Enzyme-Instructed Intracellular Molecular Self-Assembly to Boost Activity of Cisplatin against Drug-Resistant Ovarian Cancer Cells
Jie Li
Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)
Search for more papers by this authorYi Kuang
Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)
Search for more papers by this authorJunfeng Shi
Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)
Search for more papers by this authorJie Zhou
Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)
Search for more papers by this authorJamie E. Medina
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 (USA)
Search for more papers by this authorRong Zhou
Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)
Search for more papers by this authorDan Yuan
Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)
Search for more papers by this authorCuihong 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)
Search for more papers by this authorHuaimin Wang
State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin 300071 (China)
Search for more papers by this authorProf. Zhimou Yang
State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin 300071 (China)
Search for more papers by this authorProf. 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)
Search for more papers by this authorCorresponding 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)
Search for more papers by this authorCorresponding 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)
Search for more papers by this authorJie Li
Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)
Search for more papers by this authorYi Kuang
Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)
Search for more papers by this authorJunfeng Shi
Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)
Search for more papers by this authorJie Zhou
Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)
Search for more papers by this authorJamie E. Medina
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 (USA)
Search for more papers by this authorRong Zhou
Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)
Search for more papers by this authorDan Yuan
Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA)
Search for more papers by this authorCuihong 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)
Search for more papers by this authorHuaimin Wang
State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin 300071 (China)
Search for more papers by this authorProf. Zhimou Yang
State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin 300071 (China)
Search for more papers by this authorProf. 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)
Search for more papers by this authorCorresponding 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)
Search for more papers by this authorCorresponding 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)
Search for more papers by this authorGraphical 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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