To develop a methodology for bone-specific delivery of proteins,a bone-seeking aminobisphosphosphonate (aminoBP)was previously conjugated to a model protein,bovine serumal bumin (BSA).The conjugates were shown to exhibit a high affinity to bone in vitro and invivo.This study was conducted todetermine whether the systemic delivery of proteins to bone can be increased by aminoBP conjugation.Two model proteins used for this study were BSA and lysozyme (LYZ).For each protein,an unmodified and aminoBP-conjugated protein were ~(125)I-labeled and injected into rats,and the organde livery of the proteins were determined.Intravenous (IV)injection of aminoBP-BSA resulted in a 2.0 -to 3.7-fold increased delivery to bones as compared to the control protein in young rats.In osteopenic,ovariectomized rats,aminoBP conjugation enhanced the bone delivery of BSA by 2.2-to 7.5-fold.A 3.7-to 5.6-fold increased delivery was also observed for LYZ after IV injection in normal rats.In addition to IV route of administration,subcutaneous injection was also effective in delivering a higher amount of aminoBP-conjugated proteins tobone.We conclude that conjugating bone-seeking aminoBPstp proteins improved their delivery to mineralized tissues.The proposed targeting appraoch has the potential to improve the efficacy of recombinant proteins capable of stimulating bone formation by enhancing their localization to bones.
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