TY - JOUR
T1 - Bone-targeted doxorubicin-loaded nanoparticles as a tool for the treatment of skeletal metastases
AU - Salerno, M.
AU - Cenni, E.
AU - Fotia, C.
AU - Avnet, S.
AU - Granchi, D.
AU - Castelli, F.
AU - Micieli, D.
AU - Pignatello, R.
AU - Capulli, M.
AU - Rucci, N.
AU - Angelucci, A.
AU - Del Fattore, A.
AU - Teti, A.
AU - Zini, N.
AU - Giunti, A.
AU - Baldini, N.
PY - 2010/11
Y1 - 2010/11
N2 - 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,L-lactide-co-glycolic) acid and alendronate, suitable for systemic administration, and directly targeting the site of tumor-induced 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 anti-tumor 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.
AB - 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,L-lactide-co-glycolic) acid and alendronate, suitable for systemic administration, and directly targeting the site of tumor-induced 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 anti-tumor 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.
KW - Bisphosphonates
KW - Bone targeting
KW - Doxorubicin
KW - Drug delivery system
KW - Nanoparticles
KW - Osteolysis
KW - Skeletal metastases
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M3 - Article
C2 - 20578992
AN - SCOPUS:78649283150
VL - 10
SP - 649
EP - 659
JO - Current Cancer Drug Targets
JF - Current Cancer Drug Targets
SN - 1568-0096
IS - 7
ER -