title: DAFODIL: A novel liposome-encapsulated synergistic combination of doxorubicin and 5FU for low dose chemotherapy.
abstract: 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.
authors.affiliation: Center for Bioengineering, Department of Chemical Engineering, University of California at Santa Barbara, Santa Barbara, CA 93106, United States.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Camacho
authors.affiliation: 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.
authors.forename: Stefano
authors.initials: S
authors.lastname: Menegatti
authors.affiliation: Center for Bioengineering, Department of Chemical Engineering, University of California at Santa Barbara, Santa Barbara, CA 93106, United States.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Vogus
authors.affiliation: Center for Bioengineering, Department of Chemical Engineering, University of California at Santa Barbara, Santa Barbara, CA 93106, United States.
authors.forename: Anusha
authors.initials: A
authors.lastname: Pusuluri
authors.affiliation: Center for Bioengineering, Department of Chemical Engineering, University of California at Santa Barbara, Santa Barbara, CA 93106, United States.
authors.forename: Zoë
authors.initials: Z
authors.lastname: Fuchs
authors.affiliation: Center for Bioengineering, Department of Chemical Engineering, University of California at Santa Barbara, Santa Barbara, CA 93106, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Jarvis
authors.affiliation: Center for Bioengineering, Department of Chemical Engineering, University of California at Santa Barbara, Santa Barbara, CA 93106, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Zakrewsky
authors.affiliation: Center for Bioengineering, Department of Chemical Engineering, University of California at Santa Barbara, Santa Barbara, CA 93106, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Evans
authors.affiliation: Center for Bioengineering, Department of Chemical Engineering, University of California at Santa Barbara, Santa Barbara, CA 93106, United States.
authors.forename: Renwei
authors.initials: R
authors.lastname: Chen
authors.affiliation: Center for Bioengineering, Department of Chemical Engineering, University of California at Santa Barbara, Santa Barbara, CA 93106, United States.
authors.forename: Samir
authors.initials: S
authors.lastname: Mitragotri
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D002460:Cell Line; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D004338:Drug Combinations; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008081:Liposomes; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry; D014364:Tryptophan / Q000737:chemistry; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D008081:Liposomes; D011092:Polyethylene Glycols; D004317:Doxorubicin; D014364:Tryptophan; D005472:Fluorouracil
keywords: Chemotherapy; Drug combinations; Liposomes; Nanoparticles; Synergistic