title: Multifunctional nanoparticles improve therapeutic effect for breast cancer by simultaneously antagonizing multiple mechanisms of multidrug resistance.
abstract: For efficient reversal of multidrug resistance (MDR) in chemotherapy for breast cancer, multifunctional self-assembled nanoparticles (MSN) based on a new amphiphilic copolymer consisting of bioreducible poly[bis(2-hydroxylethyl)-disulfide-diacrylate-β-tetraethylenepentamine] and polycaprolactone (PBD-PCL) were constructed and characterized. shRNA targeting the apoptosis-inhibiting gene, Survivin, was incorporated into the nanoparticles with high RNA interference efficiency. PBD-PCL significantly inhibited the activity of P-glycoprotein, one of the most well-described drug-efflux pumps, and glutathione S-transferase, an important detoxification enzyme. MSN achieved colocalization of RNA and doxorubicin in tumors after intravenous administration and showed remarkable antitumor efficacy in MDR tumor-bearing mice with less side-effect than drug combination therapy. This was a new attempt to overcome MDR against three different mechanisms of MDR simutaneously: overexpression of drug efflux protein, activation of detoxification system, and blockage of apoptosis. These results indicated that the PBD-PCL-based MSN had obvious potential for therapy of breast cancer.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yin
authors.forename: Jianan
authors.initials: J
authors.lastname: Shen
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Haijun
authors.initials: H
authors.lastname: Yu
authors.forename: Lingli
authors.initials: L
authors.lastname: Chen
authors.forename: Wangwen
authors.initials: W
authors.lastname: Gu
authors.forename: Yaping
authors.initials: Y
authors.lastname: Li
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000179:Acrylates / Q000737:chemistry; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000627:therapeutic use*; D004337:Drug Carriers / Q000627:therapeutic use; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000627:therapeutic use*; D011091:Polyesters / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000179:Acrylates; D051017:Apoptosis Regulatory Proteins; C117749:Birc5 protein, mouse; D004337:Drug Carriers; D051034:Inhibitor of Apoptosis Proteins; D011091:Polyesters; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000077022:Survivin; C016240:polycaprolactone; D004317:Doxorubicin; D005982:Glutathione Transferase