular assemblies that drastically boost the activity of cisplatin against drug-resistant ovarian cancer cells. We design and synthesize small peptide precursors as the substrates of carboxylesterase (CES). CES cleaves the ester bond pre-installed on the precursors to form the peptides that self-assemble in water to form nanofibers. At the optimal concentrations, the precursors themselves are innocuous to cells, but they double or triple the activity of cisplatin against the drug-resistant ovarian cancer cells. This work illustrates a simple, yet fundamental, new way to introduce non-cytotoxic components into combination therapies with cisplatin without increasing the systemic burden or side effects.

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