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: Wei-Liang Ye, Yi-Pu Zhao, Ren Na, Fei Li, Qi-Bing Mei, Ming-Gao Zhao, Si-Yuan Zhou
• Journal: Journal of pharmaceutical sciences (J Pharm Sci) Vol. 104 Issue 7 Pg. 2293-303 (Jul 2015) ISSN: 1520-6017 [Electronic] United States
• PMID: 25980534 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Chemical References

• Doxorubicin

Topics

• Animals
• Bone Neoplasms (drug therapy)
• Cell Line, Tumor
• Doxorubicin (administration & dosage)
• Drug Delivery Systems (methods)
• Female
• Humans
• Hydrogen-Ion Concentration
• Mice
• Mice, Nude
• Xenograft Model Antitumor Assays (methods)