title: Nanometronomic treatment of 4T1 breast cancer with nanocaged doxorubicin prevents drug resistance and circumvents cardiotoxicity.
abstract: Chemotherapeutic treatment of breast cancer is based on maximum tolerated dose (MTD) approach. However, advanced stage tumors are not effectively eradicated by MTD owing to suboptimal drug targeting, onset of therapeutic resistance and neoangiogenesis. In contrast, "metronomic" chemotherapy is based on frequent drug administrations at lower doses, resulting in neovascularization inhibition and induction of tumor dormancy. Here we show the potential of H-ferritin (HFn)-mediated targeted nanodelivery of metronomic doxorubicin (DOX) in the setting of a highly aggressive and metastatic 4T1 breast cancer mouse model with DOX-inducible expression of chemoresistance. We find that HFn-DOX administered at repeated doses of 1.24 mg kg-1 strongly improves the antitumor potential of DOX chemotherapy arresting the tumor progression. We find that such a potent antitumor effect is attributable to multiple nanodrug actions beyond cell killing, including inhibition of tumor angiogenesis and avoidance of chemoresistance. Multiparametric assessment of heart tissues, including histology, ultrastructural analysis of tissue morphology, and measurement of markers of reactive oxygen species and hepatic/renal conditions, provided evidence that metronomic HFn-DOX allowed us to overcome cardiotoxicity. Our results suggest that HFn-DOX has tremendous potential for the development of "nanometronomic" chemotherapy toward safe and tailored oncological treatments.
authors.affiliation: Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Mazzucchelli
authors.affiliation: Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milano, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Bellini
authors.affiliation: Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Fiandra
authors.affiliation: Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Truffi
authors.affiliation: Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milano, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Rizzuto
authors.affiliation: Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Sorrentino
authors.affiliation: Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Longhi
authors.affiliation: Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Nebuloni
authors.affiliation: Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milano, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Prosperi
authors.affiliation: Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy.|Surgery Department, Breast Unit, ICS Maugeri S. p. A. SB, Pavia, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Corsi
mesh_terms: D059250:Administration, Metronomic; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D001052:Apoferritins / Q000737:chemistry / Q000378:metabolism; D001682:Biological Availability; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D066126:Cardiotoxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D004337:Drug Carriers; D004339:Drug Compounding; D019008:Drug Resistance, Neoplasm; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008807:Mice, Inbred BALB C; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles; D009389:Neovascularization, Pathologic; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D004317:Doxorubicin; D001052:Apoferritins
keywords: breast cancer; doxorubicin; drug resistance; metronomic chemotherapy; tumor targeting