12b80 - Hydroxybisphosphonate Linked Doxorubicin: Bone Targeted Strategy for Treatment of Osteosarcoma

Bioconjug Chem. 2019 Jun 19;30(6):1665-1676. doi: 10.1021/acs.bioconjchem.9b00210. Epub 2019 May 10.


To reply to as yet unmet medical needs to treat osteosarcoma, a form of primary bone cancer, we conceived the 12b80 compound by covalently conjugating antineoplastic compound doxorubicin to a bone targeting hydroxybisphosphonate vector and turned it into a prodrug through a custom linker designed to specifically trigger doxorubicin release in acidic bone tumor microenvironment. Synthesis of 12b80 was thoroughly optimized to be produced at gram scale. 12b80 was evaluated in vitro for high bone support affinity, specific release of doxorubicin in acidic condition, lower cytotoxicity, and cellular uptake of the prodrug. In vivo in rodents, 12b80 displayed rapid and sustained targeting of bone tissue and tumor-associated heterotopic bone and permitted a higher doxorubicin payload in tumor bone environment compared to nonvectorized doxorubicin. Consequently, 12b80 showed much lower toxicity compared to doxorubicin, promoted strong antitumor effects on rodent orthotopic osteosarcoma, displayed a dose-response therapeutic effect, and was more potent than doxorubicin/zoledronate combination.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / chemical synthesis
  • Antibiotics, Antineoplastic / chemistry*
  • Antibiotics, Antineoplastic / pharmacokinetics
  • Antibiotics, Antineoplastic / therapeutic use
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / pathology
  • Cell Line, Tumor
  • Chemistry Techniques, Synthetic
  • Diphosphonates / chemical synthesis
  • Diphosphonates / chemistry*
  • Diphosphonates / pharmacokinetics
  • Diphosphonates / therapeutic use
  • Doxorubicin / analogs & derivatives*
  • Doxorubicin / chemical synthesis
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / therapeutic use
  • Female
  • Mice, Nude
  • Osteosarcoma / drug therapy*
  • Osteosarcoma / pathology
  • Rats


  • Antibiotics, Antineoplastic
  • Diphosphonates
  • Doxorubicin