title: A dual-targeting nanocarrier based on poly(amidoamine) dendrimers conjugated with transferrin and tamoxifen for treating brain gliomas.
abstract: A pH-sensitive dual-targeting drug carrier (G4-DOX-PEG-Tf-TAM) was synthesized with transferrin (Tf) conjugated on the exterior and Tamoxifen (TAM) in the interior of the fourth generation PAMAM dendrimers for enhancing the blood-brain barrier (BBB) transportation and improving the drug accumulation in the glioma cells. It was found that, on average, 7 doxorubicine (DOX) molecules, over 30 PEG(1000) and PEG(2000) chains and one Tf group were bonded on the periphery of each G4 PAMAM dendrimer, while 29 TAM molecules were encapsulated into the interior of per dendrimer. The pH-triggered DOX release was 32% at pH 4.5 and 6% at pH 7.4, indicating a comparatively fast drug release at weak acidic condition and stable state of the carrier at physiological environment. The in vitro assay of the drug transport across the BBB model showed that G4-DOX-PEG-Tf-TAM exhibited higher BBB transportation ability with the transporting ratio of 6.06% in 3 h. The carrier was internalized into C6 glioma cells upon crossing the BBB model by the coactions of TfR-mediated endocytosis and the inhibition effect of TAM to the drug efflux transports. Moreover, it also displayed the in vitro accumulation of DOX in the avascular C6 glioma spheroids made the tumor volume effectively reduced.
authors.affiliation: Beijing National Laboratory for Molecular Sciences and Key Laboratory of Polymer Chemistry and Physics of the Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Hai
authors.initials: H
authors.lastname: He
authors.forename: Xinru
authors.initials: X
authors.lastname: Jia
authors.forename: Wan-Liang
authors.initials: WL
authors.lastname: Lu
authors.forename: Jinning
authors.initials: J
authors.lastname: Lou
authors.forename: Yen
authors.initials: Y
authors.lastname: Wei
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry*; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D005434:Flow Cytometry; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D008027:Light; D051379:Mice; D018613:Microscopy, Confocal; D049329:Nanostructures / Q000737:chemistry* / Q000648:ultrastructure; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry; D012542:Scattering, Radiation; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use*; D014168:Transferrin / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst; D014168:Transferrin; D013629:Tamoxifen; D011092:Polyethylene Glycols; D004317:Doxorubicin