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J Control Release. 2016 May 10;229:154-162. doi: 10.1016/j.jconrel.2016.03.027. Epub 2016 Mar 24.

DAFODIL: A novel liposome-encapsulated synergistic combination of doxorubicin and 5FU for low dose chemotherapy.

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Center for Bioengineering, Department of Chemical Engineering, University of California at Santa Barbara, Santa Barbara, CA 93106, United States.
Department of Chemical and Biomolecular Engineering, Department of Biomedical Engineering, Biomanufacturing Training and Education Center (BTEC), North Carolina State University, Raleigh, NC 27695, United States.


PEGylated liposomes have transformed chemotherapeutic use of doxorubicin by reducing its cardiotoxicity; however, it remains unclear whether liposomal doxorubicin is therapeutically superior to free doxorubicin. Here, we demonstrate a novel PEGylated liposome system, named DAFODIL (Doxorubicin And 5-Flurouracil Optimally Delivered In a Liposome) that inarguably offers superior therapeutic efficacies compared to free drug administrations. Delivery of synergistic ratios of this drug pair led to greater than 90% reduction in tumor growth of murine 4T1 mammary carcinoma in vivo. By exploiting synergistic ratios, the effect was achieved at remarkably low doses, far below the maximum tolerable drug doses. Our approach re-invents the use of liposomes for multi-drug delivery by providing a chemotherapy vehicle which can both reduce toxicity and improve therapeutic efficacy. This methodology is made feasible by the extension of the ammonium-sulfate gradient encapsulation method to nucleobase analogues, a liposomal entrapment method once conceived useful only for anthracyclines. Therefore, our strategy can be utilized to efficiently evaluate various chemotherapy combinations in an effort to translate more effective combinations into the clinic.


Chemotherapy; Drug combinations; Liposomes; Nanoparticles; Synergistic

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