Calcium Polyphosphate as an Anti-Cancer Drug Delivery System

Introduction: Localized drug delivery is essential for effectively eradicating chronic diseases such as osteomyelitis while avoiding harmful systemic effects. Gelling of calcium polyphosphates (CPP) prior to drying, alone and in conjunction with a subsequent compaction and re-gelling protocol, has been shown to delay the release of antibiotics such as vancomycin introduced into the matrix. What is uncertain is whether this approach can be applied to other therapeutic agents, such as those that might be used to treat osteosarcomas. Objectives: To assess the feasibility of incorporating an anti-cancer drug into CPP and the effect that processing manipulation has on drug release and activity. Methods: 60 µL of a methotrexate solution was added to ~150 mg of CPP and the resulting paste subjected to gelling in 100% relative humidity at 37°C, followed by drying to create G1 disks. Some loaded G1 disks were milled to produce fine powders (<45um), then uniaxially compacted in a die, re-gelled and dried to obtain G2 disks. Elution studies of non-gelled, G1 and G2 disks were carried out in a 0.1 M TRIS-buffered solution under gentle agitation. Media collected at several time points was assessed for MTX (UV absorbance) and calcium (atomic absorbance) levels. MTX activity was evaluated using a standard MTT Cell Cytotoxicity Assay and NIH 3T3 fibroblasts at 60-70% confluence. Results: Gelling reduced the burst release and extended the overall release of MTX compared to non-gelled disks. A subsequent G2 process virtually eliminated this burst release while maintaining release out to a minimum of 10 days. MTX largely retained its cytotoxic activity regardless of processing. Conclusion: Calcium polyphosphate modified by a controlled gelling protocol has promise as an anti-cancer drug delivery matrix. External Funding Sources: CIHR Network for Oral Research Training and Health Award [YK]; NSERC Discovery Grant [MF]