Bone-targeting dendrimer for the delivery of methotrexate and treatment of bone metastasis

Abstract

We developed a bone-targeting dendrimer for the delivery of anti-tumour agents and effective treatment of bone metastasis, in which alendronate (ALN), a bone-targeting moiety, is covalently bonded to a polyethylene glycol (PEG)-conjugated polyamidoamine (PAMAM) dendrimer (PEG-PAMAM-ALN). Approximately 7.0 and 21.9% of the administered doses of [¹¹¹In]PAMAM and PEG-PAMAM-ALN accumulated in the bones within 180 min after intravenous injection in mice, respectively. [³H]-labelled methotrexate (MTX) rapidly disappeared from the blood, and bone distribution was found to be only 1.1% of the administered dose at 180 min. In contrast, 21.5% of the administered dose of [³H]MTX-loaded PEG-PAMAM-ALN accumulated in the bones at 180 min after intravenous injection in mice, which was approximately 20-fold higher than that of [³H]MTX. In a bone metastatic tumour mouse model, in which B16-BL6/Luc cells were injected into the left ventricle of female C57BL/6 mice, the growth of metastatic tumour in the bones was significantly inhibited by intravenous injection of MTX-loaded PEG-PAMAM-ALN. These findings indicate that PEG-PAMAM-ALN is a promising bone-targeting carrier for the delivery of anti-tumour agents and treatment of bone metastasis.

Keywords:

• Dendrimer
• bone targeting
• alendronate
• methotrexate
• bone metastasis

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This study was supported in part by the Kyoto Pharmaceutical University Fund for the Promotion of Scientific Research and MEXT-Supported Program for the Strategic Research Foundation at Private Universities.