Abstract
Bone metastases contribute to morbidity in patients with common cancers, and conventional therapy provides only palliation and can induce systemic side effects. The development of nanostructured delivery systems that combine carriers with bone-targeting molecules can potentially overcome the drawbacks presented by conventional approaches. We have recently developed biodegradable, biocompatible nanoparticles (NP) made of a conjugate between poly (D,Llactide- co-glycolic) acid and alendronate, suitable for systemic administration, and directly targeting the site of tumorinduced osteolysis. Here, we loaded NP with doxorubicin (DXR), and analyzed the in vitro and in vivo activity of the drug encapsulated in the carrier system. After confirming the intracellular uptake of DXR-loaded NP, we evaluated the antitumor effects in a panel of human cell lines, representative for primary or metastatic bone tumors, and in an orthotopic mouse model of breast cancer bone metastases. In vitro, both free DXR and DXR-loaded NP, (58-580 ng/mL) determined a significant dose-dependent growth inhibition of all cell lines. Similarly, both DXR-loaded NP and free DXR reduced the incidence of metastases in mice. Unloaded NP were ineffective, although both DXR-loaded and unloaded NP significantly reduced the osteoclast number at the tumor site (P = 0.014, P = 0.040, respectively), possibly as a consequence of alendronate activity. In summary, NP may act effectively as a delivery system of anticancer drugs to the bone, and deserve further evaluation for the treatment of bone tumors.
Keywords: Bisphosphonates, bone targeting, doxorubicin, drug delivery system, nanoparticles, osteolysis, skeletal metastases.
Current Cancer Drug Targets
Title:Bone-Targeted Doxorubicin-Loaded Nanoparticles as a Tool for the Treatment of Skeletal Metastases
Volume: 10 Issue: 7
Author(s): M. Salerno, E. Cenni, C. Fotia, S. Avnet, D. Granchi, F. Castelli, D. Micieli, R. Pignatello, M. Capulli, N. Rucci, A. Angelucci, A. Del Fattore, A. Teti, N. Zini, A. Giunti and N. Baldini
Affiliation:
Keywords: Bisphosphonates, bone targeting, doxorubicin, drug delivery system, nanoparticles, osteolysis, skeletal metastases.
Abstract: Bone metastases contribute to morbidity in patients with common cancers, and conventional therapy provides only palliation and can induce systemic side effects. The development of nanostructured delivery systems that combine carriers with bone-targeting molecules can potentially overcome the drawbacks presented by conventional approaches. We have recently developed biodegradable, biocompatible nanoparticles (NP) made of a conjugate between poly (D,Llactide- co-glycolic) acid and alendronate, suitable for systemic administration, and directly targeting the site of tumorinduced osteolysis. Here, we loaded NP with doxorubicin (DXR), and analyzed the in vitro and in vivo activity of the drug encapsulated in the carrier system. After confirming the intracellular uptake of DXR-loaded NP, we evaluated the antitumor effects in a panel of human cell lines, representative for primary or metastatic bone tumors, and in an orthotopic mouse model of breast cancer bone metastases. In vitro, both free DXR and DXR-loaded NP, (58-580 ng/mL) determined a significant dose-dependent growth inhibition of all cell lines. Similarly, both DXR-loaded NP and free DXR reduced the incidence of metastases in mice. Unloaded NP were ineffective, although both DXR-loaded and unloaded NP significantly reduced the osteoclast number at the tumor site (P = 0.014, P = 0.040, respectively), possibly as a consequence of alendronate activity. In summary, NP may act effectively as a delivery system of anticancer drugs to the bone, and deserve further evaluation for the treatment of bone tumors.
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Salerno M., Cenni E., Fotia C., Avnet S., Granchi D., Castelli F., Micieli D., Pignatello R., Capulli M., Rucci N., Angelucci A., Del Fattore A., Teti A., Zini N., Giunti A. and Baldini N., Bone-Targeted Doxorubicin-Loaded Nanoparticles as a Tool for the Treatment of Skeletal Metastases, Current Cancer Drug Targets 2010; 10 (7) . https://dx.doi.org/10.2174/156800910793605767
DOI https://dx.doi.org/10.2174/156800910793605767 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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