2b80 − Hydroxybisphosphonate Linked Doxorubicin: Bone Targeted Strategy for Treatment of Osteosarcoma - Archive ouverte HAL Access content directly
Journal Articles Lancet Oncology Year : 2019

2b80 − Hydroxybisphosphonate Linked Doxorubicin: Bone Targeted Strategy for Treatment of Osteosarcoma

(1) , (1) , (1) , (1) , (1) , (1) , (1) , (1) , (1) , (1) , (2, 3, 4) , (5) , (6) , (1)
1
2
3
4
5
6

Abstract

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.
Embargoed file
Embargoed file
Ne sera jamais visible
Loading...

Dates and versions

inserm-02529711 , version 1 (02-04-2020)

Identifiers

Cite

Emmanuelle David, Sebastien Cagnol, Jean-Yves Goujon, Maxim Egorov, Julien Taurelle, et al.. 2b80 − Hydroxybisphosphonate Linked Doxorubicin: Bone Targeted Strategy for Treatment of Osteosarcoma. Lancet Oncology, 2019, 20 (1), pp.12-14. ⟨10.1021/acs.bioconjchem.9b00210⟩. ⟨inserm-02529711⟩
101 View
0 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More