title: In vivo comparative study of distinct polymeric architectures bearing a combination of paclitaxel and doxorubicin at a synergistic ratio.
abstract: Nowadays, combination therapy became a standard in oncology. In this study, we compare the activity of two polymeric carriers bearing a combination of the anticancer drugs paclitaxel (PTX) and doxorubicin (DOX), which differ mainly in their architecture and supramolecular assembly. Drugs were covalently bound to a linear polymer, polyglutamic acid (PGA) or to a dendritic scaffold, polyglycerol (PG) decorated with poly(ethylene glycol) (PEG), forming PGA-PTX-DOX and PG-PTX-bz-DOX-PEG, respectively. We explored the relationship between the polymeric architectures and their performance with the aim to augment the pharmacological benefits of releasing both drugs simultaneously at the tumor site at a synergistic ratio. We recently designed and characterized a PGA-PTX-DOX conjugate. Here, we describe the synthesis and characterization of PG dendritic scaffold bearing the combination of PTX and DOX. The performance of both conjugates was evaluated in a murine model of mammary adenocarcinoma in immunocompetent mice, to investigate whether the activity of the treatments is affected by the immune system. Drug conjugation to a nano-sized polymer enabled preferred tumor accumulation by extravasation-dependent targeting, making use of the enhanced permeability and retention (EPR) effect. Both PGA-PTX-DOX and PG-PTX-bz-DOX-PEG nano-sized conjugates exhibited superior anti-tumor efficacy and safety compared to the combination of the free drugs, at equivalent concentrations. However, while PGA-PTX-DOX was more efficient than a mixture of each drug conjugated to a separate PGA chain, as was previously shown, PG-PTX-bz-DOX-PEG had similar activity to the mixture of the PG-PTX-bz-PEG and PG-DOX-PEG conjugates. Our results show that both conjugates are potential candidates as precision combination nanomedicines for the treatment of breast cancer.
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Hemda
authors.initials: H
authors.lastname: Baabur-Cohen
authors.affiliation: Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany.
authors.forename: Laura Isabel
authors.initials: LI
authors.lastname: Vossen
authors.affiliation: Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany.
authors.forename: Harald Rune
authors.initials: HR
authors.lastname: Krüger
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Eldar-Boock
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Eilam
authors.initials: E
authors.lastname: Yeini
authors.affiliation: Neufeld Cardiac Research Institute, Sheba Medical Center, Tel-Aviv University, Tel-Hashomer, 5262000, Israel.
authors.forename: Natalie
authors.initials: N
authors.lastname: Landa-Rouben
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Galia
authors.initials: G
authors.lastname: Tiram
authors.affiliation: Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Wedepohl
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ela
authors.initials: E
authors.lastname: Markovsky
authors.affiliation: Neufeld Cardiac Research Institute, Sheba Medical Center, Tel-Aviv University, Tel-Hashomer, 5262000, Israel.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Leor
authors.affiliation: Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany. Electronic address: marcelo.calderon@fu-berlin.de.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Calderón
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: ronitsf@post.tau.ac.il.
authors.forename: Ronit
authors.initials: R
authors.lastname: Satchi-Fainaro
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004338:Drug Combinations; D016503:Drug Delivery Systems; D004357:Drug Synergism; D005260:Female; D005990:Glycerol / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry*; D011099:Polyglutamic Acid / Q000031:analogs & derivatives*; D011108:Polymers / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D011108:Polymers; D011099:Polyglutamic Acid; C043941:polyglycerol; D011092:Polyethylene Glycols; D004317:Doxorubicin; D017239:Paclitaxel; D005990:Glycerol
keywords: Combination therapy; Dendritic polymer; Doxorubicin; Paclitaxel; Polyglutamic acid; Polyglycerol; Polymeric nanomedicines