title: Incorporation of methotrexate in calcium phosphate cement: behavior and release in vitro and in vivo.
abstract: The application of antibiotic-loaded calcium phosphate bone cement in the treatment and prevention of osteomyelitis suggests that calcium phosphate cement could also be used as an anticancer drug carrier to reduce the local recurrence of bone tumors and systemic toxicities of chemotherapy. We added 0 to 400 mg of methotrexate to 40 g cement, with final methotrexate concentrations of 0% to 1% (weight/weight). The setting times, mechanical properties, microstructures, and in vitro methotrexate release kinetics of these methotrexate-calcium phosphate bone cement specimens were evaluated, along with in vivo methotrexate release kinetics in 24 rabbits. Methotrexate did not significantly alter the cement setting time. The compressive and tensile strengths of the methotrexate-calcium phosphate bone cement specimens were significantly less when 400 mg methotrexate was used, compared to control samples without methotrexate addition. Nevertheless, the cement remained compliant with the minimum requirements for clinical application. The scanning electron microscopy micrographs showed that the basic crystal structure did not alter. The methotrexate release kinetics in vitro and in vivo confirmed that methotrexate-calcium phosphate bone cement was a monolithic matrix system, with a burst effect in the initial stage and a sudden drop thereafter. Drug delivery in vivo was faster than in vitro. We estimated that the incorporated methotrexate could be continuously released over 2 to 4 months at a higher than minimum concentration. The methotrexate had no apparent toxicity on the host rabbits, even at the highest dose of methotrexate tested. The methotrexate-calcium phosphate bone cement system may be a potentially effective therapy for bone tumors in humans.
authors.affiliation: Department of Orthopedics, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, Shandong, China.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Yang
authors.forename: Jian
authors.initials: J
authors.lastname: Han
authors.forename: Jianmin
authors.initials: J
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Li
authors.forename: Shuhong
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D001843:Bone Cements / Q000009:adverse effects / Q000737:chemistry* / Q000627:therapeutic use; D002130:Calcium Phosphates / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry*; D004058:Diffusion; D004337:Drug Carriers / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D006244:Hardness; D008422:Materials Testing; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry*; D011817:Rabbits
chemical_list: D001843:Bone Cements; D002130:Calcium Phosphates; D004337:Drug Carriers; C020243:calcium phosphate; D008727:Methotrexate