title: Simultaneous delivery of doxorubicin and gemcitabine to tumors in vivo using prototypic polymeric drug carriers.
abstract: Copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA) are prototypic and well-characterized polymeric drug carriers that have been broadly implemented in the delivery of anticancer therapeutics. To demonstrate that polymers, as liposomes, can be used for simultaneously delivering multiple chemotherapeutic agents to tumors in vivo, we have synthesized and evaluated an HPMA-based polymer-drug conjugate carrying 6.4wt% of gemcitabine, 5.7wt% of doxorubicin and 1.0mol% of tyrosinamide (to allow for radiolabeling). The resulting construct, i.e. poly(HPMA-co-MA-GFLG-gemcitabine-co-MA-GFLG-doxorubicin-co-MA-TyrNH(2)), was termed P-Gem-Dox, and was shown to effectively kill cancer cells in vitro, to circulate for prolonged period of time, to localize to tumors relatively selectively, and to inhibit tumor growth. As compared to control regimens, P-Gem-Dox increased the efficacy of the combination of gemcitabine and doxorubicin without increasing its toxicity, and it more strongly inhibited angiogenesis and induced apoptosis. These findings demonstrate that passively tumor-targeted polymeric drug carriers can be used for delivering two different chemotherapeutic agents to tumors simultaneously, and they thereby set the stage for more elaborate analyses on the potential of polymer-based multi-drug targeting.
authors.affiliation: Department of Innovative Cancer Diagnosis and Therapy, DKFZ Heidelberg, German Cancer Research Center, Germany. t.lammers@dkfz.de
authors.forename: Twan
authors.initials: T
authors.lastname: Lammers
authors.forename: Vladimir
authors.initials: V
authors.lastname: Subr
authors.forename: Karel
authors.initials: K
authors.lastname: Ulbrich
authors.forename: Peter
authors.initials: P
authors.lastname: Peschke
authors.forename: Peter E
authors.initials: PE
authors.lastname: Huber
authors.forename: Wim E
authors.initials: WE
authors.lastname: Hennink
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
mesh_terms: D000178:Acrylamides / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D017209:Apoptosis; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D004317:Doxorubicin / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods; D004354:Drug Screening Assays, Antitumor; D008297:Male; D008422:Materials Testing; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D018919:Neovascularization, Physiologic; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D014018:Tissue Distribution; D000093542:Gemcitabine
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D004337:Drug Carriers; D011108:Polymers; D003841:Deoxycytidine; D004317:Doxorubicin; C032976:N-(2-hydroxypropyl)methacrylamide; D000093542:Gemcitabine