A PMMA bone cement composite that functions as a drug-refillable depot for localized, multi-window chemotherapeutic treatment of bone cancer

Abstract

ABSTRACTStandard chemotherapy for primary and secondary bone tumors typically involves systemic administration of chemotherapeutic drugs, such as doxorubicin (DOX). However, non-targeted delivery increases dose requirements, and results in off-target toxicity and suboptimal chemotherapeutic efficacy. When chemotherapy is ineffective, substantial resection of tissue and/or total amputation become necessary – a debilitating outcome for any patient. In this work, we developed a proof-of-concept, non-biodegradable, mechanically robust, and refillable composite system for chemotherapeutic (i.e. DOX) delivery comprised of poly(methyl methacrylate) (PMMA) bone cement and insoluble polymeric γ-cyclodextrin (γ-CD) microparticles. The porosity and compressive strength of DOX-filled PMMA composites were characterized. DOX filling capacity, elution kinetics, cytotoxicity against primary osteosarcoma and lung cancer cells, and refilling capacity of composites were evaluated. PMMA composites containing up to 15wt% γ-CD microparticles provided consistent, therapeutically-relevant release of DOX with ~100% of the initial DOX released after 100 days. Over the same period, only ~6% of DOX was liberated from PMMA with free DOX. Following prolonged curing, PMMA composites with up to 15wt% γ-CD surpassed compressive strength requirements outlined by international standards for acrylic bone cements. Compared to DOX-filled PMMA, DOX-filled PMMA/γ-CD composites provided long-term release with decreased burst effect, correlating to long-term cytotoxicity against cancer cells. Refillable properties demonstrated by the PMMA composite system may find utility for treating local recurrences, limiting chemoresistance, and altering drug combinations to provide customized treatment regimens. Overall, findings suggest that PMMA composites have the potential to serve as a platform for the delivery of combinatorial chemotherapeutics to treat bone tumors.