期刊
JOURNAL OF CONTROLLED RELEASE
卷 267, 期 -, 页码 191-202出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2017.08.016
关键词
Drug combinations; Polymer drug conjugates; Synergy; Breast cancer; Gemcitabine; Doxorubcin
资金
- University of California, Santa Barbara
- University of California, Office of the President
- MRSEC Program of the National Science Foundation [DMR 1121053]
- Office of The Director, National Institutes of Health of the NIH [S10OD010610]
- NSF Graduate Research Fellowship [DGE-1144085]
Combination chemotherapy is commonly used to treat advanced breast cancer. However, treatment success is often limited due to systemic toxicity. To improve therapeutic efficacy, polymer drug conjugates carrying synergistic pairs of chemotherapy drugs can be used to reduce drug administration dose. Here, we systematically evaluated the effect of temporal scheduling of doxorubicin (DOX) and gemcitabine (GEM) on drug synergy. Hyaluronic acid (HA) drug conjugates with distinct linkers conjugating both DOX and GEM were synthesized to control relative release kinetics of each drug. We show that polymer conjugates that release GEM faster than DOX are more effective at killing triple negative breast cancer cells in vitro. We further show that the optimal dual drug conjugate more effectively inhibits the growth of an aggressive, orthotopic 4T1 tumor model in vivo than free DOX and GEM and the single drug HA conjugates. The dual drug HA conjugate can inhibit 4T1 tumor growth in vivo during treatment through both intravenous and non-local subcutaneous injections. These results emphasize the importance of understanding the effect release rates have on the efficacy of synergistic drug carriers and motivate the use of HA as a delivery platform for multiple cancer types.
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