title: Bone-targeted acid-sensitive doxorubicin conjugate micelles as potential osteosarcoma therapeutics.
abstract: Osteosarcoma is a malignancy of the bone that primarily affects adolescents. Current treatments retain mortality rates, which are higher than average cancer mortality rates for the adolescent age group. We designed a micellar delivery system with the aim to increase drug accumulation in the tumor and potentially reduce side effects associated with chemotherapy. The design features are the use of the hydrophilic D-aspartic acid octapeptide as both the effective targeting agent as well as the hydrophilic micelle corona. Micelle stabilization was accomplished by binding of model drug (doxorubicin) via an acid-sensitive hydrazone bond and incorporating one to four 11-aminoundecanoic acid (AUA) moieties to manipulate the hydrophobic/hydrophilic ratio. Four micelle-forming unimers have been synthesized and their self-assembly into micelles was evaluated. Size of the micelles could be modified by changing the architecture of the unimers from linear to branched. The stability of the micelles increased with increasing content of AUA moieties. Adsorption of all micelles to hydroxyapatite occurred rapidly. Doxorubicin release occurred at pH 5.5, whereas no release was detected at pH 7.4. Cytotoxicity toward human osteosarcoma Saos-2 cells correlated with drug release data.
authors.affiliation: Department of Bioengineering and ‡Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah , Salt Lake City, Utah 84112, United States.
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Low
authors.forename: Jiyuan
authors.initials: J
authors.lastname: Yang
authors.forename: Jindřich
authors.initials: J
authors.lastname: Kopeček
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D001224:Aspartic Acid / Q000737:chemistry; D001859:Bone Neoplasms / Q000188:drug therapy*; D001842:Bone and Bones / Q000378:metabolism*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry* / Q000494:pharmacology; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D065546:Drug Liberation; D017886:Durapatite / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008823:Micelles; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D012516:Osteosarcoma / Q000188:drug therapy*
chemical_list: D000596:Amino Acids; D004337:Drug Carriers; D008823:Micelles; D009842:Oligopeptides; D001224:Aspartic Acid; D004317:Doxorubicin; D017886:Durapatite; C023820:11-aminoundecanoic acid