Doxorubicin loaded iron oxide nanoparticles overcome multidrug resistance in cancer in vitro
Multidrug resistance (MDR) is characterized by the overexpression of ATP-binding cassette (ABC) transporters that actively pump a broad class of hydrophobic chemotherapeutic drugs out of cancer cells. MDR is a major mechanism of treatment resistance in a variety of human tumors, and clinically appli...
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| Published in | Journal of controlled release Vol. 152; no. 1; pp. 76 - 83 |
|---|---|
| Main Authors | , , , , , , , |
| Format | Journal Article Conference Proceeding |
| Language | English |
| Published |
Kidlington
Elsevier B.V
30.05.2011
Elsevier |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0168-3659 1873-4995 1873-4995 |
| DOI | 10.1016/j.jconrel.2011.01.024 |
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| Abstract | Multidrug resistance (MDR) is characterized by the overexpression of ATP-binding cassette (ABC) transporters that actively pump a broad class of hydrophobic chemotherapeutic drugs out of cancer cells. MDR is a major mechanism of treatment resistance in a variety of human tumors, and clinically applicable strategies to circumvent MDR remain to be characterized. Here we describe the fabrication and characterization of a drug-loaded iron oxide nanoparticle designed to circumvent MDR. Doxorubicin (DOX), an anthracycline antibiotic commonly used in cancer chemotherapy and substrate for ABC-mediated drug efflux, was covalently bound to polyethylenimine via a pH sensitive hydrazone linkage and conjugated to an iron oxide nanoparticle coated with amine terminated polyethylene glycol. Drug loading, physiochemical properties and pH lability of the DOX-hydrazone linkage were evaluated
in vitro. Nanoparticle uptake, retention, and dose-dependent effects on viability were compared in wild-type and DOX-resistant ABC transporter over-expressing rat glioma C6 cells. We found that DOX release from nanoparticles was greatest at acidic pH, indicative of cleavage of the hydrazone linkage. DOX-conjugated nanoparticles were readily taken up by wild-type and drug-resistant cells. In contrast to free drug, DOX-conjugated nanoparticles persisted in drug-resistant cells, indicating that they were not subject to drug efflux. Greater retention of DOX-conjugated nanoparticles was accompanied by reduction of viability relative to cells treated with free drug. Our results suggest that DOX-conjugated nanoparticles could improve the efficacy of chemotherapy by circumventing MDR.
Doxorubicin (DOX) efflux from multi-drug resistance C6 glioma cells (C6-ADR) is overcome through conjugation to superparamagnetic iron oxide nanoparticles (NP-DOX), and corresponds to improved cell kill.
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| AbstractList | Multidrug resistance (MDR) is characterized by the overexpression of ATP-binding cassette (ABC) transporters that actively pump a broad class of hydrophobic chemotherapeutic drugs out of cancer cells. MDR is a major mechanism of treatment resistance in a variety of human tumors, and clinically applicable strategies to circumvent MDR remain to be characterized. Here we describe the fabrication and characterization of a drug-loaded iron oxide nanoparticle designed to circumvent MDR. Doxorubicin (DOX), an anthracycline antibiotic commonly used in cancer chemotherapy and substrate for ABC-mediated drug efflux, was covalently bound to polyethylenimine via a pH sensitive hydrazone linkage and conjugated to an iron oxide nanoparticle coated with amine terminated polyethylene glycol. Drug loading, physiochemical properties and pH lability of the DOX-hydrazone linkage were evaluated in vitro. Nanoparticle uptake, retention, and dose-dependent effects on viability were compared in wild-type and DOX-resistant ABC transporter over-expressing rat glioma C6 cells. We found that DOX release from nanoparticles was greatest at acidic pH, indicative of cleavage of the hydrazone linkage. DOX-conjugated nanoparticles were readily taken up by wild-type and drug-resistant cells. In contrast to free drug, DOX-conjugated nanoparticles persisted in drug-resistant cells, indicating that they were not subject to drug efflux. Greater retention of DOX-conjugated nanoparticles was accompanied by reduction of viability relative to cells treated with free drug. Our results suggest that DOX-conjugated nanoparticles could improve the efficacy of chemotherapy by circumventing MDR. Multidrug resistance (MDR) is characterized by the overexpression of ATP-binding cassette (ABC) transporters that actively pump a broad class of hydrophobic chemotherapeutic drugs out of cancer cells. MDR is a major mechanism of treatment resistance in a variety of human tumors, and clinically applicable strategies to circumvent MDR remain to be characterized. Here we describe the fabrication and characterization of a drug-loaded iron oxide nanoparticle designed to circumvent MDR. Doxorubicin (DOX), an anthracycline antibiotic commonly used in cancer chemotherapy and substrate for ABC-mediated drug efflux, was covalently bound to polyethylenimine via a pH sensitive hydrazone linkage and conjugated to an iron oxide nanoparticle coated with amine terminated polyethylene glycol. Drug loading, physiochemical properties and pH lability of the DOX-hydrazone linkage were evaluated in vitro. Nanoparticle uptake, retention, and dose-dependent effects on viability were compared in wild-type and DOX-resistant ABC transporter over-expressing rat glioma C6 cells. We found that DOX release from nanoparticles was greatest at acidic pH, indicative of cleavage of the hydrazone linkage. DOX-conjugated nanoparticles were readily taken up by wild-type and drug-resistant cells. In contrast to free drug, DOX-conjugated nanoparticles persisted in drug-resistant cells, indicating that they were not subject to drug efflux. Greater retention of DOX-conjugated nanoparticles was accompanied by reduction of viability relative to cells treated with free drug. Our results suggest that DOX-conjugated nanoparticles could improve the efficacy of chemotherapy by circumventing MDR. Doxorubicin (DOX) efflux from multi-drug resistance C6 glioma cells (C6-ADR) is overcome through conjugation to superparamagnetic iron oxide nanoparticles (NP-DOX), and corresponds to improved cell kill. [Display omitted] Multidrug resistance (MDR) is characterized by the overexpression of ATP-binding cassette (ABC) transporters that actively pump a broad class of hydrophobic chemotherapeutic drugs out of cancer cells. MDR is a major mechanism of treatment resistance in a variety of human tumors, and clinically applicable strategies to circumvent MDR remain to be characterized. Here we describe the fabrication and characterization of a drug-loaded iron oxide nanoparticle designed to circumvent MDR. Doxorubicin (DOX), an anthracycline antibiotic commonly used in cancer chemotherapy and substrate for ABC-mediated drug efflux, was covalently bound to polyethylenimine via a pH sensitive hydrazone linkage and conjugated to an iron oxide nanoparticle coated with amine terminated polyethylene glycol. Drug loading, physiochemical properties and pH lability of the DOX-hydrazone linkage were evaluated in vitro. Nanoparticle uptake, retention, and dose-dependent effects on viability were compared in wild-type and DOX-resistant ABC transporter over-expressing rat glioma C6 cells. We found that DOX release from nanoparticles was greatest at acidic pH, indicative of cleavage of the hydrazone linkage. DOX-conjugated nanoparticles were readily taken up by wild-type and drug-resistant cells. In contrast to free drug, DOX-conjugated nanoparticles persisted in drug-resistant cells, indicating that they were not subject to drug efflux. Greater retention of DOX-conjugated nanoparticles was accompanied by reduction of viability relative to cells treated with free drug. Our results suggest that DOX-conjugated nanoparticles could improve the efficacy of chemotherapy by circumventing MDR.Multidrug resistance (MDR) is characterized by the overexpression of ATP-binding cassette (ABC) transporters that actively pump a broad class of hydrophobic chemotherapeutic drugs out of cancer cells. MDR is a major mechanism of treatment resistance in a variety of human tumors, and clinically applicable strategies to circumvent MDR remain to be characterized. Here we describe the fabrication and characterization of a drug-loaded iron oxide nanoparticle designed to circumvent MDR. Doxorubicin (DOX), an anthracycline antibiotic commonly used in cancer chemotherapy and substrate for ABC-mediated drug efflux, was covalently bound to polyethylenimine via a pH sensitive hydrazone linkage and conjugated to an iron oxide nanoparticle coated with amine terminated polyethylene glycol. Drug loading, physiochemical properties and pH lability of the DOX-hydrazone linkage were evaluated in vitro. Nanoparticle uptake, retention, and dose-dependent effects on viability were compared in wild-type and DOX-resistant ABC transporter over-expressing rat glioma C6 cells. We found that DOX release from nanoparticles was greatest at acidic pH, indicative of cleavage of the hydrazone linkage. DOX-conjugated nanoparticles were readily taken up by wild-type and drug-resistant cells. In contrast to free drug, DOX-conjugated nanoparticles persisted in drug-resistant cells, indicating that they were not subject to drug efflux. Greater retention of DOX-conjugated nanoparticles was accompanied by reduction of viability relative to cells treated with free drug. Our results suggest that DOX-conjugated nanoparticles could improve the efficacy of chemotherapy by circumventing MDR. |
| Author | Ellenbogen, Richard G. Wang, Freddy Y. Mok, Hyejung Zhang, Miqin Fang, Chen Wang, Kui Silber, John R. Kievit, Forrest M. |
| AuthorAffiliation | 1 Department of Materials Science & Engineering, University of Washington, Seattle, Washington 98195, USA 2 Department of Neurological Surgery, University of Washington, Seattle, Washington 98195, USA |
| AuthorAffiliation_xml | – name: 2 Department of Neurological Surgery, University of Washington, Seattle, Washington 98195, USA – name: 1 Department of Materials Science & Engineering, University of Washington, Seattle, Washington 98195, USA |
| Author_xml | – sequence: 1 givenname: Forrest M. surname: Kievit fullname: Kievit, Forrest M. organization: Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, USA – sequence: 2 givenname: Freddy Y. surname: Wang fullname: Wang, Freddy Y. organization: Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, USA – sequence: 3 givenname: Chen surname: Fang fullname: Fang, Chen organization: Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, USA – sequence: 4 givenname: Hyejung surname: Mok fullname: Mok, Hyejung organization: Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, USA – sequence: 5 givenname: Kui surname: Wang fullname: Wang, Kui organization: Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, USA – sequence: 6 givenname: John R. surname: Silber fullname: Silber, John R. organization: Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA – sequence: 7 givenname: Richard G. surname: Ellenbogen fullname: Ellenbogen, Richard G. organization: Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA – sequence: 8 givenname: Miqin surname: Zhang fullname: Zhang, Miqin email: mzhang@u.washington.edu organization: Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, USA |
| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24326461$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/21277920$$D View this record in MEDLINE/PubMed |
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| Keywords | ABC NP Chemotherapy NP-DOX Glioma Brain tumors MDR Drug efflux DOX SPION Theranostics Antineoplastic agent Iron oxide Nanoparticle Doxorubicin Isomerases Multiple resistance Microparticle Drug DNA topoisomerase (ATP-hydrolysing) Intracranial Nervous system diseases Pharmaceutical technology Enzyme Enzyme inhibitor Topoisomerase II inhibitor Malignant tumor In vitro Intracranial tumor Cerebral disorder Antibiotic Treatment Central nervous system disease Anthracyclins Cancer |
| Language | English |
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| SubjectTerms | ABC transporter ABC transporters amines Animals Anthracycline Antibiotics Antibiotics, Antineoplastic - administration & dosage Biological and medical sciences Brain Neoplasms - drug therapy Brain tumors Cell Line, Tumor Chemotherapy Controlled release dose response Doxorubicin Doxorubicin - administration & dosage Doxorubicin - chemistry Doxorubicin - pharmacokinetics Drug efflux Drug resistance Drug Resistance, Multiple Drug Resistance, Neoplasm drug therapy Drugs Ferric Compounds - administration & dosage Ferric Compounds - chemistry General pharmacology Glioma Glioma - drug therapy Glioma cells humans Hydrogen-Ion Concentration Hydrophobicity iron oxides Lability Medical sciences Metal Nanoparticles - administration & dosage Metal Nanoparticles - chemistry Multidrug resistance multiple drug resistance nanoparticles neoplasm cells neoplasms Particle Size pH effects Pharmaceutical technology. Pharmaceutical industry Pharmacology. Drug treatments Polyethylene glycol Polyethylene Glycols - chemistry Polyethyleneimine - chemistry Rats Solubility Theranostics Tissue Distribution Tumors varietal resistance viability |
| Title | Doxorubicin loaded iron oxide nanoparticles overcome multidrug resistance in cancer in vitro |
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