RESUMEN
BACKGROUND: Most primary and metastatic bone tumors demonstrate increased osteoclast activity and bone resorption. Current treatment is based on a combination of surgery, radiotherapy and chemotherapy. Severe side effects are associated with chemotherapy due to use of high dosage and nonspecific uptake. Bisphosphonates have a strong affinity to Ca2+ ions and are widely used in the treatment of bone disorders. RESULTS: We have engineered a unique biodegradable bisphosphonate nanoparticle (NPs) bearing two functional surface groups: (1) primary amine groups for covalent attachment of a dye/drug (e.g. NIR dye Cy 7 or doxorubicin); (2) bisphosphonate groups for targeting and chelation to bone hydroxyapatite. In addition, these engineered NPs contain high polyethyleneglycol (PEG) concentration in order to increase their blood half life time. In vitro experiments on Saos-2 human osteosarcoma cell line, demonstrated that at a tenth of the concentration, doxorubicin-conjugated bisphosphonate NPs achieved a similar uptake to free doxorubicin. In vivo targeting experiments using the NIR fluorescence bisphosphonate NPs on both Soas-2 human osteosarcoma xenograft mouse model and orthotopic bone metastases mCherry-labeled 4T1 breast cancer mouse model confirmed specific targeting. In addition, therapeutic in vivo experiments using doxorubicin-conjugated bisphosphonate NPs demonstrated a 40% greater inhibition of tumor growth in Saos-2 human osteosarcoma xenograft mouse model when compared to free doxorubicin. CONCLUSIONS: In this research we have shown the potential use of doxorubicin-conjugated BP NPs for the targeting and treatment of primary and metastatic bone tumors. The targeted delivery of doxorubicin to the tumor significantly increased the efficacy of the anti-cancer drug, thus enabling the effective use of a lower concentration of doxorubicin. Furthermore, the targeting ability of the BP NPs in an orthotopic xenograft mouse model reinforced our findings that these BP NPs have the potential to be used for the treatment of primary and metastatic bone cancer.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Doxorrubicina/administración & dosificación , Portadores de Fármacos/química , Nanopartículas/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Difosfonatos/química , Modelos Animales de Enfermedad , Doxorrubicina/química , Doxorrubicina/farmacología , Femenino , Humanos , Proteínas Luminiscentes/química , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Polietilenglicoles/química , Trasplante Heterólogo , Proteína Fluorescente RojaRESUMEN
Bisphosphonate (BP) compounds are widely used in the treatment of bone disorders. This group of drugs with a high affinity to Ca(+2) ions is rapidly attracted to bone mineral, especially in areas of high resorption. We have engineered unique biodegradable BP nanoparticles (NPs) by dispersion co-polymerization of the monomers methacrylate-PEG-BP) and (3-Aminopropyl)mathacrylamide) with the crosslinker monomer tetra ethylene glycol diacrylate. These NPs possess a dual functionality: (1) covalent attachment of a dye (e.g. near IR dye) or a drug to the nanoparticles through the primary amine groups on the surface of the NPs; (2) chelation to the bone mineral hydroxyapatite through the BP on the surface of the NPs. This study describes the uptake of the unique near IR fluorescent Cy 7-conjugated BP NPs in bone of a young mouse model. Blood half-life studies revealed a relatively long half-life (approximately 5 h) due to a high concentration of PEG in the BP NPs as well as a relatively long whole body clearance (approximately 2 weeks). Body distribution studies showed a specific uptake of the BP NPs in bone. These unique engineered BP NPs are planned to be utilized in future work for diagnostic and drug delivery systems that are targeted to bone disorders.