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Cytotoxic effects of zoledronic acid-loaded hydroxyapatite and bone cement in malignant tumors.

ABSTRACT: Metastatic and primary bone tumors are malignant tumors affecting the skeleton. Although the prognosis of patients with these tumors has improved with the development of effective chemotherapy, the challenges of local recurrence, subsequent osteolysis, degradation of bone strength and unresectable tumors persist. Local control of these tumors is therefore a key strategy to address these limitations. The third-generation bisphosphonate (BP), zoledronic acid (ZOL), has been demonstrated to reduce osteoclasts and exhibited potent antitumor effects in a number of malignancies. Hydroxyapatite (HA) and polymethyl methacrylate (PMMA) bone cement are used in orthopedic surgery as bone graft substitutes, for implant arthroplasty and bone strengthening, and as a sustained-release system for drugs such as antibiotics. At present, the antitumor effects of ZOL-loaded HA in vitro or in vivo or of ZOL-loaded bone cement in vivo have not been described. Therefore, the present study assessed the effects of ZOL-loaded HA and bone cement in malignant tumor cells. The two materials exerted strong antitumor effects against osteosarcoma, fibrosarcoma, synovial sarcoma, renal cancer, prostate cancer and lung cancer cells upon releasing ZOL. The antitumor effects of ZOL-loaded HA were less potent compared with those of ZOL-loaded bone cement, possibly as BPs exhibit higher affinity to HA. ZOL-loaded bone cement also exerted antitumor effects against pulmonary metastases and primary lesions, without exhibiting systemic toxicity in vivo. These results demonstrate that these materials may be beneficial for the treatment of malignant bone tumors, including metastatic bone tumors. In addition, as these materials are already in clinical use, such applications may be easily implemented.

SUBMITTER: Koto K

PROVIDER: S-EPMC5529883 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Project description:The regeneration of bone remains one of the main challenges in the biomedical field, with the need to provide more personalized and multifunctional solutions. The other persistent challenge is related to the local prevention of infections after implantation surgery. To fulfill the first one and provide customized scaffolds with complex geometries, 3D printing is being investigated, with polylactic acid (PLA) as the biomaterial mostly used, given its thermoplastic properties. The 3D printing of PLA in combination with hydroxyapatite (HA) is also under research, to mimic the native mechanical and biological properties, providing more functional scaffolds. Finally, to fulfill the second one, antibacterial drugs locally incorporated into biodegradable scaffolds are also under investigation. This work aims to develop vancomycin-loaded 3D-printed PLA-HA scaffolds offering a dual functionality: local prevention of infections and personalized biodegradable scaffolds with osseointegrative properties. For this, the antibacterial drug vancomycin was incorporated into 3D-printed PLA-HA scaffolds using three loading methodologies: (1) dip coating, (2) drop coating, and (3) direct incorporation in the 3D printing with PLA and HA. A systematic characterization was performed, including release kinetics, Staphylococcus aureus antibacterial/antibiofilm activities and cytocompatibility. The results demonstrated the feasibility of the vancomycin-loaded 3D-printed PLA-HA scaffolds as drug-releasing vehicles with significant antibacterial effects for the three methodologies. In relation to the drug release kinetics, the (1) dip- and (2) drop-coating methodologies achieved burst release (first 60 min) of around 80-90% of the loaded vancomycin, followed by a slower release of the remaining drug for up to 48 h, while the (3) 3D printing presented an extended release beyond 7 days as the polymer degraded. The cytocompatibility of the vancomycin-loaded scaffolds was also confirmed.

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Cytotoxic effects of zoledronic acid-loaded hydroxyapatite and bone cement in malignant tumors.

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