title: Actively targeted delivery of doxorubicin to bone metastases by a pH-sensitive conjugation.
abstract: Alendronate-monoethyl adipate-(hydrazone)-doxorubicin conjugate (ALN-MA-hyd-DOX) was synthesized to specifically deliver doxorubicin (DOX) to bone tumor tissue. The binding kinetics of ALN-MA-hyd-DOX with hydroxyapatite (HA) and natural bone were detected by using spectrophotometer. Cytotoxicity of ALN-MA-hyd-DOX on tumor cells was determined by MTT [3-(4,5-dimethylthiaol-2-yl)-2,5-diphenyl-tetrazolium bromide] method. The cellular uptake of ALN-MA-hyd-DOX was observed by using fluorescence microscopy. The in vivo antitumor activity of ALN-MA-hyd-DOX was investigated by using tumor-bearing nude mice model. The results indicated that ALN-MA-hyd-DOX was able to quickly bind with HA and natural bone. ALN-MA-hyd-DOX immobilized on the natural bone released more DOX in pH 5.0 medium than that in pH 6.0 or 7.4 medium. The cytotoxicity of ALN-MA-hyd-DOX toward A549 cells and MDA-MB-231/ADR cells was greater than DOX. ALN-MA-hyd-DOX was rapidly uptaken by A549 cells and MDA-MB-231/ADR cells. Compared with the same dose of free DOX, ALN-MA-hyd-DOX significantly decreased tumor volume of tumor-bearing nude mice. DOX mainly distributed in bone tumor tissue after ALN-MA-hyd-DOX was intravenously administered to tumor-bearing nude mice, whereas DOX distributed through the whole body after DOX was intravenously administered to tumor-bearing nude mice. These findings implied that the ALN-MA-hyd-DOX was a promising bone-targeted conjugate for treating bone neoplasms.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Wei-Liang
authors.initials: WL
authors.lastname: Ye
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Yi-Pu
authors.initials: YP
authors.lastname: Zhao
authors.affiliation: West Changle Sanatorium for Xi'an Army Retired Cadres of Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Ren
authors.initials: R
authors.lastname: Na
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Qi-Bing
authors.initials: QB
authors.lastname: Mei
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Ming-Gao
authors.initials: MG
authors.lastname: Zhao
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Si-Yuan
authors.initials: SY
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D004317:Doxorubicin
keywords: alendronate; bone-targeted drug delivery; cancer; conjugaton; controlled release; cytotoxicity; doxorubicin; imaging methods; p-glycoprotein