title: Bone-targeted doxorubicin-loaded nanoparticles as a tool for the treatment of 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,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.
authors.affiliation: Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine, Istituto Ortopedico Rizzoli, Bologna, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Salerno
authors.forename: E
authors.initials: E
authors.lastname: Cenni
authors.forename: C
authors.initials: C
authors.lastname: Fotia
authors.forename: S
authors.initials: S
authors.lastname: Avnet
authors.forename: D
authors.initials: D
authors.lastname: Granchi
authors.forename: F
authors.initials: F
authors.lastname: Castelli
authors.forename: D
authors.initials: D
authors.lastname: Micieli
authors.forename: R
authors.initials: R
authors.lastname: Pignatello
authors.forename: M
authors.initials: M
authors.lastname: Capulli
authors.forename: N
authors.initials: N
authors.lastname: Rucci
authors.forename: A
authors.initials: A
authors.lastname: Angelucci
authors.forename: A
authors.initials: A
authors.lastname: Del Fattore
authors.forename: A
authors.initials: A
authors.lastname: Teti
authors.forename: N
authors.initials: N
authors.lastname: Zini
authors.forename: A
authors.initials: A
authors.lastname: Giunti
authors.forename: N
authors.initials: N
authors.lastname: Baldini
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D019386:Alendronate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001692:Biological Transport; D050071:Bone Density Conservation Agents / Q000737:chemistry / Q000378:metabolism; D001859:Bone Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary* / Q000648:ultrastructure; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary* / Q000648:ultrastructure; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D053769:Nanocapsules / Q000737:chemistry / Q000648:ultrastructure; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010014:Osteolysis / Q000000981:diagnostic imaging / Q000517:prevention & control; D011859:Radiography; D000071681:Tartrate-Resistant Acid Phosphatase; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D007527:Isoenzymes; D053769:Nanocapsules; D004317:Doxorubicin; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D019386:Alendronate